Collection of Toxicology Reports

The collection is a repository of open access articles dedicated to all aspects of toxicology research and clinical sciences. The collection may include articles related to the following subjects: adverse effects of xenobiotics on the health of humans and animals, influence of diseases in humans or model animals on chemically induced toxicity, toxicity of natural products and traditional medicines, clinical case reports involving exposure to toxins, environmental and occupational exposure to toxins, other areas of toxicological research.

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Diosmetin protects against retinal injury via reduction of DNA damage and oxidative stress
Z. Shen, J. Shao, J. Dai, Y. Lin, X. Yang, J. Ma, Q. He, B. Yang, K. Yao, P. Luo

Toxicology Reports (2016). Vol. 3

Abstract
Visual impairment is a global public health problem that needs new candidate drugs. Chrysanthemum is a traditional Chinese drug, famous for its eye-protective function, with an unclear mechanism of action. To determine how chrysanthemum contributes to vision, we identified, for the first time, the component of chrysanthemum, diosmetin (DIO), which acts in protecting the injured retina in an adriamycin (ADR) improving model. We observed that DIO could attenuate the apoptosis of retinal cells in Sprague–Dawley rats and verified this effect in cultured human retinal pigment epithelium (RPE) cells, ARPE-19. Our further study on the mechanism revealed the counteractive effect of DIO on the attenuation of DNA damage and oxidative stress, which occurs in a wide range of retinal disorders. These results collectively promise the potential value of DIO as a retinal-protective agent for disorders that lead to blindness. In addition, we identified, for the first time, the component of chrysanthemum, DIO, which acts in protecting the injured retina.
Abstract
Visual impairment is a global public health problem that needs new candidate drugs. Chrysanthemum is a traditional Chinese drug, famous for its eye-protective function, with [...]
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Oral administration of Nigella sativa oil ameliorates the effect of cisplatin on membrane enzymes, carbohydrate metabolism and oxidative damage in rat liver
Z. Farooqui, M. Afsar, S. Rizwan, A. Khan, F. Khan

Toxicology Reports (2016). Vol. 3

Abstract
Cisplatin (CP) is a potent anti-cancer drug widely used against solid tumors. However, it exhibits pronounced adverse effects including hepatotoxicity. Several strategies were attempted to prevent CP hepatotoxicity but were not found suitable for therapeutic application. Nigella sativa has been shown to prevent/reduce the progression of certain type of cardiovascular, kidney and liver diseases. Present study investigates whether N. sativa oil (NSO) can prevent CP induced hepatotoxic effects. Rats were divided into four groups viz. control, CP, NSO and CPNSO. Animals in CPNSO and NSO group were administered NSO (2 ml/kg bwt, orally) with or without single hepatotoxic dose of CP (6 mg/kg bwt, i.p.) respectively. CP hepatotoxicity was recorded by increased serum ALT and AST activities. CP treatment caused oxidant/antioxidant imbalances as reflected by increased lipid peroxidation and decreased enzymatic and non-enzymatic antioxidants. Furthermore, the activities of various carbohydrate metabolism and membrane enzymes were altered by CP treatment. In contrast, NSO administration to CP treated rats, markedly ameliorated the CP elicited deleterious alterations in liver. Histopathological observations showed extensive liver damage in CP treated animals while greatly reduced tissue injury in CPNSO group. In conclusion, NSO appears to protect CP induced hepatotoxicity by improving energy metabolism and strengthening antioxidant defense mechanism.
Abstract
Cisplatin (CP) is a potent anti-cancer drug widely used against solid tumors. However, it exhibits pronounced adverse effects including hepatotoxicity. Several strategies [...]
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Fish oil prevents excessive accumulation of subcutaneous fat caused by an adverse effect of pioglitazone treatment and positively changes adipocytes in KK mice
Y. Iizuka, H. Kim, M. Nakasatomi, T. Izawa, S. Hirako, A. Matsumoto

Toxicology Reports (2016). Vol. 3

Abstract
Pioglitazone, a thiazolidinedione (TZD), is widely used as an insulin sensitizer in the treatment of type 2 diabetes. However, body weight gain is frequently observed in TZD-treated patients. Fish oil improves lipid metabolism dysfunction and obesity. In this study, we demonstrated suppression of body weight gain in response to pioglitazone administration by combination therapy of pioglitazone and fish oil in type 2 diabetic KK mice. Male KK mice were fed experimental diets for 8 weeks. In safflower oil (SO), safflower oil/low-dose pioglitazone (S/PL), and safflower oil/high-dose pioglitazone (S/PH) diets, 20% of calories were provided by safflower oil containing 0%, 0.006%, or 0.012% (wt/wt) pioglitazone, respectively. In fish oil (FO), fish oil/low-dose pioglitazone (F/PL), and fish oil/high-dose pioglitazone (F/PH) diets, 20% of calories were provided by a mixture of fish oil and safflower oil. Increased body weight and subcutaneous fat mass were observed in the S/PL and S/PH groups, however, diets containing fish oil were found to ameliorate these changes. Hepatic mRNA levels of lipogenic enzymes were significantly decreased in fish oil-fed groups. These findings demonstrate that the combination of pioglitazone and fish oil decreases subcutaneous fat accumulation, ameliorating pioglitazone-induced body weight gain, through fish oil-mediated inhibition of hepatic de novo lipogenesis.
Abstract
Pioglitazone, a thiazolidinedione (TZD), is widely used as an insulin sensitizer in the treatment of type 2 diabetes. However, body weight gain is frequently observed in TZD-treated [...]
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ABC gene-ranking for prediction of drug-induced cholestasis in rats
Y. Cherkas, M. McMillian, D. Amaratunga, N. Raghavan, J. Sasaki

Toxicology Reports (2016). Vol. 3

Abstract
As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between toxicants and gene expression. In the present study, a novel “aggregating bundles of clusters” (ABC) procedure was applied to separate cholestatic from non-cholestatic drugs and model toxicants in the Johnson & Johnson (Janssen) rat liver toxicogenomics database [3] . Drug-induced cholestasis is an important issue, particularly when a new compound enters the market with this liability, with standard preclinical models often mispredicting this toxicity. Three well-characterized cholestasis-responsive genes (Cyp7a1, Mrp3 and Bsep) were chosen from a previous in-house Janssen gene expression signature, these three genes show differing, non-redundant responses across the 90+ paradigm compounds in our database. Using the ABC procedure, extraneous contributions were minimized in comparisons of compound gene responses. All genes were assigned weights proportional to their correlations with Cyp7a1, Mrp3 and Bsep, and a resampling technique was used to derive a stable measure of compound similarity. The compounds that were known to be associated with rat cholestasis generally had small values of this measure relative to each other but also had large values of this measure relative to non-cholestatic compounds. Visualization of the data with the ABC-derived signature showed a very tight, essentially identically behaving cluster of robust human cholestatic drugs and experimental cholestatic toxicants (ethinyl estradiol, LPS, ANIT and methylene dianiline, disulfiram, naltrexone, methapyrilene, phenacetin, alpha-methyl dopa, flutamide, the NSAIDs–—indomethacin, flurbiprofen, diclofenac, flufenamic acid, sulindac, and nimesulide, butylated hydroxytoluene, piperonyl butoxide, and bromobenzene), some slightly less active compounds (3′-acetamidofluorene, amsacrine, hydralazine, tannic acid), some drugs that behaved very differently, and were distinct from both non-cholestatic and cholestatic drugs (ketoconazole, dipyridamole, cyproheptadine and aniline), and many postulated human cholestatic drugs that in rat showed no evidence of cholestasis (chlorpromazine, erythromycin, niacin, captopril, dapsone, rifampicin, glibenclamide, simvastatin, furosemide, tamoxifen, and sulfamethoxazole). Most of these latter drugs were noted previously by other groups as showing cholestasis only in humans. The results of this work suggest that the ABC procedure and similar statistical approaches can be instrumental in combining data to compare toxicants across toxicogenomics databases, extract similarities among responses and reduce unexplained data varation.
Abstract
As legacy toxicogenomics databases have become available, improved data mining approaches are now key to extracting and visualizing subtle relationships between toxicants [...]
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Sulfur mustard-stimulated proteases and their inhibitors in a cultured normal human epidermal keratinocytes model: A potential approach for anti-vesicant drug development
X. Jin, R. Ray, P. Ray

Toxicology Reports (2016). Vol. 3

Abstract
Protease stimulation in cultured normal human epidermal keratinocytes (NHEK) due to sulfur mustard (SM) exposure is well documented. However, the specific protease(s) stimulated by SM and the protease substrates remain to be determined. In this study, we observed that SM stimulates several proteases and the epidermal-dermal attachment protein laminin-5 is one of the substrates. We propose that following SM exposure of the skin, laminin-5 degradation causes the detachment of the epidermis from the dermis and, therefore, vesication. We utilized gelatin zymography, Western blotting, immuno-fluorescence staining, and real-time polymerase chain reaction (RT-PCR) analyses to study the SM-stimulated proteases and laminin-5 degradation in NHEK. Two major protease bands (64 kDa and 72 kDa) were observed by zymography in SM-exposed cells. Addition of serine protease inhibitor (aprotinin, 100 μM), or the metalloprotease inhibitor (amastatin, 100 μM) to NHEK cultures prior to SM exposure decreased the SM-stimulated protease bands seen by zymography. These inhibitors completely or partially prevented SM-induced laminin-5 γ2 degradation as seen by Western blotting as well as immuno-fluorescence staining. Our results from Western blotting and RT-PCR studies also indicated that the membrane-type matrix metalloproteinase-1 (MT-MM-1) may be involved in SM-induced skin blistering. To summarize, our results in the NHEK model indicate the following: (a) SM stimulates multiple proteases including serine protease(s), and metalloproteases, (b) SM decreases the level of laminin-5 γ2, which is prevented by either a serine protease inhibitor or a metalloprotease inhibitor and (c) MT-MMP-1 maybe one of the proteases that is involved in skin blistering due to SM exposure.
Abstract
Protease stimulation in cultured normal human epidermal keratinocytes (NHEK) due to sulfur mustard (SM) exposure is well documented. However, the specific protease(s) stimulated [...]
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Inhibitory effect of Camellia sinensis , Ilex paraguariensis and Ardisia compressa tea extracts on the proliferation of human head and neck squamous carcinoma cells
M. Ramirez-Mares, H. Kobayashi, E. Mejia

Toxicology Reports (2016). Vol. 3

Abstract
In vitro cell proliferation, cell cycle arrest and induction of apoptosis were investigated, using three human head and neck squamous cell carcinoma (HNSCC) cell lines (OSCC-3, SCC-61, and SQ-20B). Aqueous extracts of Camellia sinensis, Ilex paraguariensis, and Ardisia compressa were tested and (−) epigallocatechin-3-gallate (EGCG) was used for comparison. For EGCG the IC50 values were between 80 and 166 μM and for the extracts among 75 and 505 μM eq. (+) catechin, with C. sinensis demonstrating dominant cytotoxicity. There was not a correlation between antioxidant capacity and cytotoxicity. Flow cytometry analysis revealed similarities in response for EGCG and C. sinensis . The A. compressa extract altered DNA distribution (P < 0.05) and was the most effective in induction of apoptosis via caspases (P < 0.05). Not all HNSCC cells tested responded to the same preventive agents. The fact that A. compressa inhibits HNSCC cell proliferation makes this aqueous extract a potential source of chemopreventive agents.
Abstract
In vitro cell proliferation, cell cycle arrest and induction of apoptosis were investigated, using three human head and neck squamous cell carcinoma (HNSCC) cell lines (OSCC-3, [...]
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Brain regions and monoaminergic neurotransmitters that are involved in mouse ambulatory activity promoted by bupropion
T. Umezu, Y. Shibata

Toxicology Reports (2016). Vol. 3

Abstract
Bupropion (BUP), a substituted phenyl-ethylamine, has been utilized for the treatment of depression and for smoking cessation, however, one concern is that BUP may increase a risk of psychosis similar to other substituted phenyl-ethylamine amphetamine (AMPH) and methamphetamine (MetAMPH). BUP promotes ambulation in mice and causes behavioral sensitization on the ambulation-promoting effect when repeatedly administered as well as AMPH and MetAMPH. The present study aimed to elucidate brain regions and monoaminergic neurotransmitters that are involved in the ambulation-promoting effect of BUP. c-Fos-like immunoreactivity (c-Fos-IR) mapping in brain in combination with measuring ambulatory activity was conducted to determine brain region(s) that is involved in the ambulatory effect of BUP. Three kinds of statistical analyses for c-Fos-IR in 24 brain regions consistently showed that c-Fos-IR in the Caudate putamen (CPu) is positively correlated with the ambulatory response to BUP. In addition, multiple regression analysis indicated that the ambulatory response is a function of c-Fos-IR not only in the CPu but also in the lateral septum nucleus (LS), median raphe nucleus (MnR), lateral globus pallidus (LGP), medial globus pallidus (MGP), locus coeruleus (LC) and ventral hypothalamic nucleus (VMH). Effects of BUP on monoaminergic neurotransmitters in the CPu were examined using in vivo microdialysis method, as the pharmacological experiments indicated that monoaminergic neurotransmitters, dopamine (DA) in particular, mediate the ambulatory response to BUP. Response of DA in the CPu to BUP was parallel to the ambulatory response, showing that DA in the CPu is involved in the ambulatory response to BUP. The present study also suggests that other brain regions such as the LC, the origin nucleus of norepinephrine (NE) neurons, and another neurotransmitter NE may also play some roles for the ambulatory response to BUP, however, further studies are needed to elucidate the roles.
Abstract
Bupropion (BUP), a substituted phenyl-ethylamine, has been utilized for the treatment of depression and for smoking cessation, however, one concern is that BUP may increase [...]
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Anti-cancer activity of ZnO chips by sustained zinc ion release
S. Moon, W. Choi, S. Choi, E. Kim, J. Kim, J. Lee, S. Kim

Toxicology Reports (2016). Vol. 3

Abstract
We report anti-cancer activity of ZnO thin-film-coated chips by sustained release of zinc ions. ZnO chips were fabricated by precisely tuning ZnO thickness using atomic layer deposition, and their potential to release zinc ions relative to the number of deposition cycles was evaluated. ZnO chips exhibited selective cytotoxicity in human B lymphocyte Raji cells while having no effect on human peripheral blood mononuclear cells. Of importance, the half-maximal inhibitory concentration of the ZnO chip on the viability of Raji cells was 121.5 cycles, which was comparable to 65.7 nM of daunorubicin, an anti-cancer drug for leukemia. Molecular analysis of cells treated with ZnO chips revealed that zinc ions released from the chips increased cellular levels of reactive oxygen species, including hydrogen peroxide, which led to the down-regulation of anti-apoptotic molecules (such as HIF-1α, survivin, cIAP-2, claspin, p-53, and XIAP) and caspase-dependent apoptosis. Because the anti-cancer activity of ZnO chips and the mode of action were comparable to those of daunorubicin, the development and optimization of ZnO chips that gradually release zinc ions might have clinical anti-cancer potential. A further understanding of the biological action of ZnO-related products is crucial for designing safe biomaterials with applications in disease treatment.
Abstract
We report anti-cancer activity of ZnO thin-film-coated chips by sustained release of zinc ions. ZnO chips were fabricated by precisely tuning ZnO thickness using atomic layer [...]
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Hepatoprotective effect of grape seed proanthocyanidins on Cadmium-induced hepatic injury in rats: Possible involvement of mitochondrial dysfunction, inflammation and apoptosis
S. Miltonprabu, . Nazimabashir, V. Manoharan

Toxicology Reports (2016). Vol. 3

Abstract
The present study was undertaken to evaluate the possible ameliorative role of grape seed proanthocyanidins (GSP) against Cadmium (Cd) induced hepatic inflammation, apoptosis and hepatic mitochondrial toxicity in rats. Male Wistar rats were distributed in four experimental groups: control, GSP, Cd and Cd + GSP. Exposure to a hepatotoxic dose of Cd (5 mg/kg BW) caused liver damage, coupled with enhanced reactive oxygen species (ROS) generation, increased inflammation and apoptosis in liver with increased DNA damage in hepatocytes of rats. Mitochondria were isolated from the hepatic tissues of rats from each group. Our results showed significant decrease in the tri-carboxylic acid cycle enzymes, increased mitochondrial swelling, inhibition of cytochrome c oxidase activity and complex I–III, II–III and IV mediated electron transfer, decreased mitochondrial ATPases, a reduction in calcium content and mitochondrial oxygen consumption in Cd treated rats. All these molecular changes caused by Cd were alleviated by the pre-supplementation with GSP (100 mg/kg BW). The ultra structural changes in the liver also support our findings. From our results, it is clearly indicated that the free radical scavenging, metal chelating and antioxidant potentials of GSP might be the possible reason, responsible for the rescue action against Cd induced mitochondrial damage in the liver of rats.
Abstract
The present study was undertaken to evaluate the possible ameliorative role of grape seed proanthocyanidins (GSP) against Cadmium (Cd) induced hepatic inflammation, apoptosis [...]
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Apocynin reduced doxycycline-induced acute liver injury in ovariectomized mice
S. Mitazaki, M. Hashimoto, Y. Matsuhashi, S. Honma, M. Suto, N. Kato, K. Hiraiwa, M. Yoshida, S. Abe

Toxicology Reports (2016). Vol. 3

Abstract
To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx) mice against doxycycline (DOXY)-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip) 8 weeks after the operation, 30 min after apocynin (5 mg/kg) or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox) inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.
Abstract
To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx) mice against doxycycline (DOXY)-induced [...]
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Evaluation of the anti-inflammatory activities of Quillaja saponaria Mol. saponin extract in mice
S. Sarkhel

Toxicology Reports (2016). Vol. 3

Abstract
Quillaja saponaria bark contains a high percentage of triterpene saponins and has been used for centuries as antiinflammatory and analgesic agent in Chilean folk medicine. In the Present study the anti-inflammatory activities of the aqueous extract of commercially partially purified saponin from Quillaja saponari a Mol. in in vivo animal models. Aqueous extract of the plant material was prepared by cold maceration. The anti-inflammatory activity of a commercial Quillaja saponaria Mol. (QS) saponin extract was investigated by carragenan induced mice paw edema model for acute inflammation (Winter, 1962) [16] . The anti-inflammatory activity was evaluated by carragenan in paw edema model in swiss albino mice (18–20 g). The anti-inflammatory activity was found to be dose dependent in carragenan induced paw edema. QS was found to significantly (p < 0.05) reduce the carragenan induced mice paw edema (38.59%, 20 mg/kg bw) as compared to carragenan control. The percentage inhibition of standard anti-inflammatory drug indomethacin was (55%, 10 mg/kg, bw). The results of the present study demonstrate that the aqueous extract of Quillaja saponaria saponins (QS) possess significant anti-inflammatory activity.
Abstract
Quillaja saponaria bark contains a high percentage of triterpene saponins and has been used for centuries as antiinflammatory and analgesic agent in Chilean folk medicine. [...]
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Assessment of heavy metals contamination and human health risk in shrimp collected from different farms and rivers at Khulna-Satkhira region, Bangladesh
T. Sarkar, M. Alam, N. Parvin, Z. Fardous, A. Chowdhury, S. Hossain, M. Haque, N. Biswas

Toxicology Reports (2016). Vol. 3

Abstract
This study is aimed to assess the heavy metals contamination and health risk in Shrimp (Macrobrachium rosenbergii and Penaeus monodon ) collected from Khulna-Satkhira region in Bangladesh. The results showed that the Pb concentrations (0.52–1.16 mg/kg) in all shrimp samples of farms were higher than the recommended limit. The Cd levels (0.05–0.13 mg/kg) in all samples and Cr levels in all farms except tissue content at Satkhira farm were higher than the permissible limits. The individual concentration of Pb, Cd, and Cr between shrimp tissue and shell in all rivers and farms were not statistically significant (P > 0.05). Target hazard quotient (THQ) and hazard index (HI) were estimated to assess the non-carcinogenic health risks. Shrimp samples from all locations under the current study were found to be safe for consumption, the possibility of health risk associated with non-carcinogenic effect is very low for continuous consumption for 30 years.
Abstract
This study is aimed to assess the heavy metals contamination and health risk in Shrimp (Macrobrachium rosenbergii and Penaeus monodon ) collected from Khulna-Satkhira region [...]
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Curcuminoids from Curcuma longa L. reduced intestinal mucositis induced by 5-fluorouracil in mice: Bioadhesive, proliferative, anti-inflammatory and antioxidant effects
E. Filho, P. Ávila, C. Bastos, A. Batista, L. Naves, R. Marreto, E. Lima, E. Mendonça, M. Valadares

Toxicology Reports (2016). Vol. 3

Abstract
Intestinal mucositis is a frequent limiting factor in anticancer therapy and there is currently no broadly effective treatment targeted to cure this side effect. This study aimed to evaluate the effects of a mucoadhesive formulation containing curcuminoids (MFC) from Curcuma longa L. on the pathogenesis of 5-fluorouracil (5-FU)-induced intestinal mucositis. Three intraperitoneal 5-FU injections (200 mg/kg) were used to induce intestinal mucositis in adult Swiss male mice. Treatment was provided orally (MFC 3.75, 7.5 and 15 mg/kg), thirty minutes before 5-FU injections, daily until euthanasia. Duodenal samples were collected to perform morphometric and histopathological analysis, to investigate the expression of Ki-67, p53, Bax and Bcl-2 by immunohistochemistry, to evaluate neutrophil activity myeloperoxidase (MPO)-mediated and oxidative stress by malondialdehyde (MDA) determination. Mice body weight was assessed as well. As expected, 5-FU induced a significant weight loss (∼17%, P < 0.001), shortening in villi height (∼55.4%) and crypts depth (∼47%), and increased (∼64%) the histological severity score when compared to other groups (P < 0.05). These pathological changes were markedly alleviated by the three MFC treatment doses (P < 0.05), in special with the dose MFC 15 mg/kg. This dose also stimulated cell proliferation by ∼90% in the epithelial cells lining from villi and crypts (P < 0.05), reduced MPO levels and MDA formation by 60% and 44%, respectively (P < 0.05). Our data suggest the therapeutic potential of the formulation for treating intestinal mucositis in mice. Supplementary studies are underway searching for the elucidation of mechanisms involved in the protective effects of MFC in order to make this formulation a clinical tool for mucositis treatment.
Abstract
Intestinal mucositis is a frequent limiting factor in anticancer therapy and there is currently no broadly effective treatment targeted to cure this side effect. This study [...]
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Effect of Hecogenin on DNA instability
M. Cruz, S. Barroso, J. Navoni, M. Teles, J. Barbosa-Filho, H. Rocha, V. Amaral

Toxicology Reports (2016). Vol. 3

Abstract
Hecogenin is a sapogenin found in Agave species in high quantities and is responsible for the many therapeutic effects of these medicinal plants. In addition, this compound is also widely used in the pharmaceutical industry as a precursor for the synthesis of steroidal hormones and anti-inflammatory drugs. Despite Hecogenin being widely used, little is known about its toxicological properties. Therefore, the present study aimed to investigate the cytotoxic, genotoxic and mutagenic effects of Hecogenin on HepG2 cells. Cytotoxicity was analyzed using the MTT test. Then, genotoxic and mutagenic potentials were assessed by comet assay and cytokinesis-block micronucleus assay, respectively. Cytotoxic effect was observed only when cells were exposed to concentrations of Hecogenin equal or higher than 100 μM. Although a lower concentration of Hecogenin caused DNA damage, a reduction on nuclear mutagenic markers in HepG2 cells was observed. The results indicated that Hecogenin treatment generated DNA damage, but in fact it would be repaired, avoiding dissemination of the damage throughout the cell division. Further studies need to be performed to confirm the observed protective effect of Hecogenin against genomic instability.
Abstract
Hecogenin is a sapogenin found in Agave species in high quantities and is responsible for the many therapeutic effects of these medicinal plants. In addition, this compound [...]
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Exposure of the gilthead seabream (Sparus aurata ) to sediments contaminated with heavy metals down-regulates the gene expression of stress biomarkers
S. Benhamed, F. Guardiola, S. Martínez, M. Martínez-Sánchez, C. Pérez-Sirvent, M. Mars, M. Esteban

Toxicology Reports (2016).

Abstract
Heavy metals incidence in the aquatic environment and its accumulation in fish are under constant review. Gilthead seabream (Sparus aurata ) specimens were exposed for two weeks to sediments highly concentrated in metals, collected at the Portman Bay (Murcia, Spain). The metals bioaccumulation was tested in liver, muscle and skin. The potential of the sediment exposure to induce variation of the stress biomarkers genes was conducted in liver and skin. Results revealed that sediments were highly contaminated with metals. However, following 2 weeks exposure to the sediments, Cd accumulates only in liver. Interestingly, the expression of the genes mta, hsp 70 and hsp 90 were significantly down-regulated in skin. Nevertheless, cyp1a1 gene was up-regulated only in liver. Results uphold that the stress response magnitude was organ-dependent and the skin was the most responsive tissue to metal stress conditions. These results suggest that skin should be considered as target organ for biomarkers analysis in fishes.
Abstract
Heavy metals incidence in the aquatic environment and its accumulation in fish are under constant review. Gilthead seabream (Sparus aurata ) specimens were exposed for two [...]
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Altered global gene expression profiles in human gastrointestinal epithelial Caco2 cells exposed to nanosilver
S. Sahu

Toxicology Reports (2016). Vol. 3

Abstract
Extensive consumer exposure to food- and cosmetics-related consumer products containing nanosilver is of public safety concern. Therefore, there is a need for suitable in vitro models and sensitive predictive rapid screening methods to assess their toxicity. Toxicogenomic profile showing subtle changes in gene expressions following nanosilver exposure is a sensitive toxicological endpoint for this purpose. We evaluated the Caco2 cells and global gene expression profiles as tools for predictive rapid toxicity screening of nanosilver. We evaluated and compared the gene expression profiles of Caco-2 cells exposed to 20 nm and 50 nm nanosilver at a concentration 2.5 μg/ml. The global gene expression analysis of Caco2 cells exposed to 20 nm nanosilver showed that a total of 93 genes were altered at 4 h exposure, out of which 90 genes were up-regulated and 3 genes were down-regulated. The 24 h exposure of 20 nm silver altered 15 genes in Caco2 cells, out of which 14 were up-regulated and one was down-regulated. The most pronounced changes in gene expression were detected at 4 h. The greater size (50 nm) nanosilver at 4 h exposure altered more genes by more different pathways than the smaller (20 nm) one. Metallothioneins and heat shock proteins were highly up-regulated as a result of exposure to both the nanosilvers. The cellular pathways affected by the nanosilver exposure is likely to lead to increased toxicity. The results of our study presented here suggest that the toxicogenomic characterization of Caco2 cells is a valuable in vitro tool for assessing toxicity of nanomaterials such as nanosilver.
Abstract
Extensive consumer exposure to food- and cosmetics-related consumer products containing nanosilver is of public safety concern. Therefore, there is a need for suitable in [...]
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Evaluation of biological effects of intermediate frequency magnetic field on differentiation of embryonic stem cell
S. Yoshie, Y. Ogasawara, M. Ikehata, K. Ishii, Y. Suzuki, K. Wada, K. Wake, S. Nakasono, M. Taki, C. Ohkubo

Toxicology Reports (2016). Vol. 3

Abstract
The embryotoxic effect of intermediate frequency (IF) magnetic field (MF) was evaluated using murine embryonic stem (ES) cells and fibroblast cells based on the embryonic stem cell test (EST). The cells were exposed to 21 kHz IF–MF up to magnetic flux density of 3.9 mT during the cell proliferation process (7 days) or the cell differentiation process (10 days) during which an embryonic body differentiated into myocardial cells. As a result, there was no significant difference in the cell proliferation between sham- and IF–MF-exposed cells for both ES and fibroblast cells. Similarly, the ratio of the number of ES-derived cell aggregates differentiated to myocardial cells to total number of cell aggregates was not changed by IF–MF exposure. In addition, the expressions of a cardiomyocytes-specific gene, Myl2, and an early developmental gene, Hba-x, in the exposed cell aggregate were not altered. Since the magnetic flux density adopted in this study is much higher than that generated by an inverter of the electrical railway, an induction heating (IH) cooktop, etc . in our daily lives, these results suggested that IF–MF in which the public is exposed to in general living environment would not have embryotoxic effect.
Abstract
The embryotoxic effect of intermediate frequency (IF) magnetic field (MF) was evaluated using murine embryonic stem (ES) cells and fibroblast cells based on the embryonic [...]
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14-day toxicity studies of tetravalent and pentavalent vanadium compounds in Harlan Sprague Dawley rats and B6C3F1/N mice via drinking water exposure
G. Roberts, M. Stout, B. Sayers, D. Fallacara, M. Hejtmancik, S. Waidyanatha, M. Hooth

Toxicology Reports (2016).

Abstract
The National Toxicology Program (NTP) performed short-term toxicity studies of tetra- and pentavalent vanadium compounds, vanadyl sulfate and sodium metavanadate, respectively. Due to widespread human exposure and a lack of chronic toxicity data, there is concern for human health following oral exposure to soluble vanadium compounds. To compare the potency and toxicological profile of vanadyl sulfate and sodium metavanadate using a short-term in vivo toxicity assay. Adult male and female Harlan Sprague Dawley (HSD) rats and B6C3F1/N mice, 5 per group, were exposed to vanadyl sulfate or sodium metavanadate, via drinking water, at concentrations of 0, 125, 250, 500, 1000 or 2000 mg/L for 14 days. Water consumption, body weights and clinical observations were recorded throughout the study, organ weights were collected at study termination. Lower water consumption, up to −80% at 2000 mg/L, was observed at most exposure concentrations for animals exposed to either vanadyl sulfate or sodium metavanadate and was accompanied by decreased body weights at the highest concentrations for both compounds. Animals in the 1000 and 2000 mg/L sodium metavanadate groups were removed early due to overt toxicity. Thinness was observed in high-dose animals exposed to either compound, while lethargy and abnormal gait were only observed in vanadate-exposed animals. Based on clinical observations and overt toxicity, sodium metavanadate appears to be more toxic than vanadyl sulfate. Differential toxicity cannot be explained by differences in total vanadium intake, based on water consumption, and may be due to differences in disposition or mechanism of toxicity.
Abstract
The National Toxicology Program (NTP) performed short-term toxicity studies of tetra- and pentavalent vanadium compounds, vanadyl sulfate and sodium metavanadate, respectively. [...]
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Evaluation of toxicity of biorational insecticides against larvae of the alfalfa weevil
G. Reddy, F. Antwi, G. Shrestha, T. Kuriwada

Toxicology Reports (2016). Vol. 3

Abstract
The alfalfa weevil, Hypera postica (Coleoptera: Curculionidae), is a major pest of alfalfa Medicago sativa L. (Fabaceae). While H. postica usually causes the most damage before the first cutting, in summer of 2015 damaging levels of the pest persisted in Montana well after the first harvest of alfalfa. Although conventional insecticides can control H. postica, these chemicals have adverse effects on non-target organisms including pollinators and natural enemy insects. In this context, use of biorational insecticides would be the best alternative options, as they are known to pose less risk to non-target organisms. We therefore examined the six commercially available biorational insecticides against H. postica under laboratory condition: Mycotrol® ESO (Beauveria bassiana GHA), Aza-Direct® (Azadirachtin), Met52® EC (Metarhizium brunneum F52), Xpectro OD® (B. bassiana GHA + pyrethrins), Xpulse OD® (B. bassiana GHA + Azadirachtin) and Entrust WP® (spinosad 80%). Concentrations of 0.1, 0.5, 1.0, and 2.0 times the lowest labelled rates were tested for all products. However, in the case of Entrust WP, additional concentrations of 0.001 and 0.01 times the lowest label rate were also assessed. Mortality rates were determined at 1–9 days post treatment. Based on lethal concentrations and relative potencies, this study clearly showed that Entrust was the most effective, causing 100% mortality within 3 days after treatment among all the tested materials. With regard to other biorational, Xpectro was the second most effective insecticide followed by Xpulse, Aza-Direct, Met52, and Mycotrol. Our results strongly suggested that these biorational insecticides could potentially be applied for H. postica control.
Abstract
The alfalfa weevil, Hypera postica (Coleoptera: Curculionidae), is a major pest of alfalfa Medicago sativa L. (Fabaceae). While H. postica usually causes the most damage before [...]
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Antioxidant protection of gallic acid against toxicity induced by Pb in blood, liver and kidney of rats
P. Reckziegel, V. Dias, D. Benvegnú, N. Boufleur, R. Barcelos, H. Segat, C. Pase, C. Santos, É. Flores, M. Bürger

Toxicology Reports (2016). Vol. 3

Abstract
The effect of the antioxidant gallic acid (GA) on Pb toxicity in blood, liver and kidney was investigated in the present study. Rats Wistar received Pb nitrate (50 mg/Kg/day, i.p., 5 days) followed by GA (13.5 mg/Kg, p.o., 3 days) or a chelating agent (EDTA, 55 mg/Kg, i.p.). As result, Pb decreased body weight, hematocrit and blood δ-aminolevulinic acid dehydratase (ALA-D) activity. In addition, high Pb levels were observed in blood and tissues, together with increased (1) lipid peroxidation in erythrocytes, plasma and tissues, (2) protein oxidation in tissues and (3) plasma aspartate transaminase (AST) levels. These changes were accompanied by decreasing in antioxidant defenses, like superoxide dismutase (SOD) activity in tissues and catalase (CAT) activity and reduced glutathione (GSH) in liver. GA was able to reverse Pb-induced decrease in body weight and ALA-D activity, as well as Pb-induced oxidative damages and most antioxidant alterations, however it did not decrease Pb bioaccumulation herein as EDTA did. Furthermore, EDTA did not show antioxidant protection in Pb-treated animals as GA did. In conclusion, GA decreased Pb-induced oxidative damages not by decreasing Pb bioaccumulation, but by improving antioxidant defenses, thus GA may be promising in the treatment of Pb intoxications.
Abstract
The effect of the antioxidant gallic acid (GA) on Pb toxicity in blood, liver and kidney was investigated in the present study. Rats Wistar received Pb nitrate (50 mg/Kg/day, [...]
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Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice
S. Rebholz, T. Jones, R. Herrick, C. Xie, A. Calafat, S. Pinney, L. Woollett

Toxicology Reports (2016).

Abstract
Perfluorooctanoic acid (PFOA) is a man-made surfactant with a number of industrial applications. It has a long half-life environmentally and biologically. Past studies suggest a direct relationship between plasma cholesterol and PFOA serum concentrations in humans and an inverse one in rodents fed standard rodent chow, making it difficult to examine mechanisms responsible for the potential PFOA-induced hypercholesterolemia and altered sterol metabolism. To examine dietary modification of PFOA-induced effects, C57BL/6 and BALB/c mice were fed PFOA in a fat- and cholesterol-containing diet. When fed these high fat diets, PFOA ingestion resulted in marked hypercholesterolemia in male and female C57BL/6 mice and less robust hypercholesterolemia in male BALB/c mice. The PFOA-induced hypercholesterolemia appeared to be the result of increased liver masses and altered expression of genes associated with hepatic sterol output, specifically bile acid production. mRNA levels of genes associated with sterol input were reduced only in C57BL/6 females, the mice with the greatest increase in plasma cholesterol levels. Strain-specific PFOA-induced changes in cholesterol concentrations in mammary tissues and ovaries paralleled changes in plasma cholesterol levels. mRNA levels of sterol-related genes were reduced in ovaries of C57BL/6 but not in BALB/c mice and not in mammary tissues. Our data suggest that PFOA ingestion leads to hypercholesterolemia in mice fed fat and cholesterol and effects are dependent upon the genetic background and gender of the mice with C57BL/6 female mice being most responsive to PFOA.
Abstract
Perfluorooctanoic acid (PFOA) is a man-made surfactant with a number of industrial applications. It has a long half-life environmentally and biologically. Past studies suggest [...]
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GLP-1 receptor agonist exenatide restores atypical antipsychotic clozapine treatment-associated glucose dysregulation and damage of pancreatic islet beta cells in mice
B. Hsu, S. Fu

Toxicology Reports (2016). Vol. 3

Abstract
The aim of this study was to investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), exenatide, on clozapine-associated glucose dysregulation in mice. We randomly separated B6 male mice into four groups (A to D). Mice in groups C and D received a daily oral dose of 13.5 mg/kg body weight of clozapine for 4 months. Mice in groups B and D received 1 μg of exenatide daily. The body weight and blood glucose before and 2 h after clozapine treatment were measured twice a week. Intraperitoneal glucose tolerance test (IPGTT) scores and the amount of daily food intake were recorded. The pancreases of the mice were removed for insulin content (PIC) measurement and histological examination after sacrifice. The mean non-fasting blood glucose levels were not different, and the mean changes in blood glucose 2 h after oral clozapine were 0 ± 4, −40 ± 2, 25 ± 3, and −39 ± 2, in groups A to D, respectively. There was no significant difference in daily calorie intake or area under the curve of IPGTT among the four groups. At sacrifice, the PIC of mice treated with clozapine was significantly lower than that of the control mice, however the PIC was completely restored in the mice treated with exenatide. Histological examination of the pancreas revealed that exenatide treatment reversed the clozapine-induced apoptosis of islet cells. Our results provide preclinical evidence of a pharmaceutical role of GLP-1RA in managing glucose dysregulation in schizophrenic patients under long-term atypical antipsychotic treatments.
Abstract
The aim of this study was to investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), exenatide, on clozapine-associated glucose dysregulation in mice. [...]
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Arsenic induced hematological and biochemical responses in nutritionally important catfish Clarias batrachus (L.)
R. Kumar, T. Banerjee

Toxicology Reports (2016).

Abstract
The impact of sublethal toxicity of sodium arsenite on hematological and certain biochemical parameters of the fresh water catfish Clarias batrachus has been analyzed following exposure of sublethal concentration (1 mg/L, 5% of LC50 value) of sodium arsenite for 10, 30, 45, and 60 days. Arsenic bioaccumulation in the blood tissue of the fish increased progressively with increased period of exposure. The values of total erythrocyte count (TECs), total leucocytes count (TLCs), hemoglobin concentration, and packed cell volume (PCV) 1.40 ± 0.03 × 106 /mm3, 174.83 ± 2.74 × 103 /mm3, 5.01 ± 0.26 g/100 ml, 25.00 ± 1.06 were observed respectively at the end of 60 days of exposure. The results of hematological indices were found to be 179.23 ± 8.81fl/cell for mean corpuscular volume (MCV), 35.92 ± 1.89 pg/cell for mean corpuscular hemoglobin (MCH) and 20.17 ± 1.12 g/dl for mean corpuscular hemoglobin concentration (MCHC). The present findings are clearly indicating severe fish anemia due to the arsenic salt exposure. The continued arsenic toxicity results in decreased serum protein concentration that might be a cause for the loss of weight as well as weakness in the fish.
Abstract
The impact of sublethal toxicity of sodium arsenite on hematological and certain biochemical parameters of the fresh water catfish Clarias batrachus has been analyzed following [...]
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Ceramide-1-phosphate protection of cochlear hair cells against cisplatin ototoxicity
Q. Le, K. Tabuchi, A. Hara

Toxicology Reports (2016). Vol. 3

Abstract
Ceramide-1-phosphate (C1P) is a phosphorylated form of ceramide. While ceramide is known to be an inducer of apoptosis of cochlear hair cells in cisplatin ototoxicity, little is known about the function of C1P in cochlear diseases. The present study was designed to examine whether C1P could protect cochlear hair cells against cisplatin ototoxicity. Explants of cochlear basal turns collected from C57BL/6J mice at postnatal days 3–5 were used in all experiments. Cochlear explants were exposed to 5 or 10 μM cisplatin for 48 h to assess the effects of C1P, NVP-231 (a ceramide kinase inhibitor), or ceramide. Western blotting of pAkt/Akt and pMAPK/MAPK was examined to check whether this pathway was modulated by C1P. C1P activated the Akt and MAPK pathway and significantly reduced cochlear cell death induced by cisplatin. Coadministration of cisplatin and ceramide significantly increased cochlear hair cell death. In addition, when treating cochlear hair cells with NVP-231 in the presence of cisplatin or ceramide, a remarkable increase in apoptosis of hair cells was observed. The present findings confirmed the protective effects of C1P in the cisplatin ototoxicity. The balance between ceramide and C1P may play a critical role in the determination of hair cell fate in cisplatin ototoxicity.
Abstract
Ceramide-1-phosphate (C1P) is a phosphorylated form of ceramide. While ceramide is known to be an inducer of apoptosis of cochlear hair cells in cisplatin ototoxicity, little [...]
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Occupational exposure to pesticides and occurrence of the chromosomal translocation t(14;18) among farmers in Jordan
B. Qaqish, O. Al-Dalahmah, Y. Al-Motassem, A. Battah, S. Ismail

Toxicology Reports (2016).

Abstract
An increased incidence of non-Hodgkin’s lymphoma (NHL) has been reported in farmers and other occupational groups working with pesticides. In these individuals, an increased prevalence of the chromosomal translocation t(14, 18)(q32, q21), one of the most common chromosomal abnormalities in NHL, has been detected in peripheral blood lymphocytes. This translocation juxtaposes the antiapoptotic BCL2 protein to the immunoglobulin heavy chain gene locus (IGH) leading to overexpression of BCL2. This causes an increase in cell survival, paving the way for malignant transformation. The present study aimed to evaluate the association between the occurrence of the chromosomal translocation t(14, 18) and occupational exposure to pesticides among a group of Jordanian farmers. A total of 192 male subjects including 96 agricultural workers and 96 control subjects participated in this study. BCL2-IGH t(14, 18) fusions were detected by a nested polymerase chain reaction (PCR) assay targeting the major breakpoint region (MBR). We found that occupational exposure to pesticides in open-field farming and insecticide used on animals increased the frequency of the chromosomal translocation t(14, 18). Farmers occupationally exposed to pesticides and insecticide were 13.5 times more likely to harbor t(14, 18). 63.5% (61 of 96) of farmers compared to 11.5% (11 of 96) of controls carried the translocation (odds ratio: 13.5, 95% confidence interval (CI) = 6.3–28.6). We ruled out the influence of possible confounding factors such as age, duration of sun exposure, alcohol intake, smoking, and use of personal protective equipment. Our results indicate that pesticides increased the frequency of chromosomal translocation in the 14q32 region. Accordingly, the presented data agrees with previous suggestions from the literature that pesticides might be involved in the development of NHL through the t(14, 18) pathway.
Abstract
An increased incidence of non-Hodgkin’s lymphoma (NHL) has been reported in farmers and other occupational groups working with pesticides. In these individuals, an increased [...]
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Comment on “Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice” by Rebholz S.L. et al. Toxicol. Rep. 2016 (3) 46–54
H. Princen, M. Pouwer, E. Pieterman

Toxicology Reports (2016).
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Hepato- and neuro-protective effects of watermelon juice on acute ethanol-induced oxidative stress in rats
O. Oyenihi, B. Afolabi, A. Oyenihi, O. Ogunmokun, O. Oguntibeju

Toxicology Reports (2016).

Abstract
Chronic and acute alcohol exposure has been extensively reported to cause oxidative stress in hepatic and extra-hepatic tissues. Watermelon (Citrullus lanatus ) is known to possess various beneficial properties including, antioxidant, anti-inflammatory, analgesic, anti-diabetic, anti-ulcerogenic effects. However, there is a lack of pertinent information on its importance in acute alcohol-induced hepato- and neuro-toxicity. The present study evaluated the potential protective effects of watermelon juice on ethanol-induced oxidative stress in the liver and brain of male Wistar rats. Rats were pre-treated with the watermelon juice at a dose of 4 ml/kg body weight for a period of fifteen days prior to a single dose of ethanol (50%, 12 ml/kg body weight). Ethanol treatment reduced body weight gain and significantly altered antioxidant status in the liver and brain. This is evidenced by the significant elevation of malondialdehyde (MDA) concentration, depletion in reduced glutathione (GSH) levels and an increased catalase (CAT) activity in the brain and liver. There was no significant difference in the activity of glutathione peroxidase (GPX) in the liver and brain. Oral administration of watermelon juice for fifteen (15) days prior to ethanol intoxication, significantly reduced the concentration of MDA in the liver and brain of rats. In addition, water melon pre-treatment increased the concentration of GSH and normalized catalase activity in both tissues in comparison to the ethanol control group. Phytochemical analysis revealed the presence of phenol, alkaloids, saponins, tannins and steroids in watermelon juice. Our findings indicate that watermelon juice demonstrate anti-oxidative effects in ethanol-induced oxidation in the liver and brain of rats, which could be associated with the plethora of antioxidant phyto-constituents present there-in.
Abstract
Chronic and acute alcohol exposure has been extensively reported to cause oxidative stress in hepatic and extra-hepatic tissues. Watermelon (Citrullus lanatus ) is known to [...]
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Hepatic histomorphological and biochemical changes following highly active antiretroviral therapy in an experimental animal model: Does Hypoxis hemerocallidea exacerbate hepatic injury?
O. Azu, A. Jegede, O. Ugochukwu, I. Onanuga, S. Kharwa, E. Naidu

Toxicology Reports (2016). Vol. 3

Abstract
As the roll-out of antiretroviral therapy continues to drive downwards morbidity and mortality in people living with HIV/AIDS (PLWHAs), organ toxicities (especially the liver) are frequently becoming a major concern for researchers, scientists and healthcare planners. This study was conducted to investigate the possible protective effect of Hypoxis hemerocallidea (AP) against highly active antiretroviral therapy (HAART)-induced hepatotoxicity. A total of 63 pathogen-free adult male Sprague-Dawley rats were divided into 9 groups and treated according to protocols. While no mortality was reported, animals treated with adjuvant HAART and AP recorded least% body weight gain. Significant derangements in serum lipid profiles were exacerbated by treatment of with AP as LDL (increased p < 0.03), triglycerides (increased p < 0.03) with no change in total cholesterol levels. Adjuvant AP with HAART caused reduction in LDL (p < 0.05 and 0.03), increased HDL (p < 0.05) and TG (p < 0.05 and 0.001 for AP100 and AP200 doses respectively). Markers of liver injury assayed showed significant increase (p < 0.003, 0.001) in AST in AP alone as well as HAART+ vitamins C and E groups respectively. Adjuvant HAART and AP and vitamins C and E also caused significant declines in ALT and ALP levels. Serum GGT was not markedly altered. Disturbances in histopathology ranged from severe hepatocellular distortions, necrosis and massive fibrosis following co-treatment of HAART with vitamins C and E as well as HAART alone. These results warrant caution on the adjuvant use of AP with HAART by PLWHAs as implications for hepatocellular injuries are suspect with untoward cardiometabolic changes.
Abstract
As the roll-out of antiretroviral therapy continues to drive downwards morbidity and mortality in people living with HIV/AIDS (PLWHAs), organ toxicities (especially the liver) [...]
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Assessment of PAHs levels in some fish and seafood from different coastal waters in the Niger Delta
E. Nwaichi, S. Ntorgbo

Toxicology Reports (2016). Vol. 3

Abstract
Levels of sixteen polycyclic aromatic hydrocarbons (PAHs) in 30 edible tissues of selected frequently-consumed fish and seafood collected from three coastal waters of Niger Delta, namely, Sime, Kporghor and Iko were investigated in 2014. Gas chromatographic analysis were employed for PAHs determination. Observed mean PAHs levels in the samples ranged from below detection limit (BD) of analytical instrument to 22.400 ± 0.050 μg kg−1 wet wt. in Littorina littorea, BD to 87.400 ± 0.030 μg kg−1 wet wt. in Crassostrea virginica and from BD to 171.000 ± 0.430 μg kg−1 wet wt. in Periophthalmus koeleuteri. The highest average concentration of 171.000 ± 0.430 μg kg−1 wet wt. was recorded for Indeno [1, 2, 3-cd]pyrene from Sime water. High molecular weight PAHs (HMW-PAHs) were generally predominant compared to low molecular weight PAHs (LMW-PAHs). The LMW- PAH/HMW-PAH ratio was
Abstract
Levels of sixteen polycyclic aromatic hydrocarbons (PAHs) in 30 edible tissues of selected frequently-consumed fish and seafood collected from three coastal waters of Niger [...]
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Categorization of nano-structured titanium dioxide according to physicochemical characteristics and pulmonary toxicity
N. Hashizume, Y. Oshima, M. Nakai, T. Kobayashi, T. Sasaki, K. Kawaguchi, K. Honda, M. Gamo, K. Yamamoto, Y. Tsubokura, S. Ajimi, Y. Inoue, N. Imatanaka

Toxicology Reports (2016). Vol. 3

Abstract
A potentially useful means of predicting the pulmonary risk posed by new forms of nano-structured titanium dioxide (nano-TiO2 ) is to use the associations between the physicochemical properties and pulmonary toxicity of characterized forms of TiO2 . In the present study, we conducted intratracheal administration studies in rats to clarify the associations between the physicochemical characteristics of seven characterized forms of TiO2 and their acute or subacute pulmonary inflammatory toxicity. Examination of the associations between the physicochemical characteristics of the TiO2 and the pulmonary inflammatory responses they induced revealed (1) that differences in the crystallinity or shape of the TiO2 particles were not associated with the acute pulmonary inflammatory response, (2) that particle size was associated with the acute pulmonary inflammatory response, and (3) that TiO2 particles coated with Al(OH)3 induced a greater pulmonary inflammatory response than did non-coated particles. We separated the seven TiO2 into two groups: a group containing the six TiO2 with no surface coating and a group containing the one TiO2 with a surface coating. Intratracheal administration to rats of TiO2 from the first group (i.e., non-coated TiO2 ) induced only acute pulmonary inflammatory responses, and within this group, the acute pulmonary inflammatory response was equivalent when the particle size was the same, regardless of crystallinity or shape. In contrast, intratracheal administration to rats of the TiO2 from the second group (i.e., the coated TiO2 ) induced a more severe, subacute pulmonary inflammatory response compared with that produced by the non-coated TiO2 . Since alteration of the pulmonary inflammatory response by surface treatment may depend on the coating material used, the pulmonary toxicities of coated TiO2 need to be further evaluated. Overall, the present results demonstrate that physicochemical properties may be useful for predicting the pulmonary risk posed by new nano-TiO2 materials.
Abstract
A potentially useful means of predicting the pulmonary risk posed by new forms of nano-structured titanium dioxide (nano-TiO2 ) is to use the associations between the physicochemical [...]
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Severe anaphylactic reaction to mediterranean jellyfish (Ropilhema nomadica ) envenomation: Case report
N. Friedel, D. Scolnik, D. Adir, M. Glatstein

Toxicology Reports (2016). Vol. 3

Abstract
We present a 15-year-old female patient with an anaphylactic reaction to a jellyfish sting, sustained while surfing in the Mediterranean Sea. She experienced immediate difficulty in breathing, hoarseness and itching and was taken by ambulance to the emergency department, receiving intramuscular adrenaline on the way. She presented with periorbital swelling and facial edema and improved with systemic steroids and antihistamines. She was discharged 2 days later with allergy service follow up at our institution. This is the first case report documenting anaphylaxis due to Mediterranean jellyfish envenomation.
Abstract
We present a 15-year-old female patient with an anaphylactic reaction to a jellyfish sting, sustained while surfing in the Mediterranean Sea. She experienced immediate difficulty [...]
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Toxicity determinants of multi-walled carbon nanotubes: The relationship between functionalization and agglomeration
M. Allegri, D. Perivoliotis, M. Bianchi, M. Chiu, A. Pagliaro, M. Koklioti, A. Trompeta, E. Bergamaschi, O. Bussolati, C. Charitidis

Toxicology Reports (2016).

Abstract
The elucidation of toxicity determinants of multi-walled carbon nanotubes (MWCNT) is still incomplete. Functionalization with carboxyl groups is, however, commonly used to mitigate MWCNT toxicity, although the rationale for the mitigating effect has not been fully clarified yet. In this work, two optimized chemical vapor deposition methods were employed to obtain MWCNT of comparable length but different diameter, which were subsequently functionalized. For MWCNT of diameter larger than 40 nm, no detrimental effects on cell viability of macrophages were observed, while mild cytotoxicity was recorded for diameters between 15 and 40 nm, with a mitigating effect of functionalization. To investigate the factors responsible for the mitigation, we used the thinnest MWCNT preparation on different cell models, evaluating several endpoints, such as viability, production of nitric oxide (NO), expression of pro-inflammatory markers, the Trans-Epithelial Electrical Resistance (TEER), and clonogenic activity. Substantial mitigation of the changes caused by pristine MWCNT was observed not only with carboxyl- but also with amino-functionalized MWCNT, suggesting that negative or positive surface charge was not the main factor responsible for the effect. Instead, either functionalized preparation exhibited a stronger tendency to agglomerate that was strictly dependent on the presence of proteins. Moreover, we found that either carboxyl- or amino-functionalized MWCNT adsorbed a larger amount of serum proteins than pristine counterparts, with a distinctive pattern for each type of MWCNT. We propose, therefore, that the formation of larger agglomerates, dependent upon different protein coronae, contributes to mitigate the biological effects of functionalized MWCNT in protein-rich biological media.
Abstract
The elucidation of toxicity determinants of multi-walled carbon nanotubes (MWCNT) is still incomplete. Functionalization with carboxyl groups is, however, commonly used to [...]
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Prevalence of aflatoxin and fumonisins (B1 + B2 ) in maize consumed in rural Malawi
D. Mwalwayo, B. Thole

Toxicology Reports (2016). Vol. 3

Abstract
A study was carried out to assess levels of contamination of aflatoxins and fumonisins (B1 + B2 ) in maize produced, stored and consumed in rural households in Malawi. A total of 9 districts were selected across the country representing 3 districts from each of the Northern, Central and Southern regions respectively. Households were selected at random in each district where 10 maize samples were collected for laboratory analysis. Aflatoxins and fumonisins were analyzed using a single step lateral flow immunochromatographic assay based on a competitive immunoassay format. The detection limit for aflatoxins was 2 μg/kg with a quantitation range of 2–150 μg/kg and that for fumonisins was 1 mg/kg with a quantitation range of 1–7 mg/kg. It was found that samples in the Southern region were highly contaminated, with the Chikhwawa district having high levels of both aflatoxins and fumonisins in maize. The Northern region had the least contamination. The maximum detected amount of aflatoxins was 140 μg/kg. The maximum detected amounts of fumonisins was 7 mg/kg. About 20% of maize samples exceeded the tolerable maximum limit for aflatoxins in Malawi. Aflatoxins and fumonisins were found to co-occur with contamination levels exceeding 100 μg/kg for both aflatoxins and fumonisins.
Abstract
A study was carried out to assess levels of contamination of aflatoxins and fumonisins (B1 + B2 ) in maize produced, stored and consumed in rural households in Malawi. A total [...]
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In vitro exposure of Adhatoda zeylanica to human renal cells lacks acute toxicity
M. Mossoba, T. Flynn, S. Vohra, P. Wiesenfeld, R. Sprando

Toxicology Reports (2016).

Abstract
Adhatoda zeylanica is a dietary supplement ingredient present in several types of dietary supplements, including weight loss, respiratory relief, and immune regulating products. Due to its reported wide range of uses in folk medicine, it was hypothesized that it may have the potential to target multiple organs and lead to a range of toxicity features. As a preliminary evaluation of the safety of this herbal ingredient, an investigation into its effects on the kidney was sought. An in vitro study of its potential nephrotoxicity using the HK-2 human proximal tubule cell line in a variety of functional indicators was performed to capture both general forms of cellular toxicity as well as ones that are specific to proximal tubules. A. zeylanica was only capable of inducing detrimental short-term toxicity to HK-2 cells at relatively high treatment concentrations when exposed directly to the cells. The lack of acute and potent toxicity of A. zeylanica under our experimental conditions calls for further studies to better define its toxicant threshold and establish safe dosage levels.
Abstract
Adhatoda zeylanica is a dietary supplement ingredient present in several types of dietary supplements, including weight loss, respiratory relief, and immune regulating products. [...]
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13-week dietary study and in vitro and in vivo genotoxicity studies of a structuring fat produced through a microalgal fermentation process
R. Matulka, T. Chan, R. Green, J. Carney, S. Franklin, P. Licari

Toxicology Reports (2016). Vol. 3

Abstract
Microalgae are increasingly being utilized as food ingredients for a variety of applications, including as sources of protein, egg and dairy substitutes, and cooking oils. The dietary safety of a new structuring fat produced using a heterotrophic fermentation process by a strain of Prototheca moriformis was evaluated in a 13-week dietary toxicity study and compared with kokum fat, a structuring fat of similar composition used in the food industry and derived from Garcinia indica seeds. The algal structuring fat was evaluated for its genotoxic potential using both in vitro and in vivo assays. No treatment-related adverse events occurred in rats consuming algal structuring fat or kokum fat in the 13-week study, no treatment-related effects were reported for body weight, food consumption, urinalysis, hematology, clinical chemistry, gross pathology, organ weights, or histopathology. While statistically significant effects occurred in some parameters, none were dose-related or considered adverse. Overall, the NOAELs for the algal structuring fat and the kokum fat were 100 000 ppm, the highest concentrations tested. The algal structuring fat was not mutagenic in the bacterial reverse mutation assay in the Salmonella typhimurium or Escherichia coli strains tested and was not clastogenic in the in vivo mouse bone marrow chromosome aberration assay.
Abstract
Microalgae are increasingly being utilized as food ingredients for a variety of applications, including as sources of protein, egg and dairy substitutes, and cooking oils. [...]
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Heat-induced alterations in cashew allergen solubility and IgE binding
C. Mattison, Y. Bren-Mattison, B. Vant-Hull, A. Vargas, R. Wasserman, C. Grimm

Toxicology Reports (2016).

Abstract
Cashew nuts are an increasingly common cause of food allergy. We compare the soluble protein profile of cashew nuts following heating. SDS-PAGE indicate that heating can alter the solubility of cashew nut proteins. The 11S legumin, Ana o 2, dominates the soluble protein content in ready to eat and mildly heated cashew nuts. However, we found that in dark-roasted cashew nuts, the soluble protein profile shifts and the 2S albumin Ana o 3 composes up to 40% of the soluble protein. Analysis of trypsin-treated extracts by LC/MS/MS indicate changes in the relative number and intensity of peptides. The relative cumulative intensity of the 5 most commonly observed Ana o 1 and 2 peptides are altered by heating, while those of the 5 most commonly observed Ana o 3 peptides remaine relatively constant. ELISA experiments indicate that there is a decrease in rabbit IgG and human serum IgE binding to soluble cashew proteins following heating. Our findings indicate that heating can alter the solubility of cashew allergens, resulting in altered IgE binding. Our results support the use of both Ana o 2 and Ana o 3 as potential cashew allergen diagnostic targets.
Abstract
Cashew nuts are an increasingly common cause of food allergy. We compare the soluble protein profile of cashew nuts following heating. SDS-PAGE indicate that heating can alter [...]
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Genetic and rat toxicity studies of cyclodextrin glucanotransferase
R. Maronpot, C. Hobbs, J. Davis, C. Swartz, M. Boyle, M. Koyanagi, S. Hayashi

Toxicology Reports (2016). Vol. 3

Abstract
Microbiologically derived cyclodextrin glucanotransferase (CGTase) is used commercially as a processing agent in manufacture of food, pharmaceuticals, and cosmetics. Its toxic potential was evaluated in anticipation of use in the production of alpha -glycosyl isoquercitrin, a water-soluble form of quercetin. Following OECD guidelines, CGTase, produced by Bacillus pseudalcaliphilus DK-1139, was evaluated in a genotoxicity battery consisting of a bacterial reverse mutation assay, an in vitro micronucleus (MN) assay and MN and comet assays using B6C3F1 male and female mice. These same genotoxicity assays were also conducted for sodium sulfate, a contaminant of CGTase preparation. In a 90-day Sprague Dawley rat toxicity study, CGTase was administered by gavage in water at daily doses of 0, 250, 500, and 1000 mg/kg/day. CGTase did not induce mutations with or without metabolic activation in the bacterial reverse mutation assay. Formation of micronuclei was not induced in either in vitro or in vivo MN assays with or without metabolic activation. No induction of DNA damage was detected in male or female mouse liver, stomach, or duodenum in the comet assay. Sodium sulfate also tested negative in these same genotoxicity assays. In the 90-day repeated dose rat study there were no treatment-related adverse clinical or pathological findings. The genotoxicity assays and repeated dose toxicity study support the safe use of CGTase in production of alpha -glycosyl isoquercitrin.
Abstract
Microbiologically derived cyclodextrin glucanotransferase (CGTase) is used commercially as a processing agent in manufacture of food, pharmaceuticals, and cosmetics. Its toxic [...]
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Omega-3 and alpha-tocopherol provide more protection against contaminants in novel feeds for Atlantic salmon (Salmo salar L.) than omega-6 and gamma tocopherol
L. Søfteland, M. Berntssen, J. Kirwan, T. Størseth, M. Viant, B. Torstensen, R. Waagbø, P. Olsvik

Toxicology Reports (2016).

Abstract
Extended use of plant ingredients in Atlantic salmon farming has increased the need for knowledge on the effects of new nutrients and contaminants in plant based feeds on fish health and nutrient-contaminant interactions. Primary Atlantic salmon hepatocytes were exposed to a mixture of PAHs and pesticides alone or in combination with the nutrients ARA, EPA, α-tocopherol, and γ-tocopherol according to a factorial design. Cells were screened for effects using xCELLigence cytotoxicity screening, NMR spectroscopy metabolomics, mass spectrometry lipidomics and RT-qPCR transcriptomics. The cytotoxicity results suggest that adverse effects of the contaminants can be counteracted by the nutrients. The lipidomics suggested effects on cell membrane stability and vitamin D metabolism after contaminant and fatty acid exposure. Co-exposure of the contaminants with EPA or α-tocopherol contributed to an antagonistic effect in exposed cells, with reduced effects on the VTG and FABP4 transcripts. ARA and γ-tocopherol strengthened the contaminant-induced response, ARA by contributing to an additive and synergistic induction of CYP1A, CYP3A and CPT2, and γ-tocopherol by synergistically increasing ACOX1. Individually EPA and α-tocopherol seemed more beneficial than ARA and γ-tocopherol in preventing the adverse effects induced by the contaminant mixture, though a combination of all nutrients showed the greatest ameliorating effect.
Abstract
Extended use of plant ingredients in Atlantic salmon farming has increased the need for knowledge on the effects of new nutrients and contaminants in plant based feeds on [...]
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Safety assessment of a standardized polyphenolic extract of clove buds: Subchronic toxicity and mutagenicity studies
L. Vijayasteltar, G. Nair, B. Maliakel, R. Kuttan, K. I.M.

Toxicology Reports (2016). Vol. 3

Abstract
Despite the various reports on the toxicity of clove oil and its major component eugenol, systematic evaluations on the safety of polyphenolic extracts of clove buds have not been reported. Considering the health beneficial pharmacological effects and recent use of clove polyphenols as dietary supplements, the present study investigated the safety of a standardized polyphenolic extract of clove buds (Clovinol), as assessed by oral acute (5 g/kg b.wt. for 14 days) and subchronic (0.25, 0.5 and 1 g/kg b.wt. for 90 days) toxicity studies on Wistar rats and mutagenicity studies employing Salmonella typhimurium strains. Administration of Clovinol did not result in any toxicologically significant changes in clinical/behavioural observations, ophthalmic examinations, body weights, organ weights, feed consumption, urinalysis, hematology and clinical biochemistry parameters when compared to the untreated control group of animals, indicating the no observed-adverse-effect level (NOAEL) as 1000 mg/kg b.wt./day, the highest dose tested. Terminal necropsy did not reveal any treatment-related histopathology changes. Clovinol did not show genotoxicity when tested on TA-98, TA-100 and TA-102 with or without metabolic activation, rather exhibited significant antimutagenic potential against the known mutagens, sodium azide, NPD and tobacco as well as against 2-acetamidoflourene, which needed metabolic activation for mutagenicity.
Abstract
Despite the various reports on the toxicity of clove oil and its major component eugenol, systematic evaluations on the safety of polyphenolic extracts of clove buds have [...]
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Melatonin modulates drug-induced acute porphyria
S. Lelli, M. Mazzetti, L. Viale

Toxicology Reports (2016).

Abstract
This work investigated the modulation by melatonin (Mel) of the effects of the porphyrinogenic drugs 2-allyl-2-isopropylacetamide (AIA) and 3, 5-diethoxycarbonyl-1, 4-dihydro-2, 4, 6-collidine (DDC) on oxidative environment, glucose biosynthesis and heme pathway parameters. Administration of Mel before rat intoxication with AIA/DDC showed a clear beneficial effect in all cases. Mel induced decreases of 42% and 35% in the excretion of the hemeprecursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), respectively, and a 33% decrease in the induction of the heme regulatory enzyme 5-aminolevulinic acid-synthase (ALA-S). The activity of the glucose metabolism enzyme phosphoenolpyruvate carboxykinase (PEPCK), which had been diminished by the porphyrinogenic treatment, was restored by 45% when animals were pre-treated with Mel. Mel abolished the modest decrease in glucose 6-phospatase (G6Pase) activity caused by AIA/DDC treatment. The oxidative status of lipids was attenuated by Mel treatment in homogenates by 47%, whereas no statistically significant AIA/DDC-induced increase in thiobarbituric acid reactive substances (TBARS) was observed in microsomes after Mel pre-treatment. We hypothesize that Mel may be scavenging reactive species of oxygen (ROS) that could be damaging lipids, PEPCK, G6Pase and ferrochelatase (FQ). Additionally, Mel administration resulted in the repression of the key enzyme ALA-S, and this could be due to an increase in glucose levels, which is known to inhibit ALA-S induction. The consequent decrease in levels of the heme precursors ALA and PBG had a beneficial effect on the drug-induced porphyria. The results obtained open the possibility of further research on the use of melatonin as a co-treatment option in acute porphyria.
Abstract
This work investigated the modulation by melatonin (Mel) of the effects of the porphyrinogenic drugs 2-allyl-2-isopropylacetamide (AIA) and 3, 5-diethoxycarbonyl-1, 4-dihydro-2, [...]
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Safety studies conducted on pecan shell fiber, a food ingredient produced from ground pecan shells
L. Dolan, R. Matulka, J. Worn, J. Nizio

Toxicology Reports (2016). Vol. 3

Abstract
Use of pecan shell fiber in human food is presently limited, but could increase pending demonstration of safety. In a 91-day rat study, pecan shell fiber was administered at dietary concentrations of 0 (control), 50 000, 100 000 or 150 000 ppm. There was no effect of the ingredient on body weight of males or females or food consumption of females. Statistically significant increases in food consumption were observed throughout the study in 100 000 and 150 000 ppm males, resulting in intermittent decreases in food efficiency (150 000 ppm males only) that were not biologically relevant. All animals survived and no adverse clinical signs or functional changes were attributable to the test material. There were no toxicologically relevant changes in hematology, clinical chemistry or urinalysis parameters or organ weights in rats ingesting pecan shell fiber. Any macroscopic or microscopic findings were incidental, of normal variation and/or of minimal magnitude for test substance association. Pecan shell fiber was non-mutagenic in a bacterial reverse mutation test and non-clastogenic in a mouse peripheral blood micronucleus test. Based on these results, pecan shell fiber has an oral subchronic (13-week) no observable adverse effect level (NOAEL) of 150 000 ppm in rats and is not genotoxic at the doses analyzed.
Abstract
Use of pecan shell fiber in human food is presently limited, but could increase pending demonstration of safety. In a 91-day rat study, pecan shell fiber was administered [...]
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Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases
L. Takser, N. Benachour, B. Husk, H. Cabana, D. Gris

Toxicology Reports (2016). Vol. 3

Abstract
Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN), microcystin-LR (MC-LR), and anatoxin-a (ATX-a), individually as well as their mixture. In addition, we studied the neurotoxins β-N -methylamino-l -alanine (BMAA) and its isomer 2, 4-diaminobutyric acid (DAB), as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3–15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food.
Abstract
Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study [...]
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Metallothionein’s role in PCB126 induced hepatotoxicity and hepatic micronutrient disruption
W. Klaren, S. Flor, K. Gibson-Corley, G. Ludewig, L. Robertson

Toxicology Reports (2016). Vol. 3

Abstract
Polychlorinated biphenyls (PCBs), industrial chemicals and persistent environmental pollutants, are found in rural and urban settings. Rodent studies have shown that exposure to PCB126, a dioxin-like PCB, causes a significant disruption of hepatic micronutrient homeostasis and an increase in metallothionein (MT), an antioxidant protein and metal carrier. A MT knockout mouse strain was used to assess metallothionein’s role in micronutrient disruption and overall hepatotoxicity. Twenty four 129S male mice (12 wild type (WT) and 12 MT knockout (MTKO)) were placed on a purified diet (AIN-93G) for 3 weeks to achieve hepatic metal equilibrium. Mice were then given a single IP injection of either vehicle or 150 μmol/kg PCB126 in vehicle. The animals were sacrificed 2 weeks later and organs processed for analysis. Liver histology, hepatic lipids, gene expression, micronutrient and ROS status were investigated. Liver weights, liver lipids, ROS, and hepatocyte vacuolation were increased with PCB126 exposure along with AhR responsive genes. The MTKO animals had more severe histological changes in the liver and elevated liver lipids than their wild type counterparts. Hepatic and renal metals levels (Cu, Zn, Se and Mn) were mostly reduced by PCB126 treatment. Renal micronutrients were more affected by PCB126 treatment in the MTKO animals. This research suggests that MT may not be the sole/primary cause of the metal disruption caused by PCB126 exposure in mice, but may provide protection against overall hepatotoxicity.
Abstract
Polychlorinated biphenyls (PCBs), industrial chemicals and persistent environmental pollutants, are found in rural and urban settings. Rodent studies have shown that exposure [...]
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Food safety risk assessment for estimating dietary intake of sulfites in the Taiwanese population
K. Lien, D. Hsieh, H. Huang, C. Wu, S. Ni, M. Ling

Toxicology Reports (2016). Vol. 3

Abstract
The purpose of this study was to assess the health risk associated with dietary intake of sulfites for Taiwanese general consumers by conducting a total diet study (TDS). We evaluated the exposure of Taiwanese to sulfites in the diet and its associated health risk. This study used a list of 128 food items representing 83% of the total daily diet. Among the 128 food items, 59 items may contain sulfites. Samples of the 59 food items were collected and subjected to chemical analysis to determine the sulfur dioxide concentration. Health risk was assessed by calculating the ratio of exposure level to the acceptable daily intake (ADI) level of the analyte. For high-intake consumers, the HI of sulfites was 19.7% ADI for males over the age of three years at the 95th percentile, whereas for females over the age of 66, the HI was 17.8% ADI. The HI for high-intake consumers was above 10% ADI. This suggests that regulatory actions must be continued and that consumers should be advised to be aware of processed foods with relatively high contamination to avoid excessive exposure.
Abstract
The purpose of this study was to assess the health risk associated with dietary intake of sulfites for Taiwanese general consumers by conducting a total diet study (TDS). [...]
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Toxicological evaluation of a novel umami flavour compound: 2-(((3-(2,3-Dimethoxyphenyl)-1H -1,2,4-triazol-5-yl)thio)methyl)pyridine
D. Karanewsky, A. Arthur, H. Liu, B. Chi, L. Ida, S. Markison

Toxicology Reports (2016). Vol. 3

Abstract
A toxicological evaluation of a umami flavour compound, 2-(((3-(2, 3-dimethoxyphenyl)-1H -1, 2, 4-triazol-5-yl)thio)methyl)pyridine (S3643, CAS 902136-79-2), was completed for the purpose of assessing its safety for use in food and beverage applications. S3643 undergoes extensive oxidative metabolism in vitro with rat microsomes producing the S3643-sulfoxide and 4′-hydroxy-S3643 as the major metabolites. In incubations with human microsomes, the O -demethyl-S3643 and S3643-sulfoxide were produced as the major metabolites. In pharmacokinetic studies in rats, the S3643-sulfoxide represents the dominant biotransformation product. S3643 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in CHO-WBL cells. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S3643 was 100 mg/kg bw/day (highest dose tested) when administered in the diet for 90 consecutive days.
Abstract
A toxicological evaluation of a umami flavour compound, 2-(((3-(2, 3-dimethoxyphenyl)-1H -1, 2, 4-triazol-5-yl)thio)methyl)pyridine (S3643, CAS 902136-79-2), was completed [...]
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Sequencing the exposome: A call to action
D. Jones

Toxicology Reports (2016). Vol. 3

Abstract
The exposome is a complement to the genome that includes non-genetic causes of disease. Multiple definitions are available, with salient points being global inclusion of exposures and behaviors, and cumulative integration of associated biologic responses. As such, the concept is both refreshingly simple and dauntingly complex. This article reviews high-resolution metabolomics (HRM) as an affordable approach to routinely analyze samples for a broad spectrum of environmental chemicals and biologic responses. HRM has been successfully used in multiple exposome research paradigms and is suitable to implement in a prototype universal exposure surveillance system. Development of such a structure for systematic monitoring of environmental exposures is an important step toward sequencing the exposome because it builds upon successes of exposure science, naturally connects external exposure to body burden and partitions the exposome into workable components. Practical results would be repositories of quantitative data on chemicals according to geography and biology. This would support new opportunities for environmental health analysis and predictive modeling. Complementary approaches to hasten development of exposome theory and associated biologic response networks could include experimental studies with model systems, analysis of archival samples from longitudinal studies with outcome data and study of relatively short-lived animals, such as household pets (dogs and cats) and non-human primates (common marmoset). International investment and cooperation to sequence the human exposome will advance scientific knowledge and also provide an important foundation to control adverse environmental exposures to sustain healthy living spaces and improve prediction and management of disease.
Abstract
The exposome is a complement to the genome that includes non-genetic causes of disease. Multiple definitions are available, with salient points being global inclusion of exposures [...]
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Sodium sulfite promotes the assembly and secretion of very low-density lipoprotein in HL-7702 hepatocytes
J. Bai, P. Lei, C. Zhao, Y. Wang, D. Yan, S. Yang

Toxicology Reports (2016). Vol. 3

Abstract
This study investigated the effects of Na2 SO3 on the fat metabolism in human normal diploid HL-7702 (referred as L-02) hepatocytes. After 24 h and 48 h, treatment with different concentrations of Na2 SO3, the intra and extra-hepatocellular triglyceride (TG) contents of L-02 were determined using chemical-enzymatic method. The contents of very low-density lipoprotein (VLDL) and apolipoprotein B100 (apoB100) in the culture supernatants were determined using enzyme-linked immunosorbent assay (ELISA). Western blot was applied to detect the expressions of fatty acid oxidation and fat synthesis related proteins, VLDL assembly and secretion in L-02 cells. Na2 SO3 treatment (10 mM, 24 h/48 h) significantly increased the intra TG level in the hepatocytes. Different concentrations of Na2 SO3 increased the extra-hepatocellular TG content. After 24 h exposure, the extracellular VLDL levels and secretions of apoB100 in 0.1–10 mM Na2 SO3 groups were significantly higher than that of the negative control (P < 0.05). Meanwhile, the expression of CPT1 and SREBP1 protein were significantly reduced by Na2 SO3 . MTP and TGH protein expressions were significantly elevated in each Na2 SO3 treatment group. The expression level of LDLR in hepatocytes was reduced by Na2 SO3 . Na2 SO3 exposure may promote the hepatocellular VLDL assembly and secretion, through increasing of MTP and TGH expressions and inhibiting the uptake of extracelluar VLDL.
Abstract
This study investigated the effects of Na2 SO3 on the fat metabolism in human normal diploid HL-7702 (referred as L-02) hepatocytes. After 24 h and 48 h, treatment with different [...]
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Concentrations and exposure risks of some metals in facial cosmetics in Nigeria
C. Iwegbue, F. Bassey, G. Obi, G. Tesi, B. Martincigh

Toxicology Reports (2016).

Abstract
The concentrations of nine metals (Cd, Pb, Ni, Cr, Co, Cu, Fe, Mn and Zn) were determined in lip sticks, lip glosses, lip balms, eye pencils, eyeliners, eye shadows, blushes, mascaras and face powders. The study was aimed at providing information on the risk associated with human exposure to metals in these facial cosmetic products. The concentrations of metals in the samples were measured by atomic absorption spectrometry after digestion with a mixture of nitric acid, hydrochloric acid and hydrogen peroxide. The mean concentrations of metals in these facial cosmetics ranged from 3.1 to 8.4 μg g−1 Cd, 12–240 μg g−1 Pb, 9.1–44 μg g−1 Cr, 18–288 μg g−1 Ni, 1.6–80 μg g−1 Cu, 7.9–17 μg g−1 Co, 2.3–28 mg g−1 Fe, 12–230 μg g−1 Mn, and from 18 to 320 μg g−1 Zn. The concentrations of Ni, Cr and Co were above the suggested safe limit of 1 μg g−1 for skin protection, while Cd and Pb were above the Canadian specified limits. The systemic exposure dosage (SED) values for these metals obtained from the use of these facial cosmetic products were below their respective provisional tolerable daily intake (PTDI)/or recommended daily intake (RDI) values. The margin of safety values obtained were greater than 100 which indicated that the concentrations of the metals investigated in these facial cosmetics do not present considerable risk to the users except in the case of face powders.
Abstract
The concentrations of nine metals (Cd, Pb, Ni, Cr, Co, Cu, Fe, Mn and Zn) were determined in lip sticks, lip glosses, lip balms, eye pencils, eyeliners, eye shadows, blushes, [...]
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Downregulation of nicotinic and muscarinic receptor function in rats after subchronic exposure to diazinon
S. Ivanović, B. Dimitrijević, V. Ćupić, M. Jezdimirović, S. Borozan, M. Savić, D. Savić

Toxicology Reports (2016). Vol. 3

Abstract
Diazinon (DZN) is an organophosphate insecticide which exerts its effect through the inhibition of acetylcholinesterase enzyme (AChE). In this work, we studied the development of tolerance to subchronic p.o. administration of DZN in rats, under both in vivo and in vitro conditions. A group of 20 rats (2 groups, n = 10) was administered p.o. the 1/10 of established LD50 DZN (namely 55.87 mg/kg bw) for 28 days. On the 14th and 28th day of study with isolated diaphragm and ileum, we examined the downregulation of nicotinic and muscarinic receptor function through Electrical Field Stimulation (EFS). Maximum contractility of the diaphragm was recorded on the 14th day of the study (25% higher compared to the non-treated rats), while on the 28th day the contractions almost did not differ from the values found in non-treated rats. EFS of isolated ileum on the 14th day of study caused significantly higher contractions compared to the non-treated rats, but after 28 days, ileum contractions decreased approximately to the level of contractions in non-treated rats. On the 14th study day, we also recorded increased amplitude of spontaneous ileum contractions, compared to non-treated rats. The application of increasing ACh concentrations caused dose-dependent ileum contractions, without statistically significant differences of median effective concentration (EC50 ) values in non-treated and treated rats. Tolerance to subchronic DZN administration develops due to various adaptation mechanisms, including the most important one—downregulation of nicotinic and muscarinic receptor function.
Abstract
Diazinon (DZN) is an organophosphate insecticide which exerts its effect through the inhibition of acetylcholinesterase enzyme (AChE). In this work, we studied the development [...]
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Does amikacin treatment cause subclinical hearing loss in patients with cystic fibrosis?
F. Solmaz, E. Gündoğdu, D. Akduman, M. Haksever, O. Dikici, F. Ünal

Toxicology Reports (2016). Vol. 3

Abstract
Aminoglycosides (AGs) have been widely used for potential life-threatening bacterial infections. Although AGs are well known for their ototoxic side effects, some AGs such as amikacin are considered less harmful to auditory functions, thus, auditory monitoring is mostly neglected during treatment with these drugs. To reflect the potential auditory hazards of repeated amikacin use on the patients with cystic fibrosis (CF). 32CF patients with prior exposure to at least 3 courses of amikacin (the CF group) and 35 non-CF patients visiting the outpatient clinic with any complaint other than hearing loss and no history of treatment with any AG(the control, or C group) were compared with pure-tone audiometry(PTA). The diagnosis of CF was made by Nanoduck sweat test. The average age of the participants were 8.25 ± 2.76 years in the CF group and 8.58 ± 2.00 years in the C group (ranging from 5 to 13 years). 29 (43.28%) of the cases were female and 38 (56.71%) were male. Clinical SNHL(sensorineural hearing loss) was detected in 4 of the 32 subjects in the CF group. None of the subjects in the C group exhibited clinical SNHL. There was no statistically significant difference between the groups with regard to presence or absence of clinical SNHL (p > 0.05). However, hearing levels of the CF group were around 20 dB(decibel) HL(hearing loss), whereas hearing levels of the C group were around 5 dB. This difference was statistically significant for the pure tone averages of both all frequencies and speech frequencies (p < 0.05). Repetitive exposure to AGs can cause permanent, although mild, sensorineural hearing loss. For prevention, hearing status of the patient should be closely monitored and treatment of choice should be precisely tailored according to the audiological evaluation. This is especially important in patients with CF who frequently experience medical conditions necessitating AGs use.
Abstract
Aminoglycosides (AGs) have been widely used for potential life-threatening bacterial infections. Although AGs are well known for their ototoxic side effects, some AGs such [...]
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Cytotoxic effects of nickel nanowires in human fibroblasts
L. Felix, J. Perez, M. Contreras, T. Ravasi, J. Kosel

Toxicology Reports (2016).

Abstract
The increasing interest in the use of magnetic nanostructures for biomedical applications necessitates rigorous studies to be carried out in order to determine their potential toxicity. This work attempts to elucidate the cytotoxic effects of nickel nanowires (NWs) in human fibroblasts WI-38 by a colorimetric assay (MTT) under two different parameters: NW concentration and exposure time. This was complemented with TEM and confocal images to assess the NWs internalization and to identify any changes in the cell morphology. Ni NWs were fabricated by electrodeposition using porous alumina templates. Energy dispersive X-ray analysis, scanning electron microscopy and transmission electron microscopy imaging were used for NW characterization. The results showed decreased cell metabolic activity for incubation times longer than 24 h and no negative effects for exposure times shorter than that. The cytotoxicity effects for human fibroblasts were then compared with those reported for HCT 116 cells, and the findings point out that it is relevant to consider the cellular size. In addition, the present study compares the toxic effects of equivalent amounts of nickel in the form of its salt to those of NWs and shows that the NWs are more toxic than the salts. Internalized NWs were found in vesicles inside of the cells where their presence induced inflammation of the endoplasmic reticulum.
Abstract
The increasing interest in the use of magnetic nanostructures for biomedical applications necessitates rigorous studies to be carried out in order to determine their potential [...]
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Chemical and biological studies of β -carotene after exposure to Cannabis sativa smoke
D. Monte, J. Tenório, I. Bastos, F. Mendonça, J. Neto, T. Silva, C. Ramos

Toxicology Reports (2016).

Abstract
Considering the increase in consumption of Cannabis sativa and the use of the compound β- carotene (BC) as supplement, we investigated potential changes in the chemical and biological proprieties of BC after exposure to C. sativa smoke (CSS). Our results showed that the BC exposed to CSS underwent 98.8% degradation and suffered loss of its antiradical activity. The major degradation products identified were 3-hydroxy-2, 4, 4-trimethylpentyl)2-methylpropanoate and (2-ethyl-3-hydroxyhexyl)2-methylpropanoate compounds. These are found in higher levels in the exhalations of colorectal cancer patients and are similar to the toxic products associated with lipid peroxidation of polyunsaturated fatty acids. In toxicological assays using micro-crustacean Artemia salina the BC was non-toxic, while the BC degraded by CSS had a toxicity of LC50 = 397.35 μg/mL. In Wistar rats, females treated with BC degraded by CSS (BCCSS) showed whitish liver spots, alterations in liver weight and in bilirubin and alkaline phosphatase levels, and decrease in the number of leukocytes associated with atypical lymphocytosis. In male rats, there was an increase in the number of leukocytes when compared to the control group. In the histopathological analysis, the cortical region of the kidneys showed the presence of discrete amorphous eosinophilic material (cylinders) in the lumen of the proximate and distal convoluted tubules. In general, the BC in contact with CSS undergoes chemical changes and exhibits toxicity to rats and Artemia salina .
Abstract
Considering the increase in consumption of Cannabis sativa and the use of the compound β- carotene (BC) as supplement, we investigated potential changes in the chemical and [...]
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Use of Bidens pilosa L. (Asteraceae) and Curcuma longa L. (Zingiberaceae) to treat intestinal mucositis in mice: Toxico-pharmacological evaluations
C. Bastos, P. Ávila, E. Filho, R. Ávila, A. Batista, S. Fonseca, E. Lima, R. Marreto, E. Mendonça, M. Valadares

Toxicology Reports (2016).

Abstract
Several studies towards the development of an effective treatment for intestinal mucositis have been reported, since this condition represents a major problem in clinical oncology practice due to cytotoxic effects of chemotherapy. However standardized protocols and universally accepted treatment options are yet to be established. Given above, this study evaluated the protective effects of a mucoadhesive formulation containing both Bidens pilosa L. (Asteraceae) (BP) and curcuminoids from Curcuma longa L. (Zingiberaceae) (CL) on intestinal mucositis induced by 5-fluoruoacil (5-FU) in mice. As expected, animals only treated with 5-FU (200 mg/kg) showed a significant reduction of 60.3 and 42.4% in villi and crypts size, respectively, when compared to control. On the other hand, the proposed therapeutic/prophylactic treatment with mucoadhesive formulations managed to reduce histopathologic changes in mice bearing mucositis, especially at 125 mg/kg BP + 15 mg/kg CL dose. The formulation promoted an increase of 275.5% and 148.7% for villi and crypts size, respectively. Moreover, chemotherapy-related weight loss was reduced by 7.4% following the treatment. In addition, an increase of 10 and 30.5% in red and white blood cells was observed when compared to 5-FU group. Furthermore, treatments with the mucoadhesive formulation containing BP/CL up modulated Ki-67 and Bcl-2 expression while reduced pro-apoptotic regulator Bax. The formulation also modulated inflammatory response triggered by 5-FU through reduction of 68% of myeloperoxidase activity and a 4-fold increase in anti-inflammatory IL-10 levels. In parallel, the oxidative stress via lipid peroxidation was reduced as indicated by decrease of 63% of malondialdehyde concentrations. Additionally, the new formulation presented low acute oral systemic toxicity, being classified in the category 5 (2000 mg/kg < LD50 < 5000 mg/kg) of the Globally Harmonized Classification System. This study showed an interesting potential of the mucoadhesive formulation of BP/CL for the treatment of 5-FU-induced intestinal mucositis. Given the perspectives for the development of a new medicine, clinical studies are in progress to better understand the protective effects of this innovative formulation in treating mucositis.
Abstract
Several studies towards the development of an effective treatment for intestinal mucositis have been reported, since this condition represents a major problem in clinical [...]
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Transcriptomics analysis and hormonal changes of male and female neonatal rats treated chronically with a low dose of acrylamide in their drinking water
R. Collí-Dulá, M. Friedman, B. Hansen, N. Denslow

Toxicology Reports (2016). Vol. 3

Abstract
Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) from gestation day 6 to delivery and then through their drinking water to postnatal day 35. In order to identify potential mechanisms of carcinogenesis in the thyroid glands, we used a transcriptomics approach. Thyroid glands were collected from male pups at 10 PM and female pups at 10 AM or 10 PM in order to establish whether active exposure to acrylamide influenced gene expression patterns or pathways that could be related to carcinogenesis. While all animals exposed to acrylamide showed changes in expected target pathways related to carcinogenesis such as DNA repair, DNA replication, chromosome segregation, among others, animals that were sacrificed while actively drinking acrylamide-laced water during their active period at night showed increased changes in pathways related to oxidative stress, detoxification pathways, metabolism, and activation of checkpoint pathways, among others. In addition, thyroid hormones, triiodothyronine (T3) and thyroxine (T4), were increased in acrylamide-treated rats sampled at night, but not in quiescent animals when compared to controls. The data clearly indicate that time of day for sample collection is critical to identifying molecular pathways that are altered by the exposures. These results suggest that carcinogenesis in the thyroids of acrylamide treated rats may ensue from several different mechanisms such as hormonal changes and oxidative stress and not only from direct genotoxicity, as has been assumed to date.
Abstract
Acrylamide is known to produce follicular cell tumors of the thyroid in rats. RccHan Wistar rats were exposed in utero to a carcinogenic dose of acrylamide (3 mg/Kg bw/day) [...]
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Specific long non-coding RNAs response to occupational PAHs exposure in coke oven workers
C. Gao, Z. He, J. Li, X. Li, Q. Bai, Z. Zhang, X. Zhang, S. Wang, X. Xiao, F. Wang, . Yan, D. Li, L. Chen, X. Zeng, Y. Xiao, G. Dong, Y. Zheng, Q. Wang, W. Chen

Toxicology Reports (2016). Vol. 3

Abstract
To explore whether the alteration of lncRNA expression is correlated with polycyclic aromatic hydrocarbons (PAHs) exposure and DNA damage, we examined PAHs external and internal exposure, DNA damage and lncRNAs (HOTAIR, MALAT1, TUG1 and GAS5) expression in peripheral blood lymphocytes (PBLCs) of 150 male coke oven workers and 60 non-PAHs exposure workers. We found the expression of HOTAIR, MALAT1, and TUG1 were enhanced in PBLCs of coke oven workers and positively correlated with the levels of external PAHs exposure (adjusted Ptrend < 0.001 for HOTAIR and MALAT1, adjusted Ptrend = 0.006 for TUG1). However, only HOTAIR and MALAT1 were significantly associated with the level of internal PAHs exposure (urinary 1-hydroxypyrene) with adjusted β = 0.298, P = 0.024 for HOTAIR and β = 0.090, P = 0.034 for MALAT1. In addition, the degree of DNA damage was positively associated with MALAT1 and HOTAIR expression in PBLCs of all subjects (adjusted β = 0.024, P = 0.002 for HOTAIR and β = 0.007, P = 0.003 for MALAT1). Moreover, we revealed that the global histone 3 lysine 27 trimethylation (H3K27me3) modification was positively associated with the degree of genetic damage (β = 0.061, P < 0.001) and the increase of HOTAIR expression (β = 0.385, P = 0.018). Taken together, our findings suggest that altered HOTAIR and MALAT1 expression might be involved in response to PAHs-induced DNA damage.
Abstract
To explore whether the alteration of lncRNA expression is correlated with polycyclic aromatic hydrocarbons (PAHs) exposure and DNA damage, we examined PAHs external and internal [...]
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Dose- and time-dependent changes in tissue levels of tetrabromobisphenol A (TBBPA) and its sulfate and glucuronide conjugates following repeated administration to female Wistar Han Rats
S. Borghoff, D. Wikoff, S. Harvey, L. Haws

Toxicology Reports (2016). Vol. 3

Abstract
Tetrabromobisphenol A (TBBPA), a nongenotoxic flame retardant, causes uterine tumors in female rats. A proposed mode of action (MoA) for these tumors involves an increase in the bioavailability of estradiol as a result of TBBPA inhibiting estrogen sulfotransferases (ES), the enzymes responsible for inactivating and enhancing the elimination of estradiol. The objective of this study was to evaluate the effect of dose and repeated administration of TBBPA on the level of TBBPA, TBBPA-glucuronide (GA) and TBBPA-sulfate (S) conjugates in plasma, liver and uterus of female Wistar Han rats administered TBBPA (50, 100, 250, 500 or 1000 mg/kg) for 28 consecutive days. In accordance with this objective, TBBPA sulfation was used as a surrogate for evaluating the potential for estradiol sulfation to be limited at high dose levels of TBBPA. Blood samples were collected at 4 and 8 h post-dosing on study day 7, 14, and 28, while liver and uterus were collected at the same time points following 28 days of dosing. Tissue samples were analyzed for TBBPA, TBBPA-GA and TBBPA-S by LC–MS/MS. A dose-related increase in the concentration of all three analytes occurred in plasma (day 7, 14, and 28) as well as liver and uterus tissue (day 28) at both 4 and 8 h post dose. The plasma concentration of TBBPA-GA and TBBPA-S was higher in animals dosed for 28 days compared to those dosed for 7 or 14 days showing an increase in systemic circulation of these conjugates with repeated administration. The balance of these conjugates was also different in tissues with TBBPA-S > TBBPA-GA at high doses in the liver and TBBPA-GA > TBBPA-S in both plasma and uterus. In all three tissues the ratio of TBBPA-S/TBBPA-GA showed a decreasing trend with dose, suggesting that at high TBBPA dose levels sulfation of TBBPA becomes limited. This effect was most apparent in the liver and plasma at 28 days of administration. Together these data show that administration of high doses of TBBPA associated with the induction of uterine tumors, results in a disruption in the balance of conjugates reflected by a decrease in the TBBPA-S/TBBPA-GA ratio. A limitation in the sulfation of TBBPA in vivo supports in vitro data defining TBBPA as an inhibitor of ES activity, thus providing further support that the proposed MoA occurs under conditions of high dose, chronic TBBPA administration to Wistar Han rats. Given that the uterine tumors observed in rats (250–1000 mg/kg-day) only occur at very high doses that perturb homeostatic control, it is unlikely such effects would occur in humans given that current TBBPA exposure levels are approximately eight orders of magnitude lower than these doses that are associated with exceeding the capacity of conjugation pathways in animal studies.
Abstract
Tetrabromobisphenol A (TBBPA), a nongenotoxic flame retardant, causes uterine tumors in female rats. A proposed mode of action (MoA) for these tumors involves an increase [...]
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Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia
B. Ramachandran, S. Jayavelu, K. Murhekar, T. Rajkumar

Toxicology Reports (2016). Vol. 3

Abstract
EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.
Abstract
EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite [...]
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Arsenic inhibits stem cell differentiation by altering the interplay between the Wnt3a and Notch signaling pathways
L. Bain, J. Liu, R. League

Toxicology Reports (2016). Vol. 3

Abstract
Millions of people are exposed to arsenic through their drinking water and food, but the mechanisms by which it impacts embryonic development are not well understood. Arsenic exposure during embryogenesis is associated with neurodevelopmental effects, reduced weight gain, and altered locomotor activity, and in vitro data indicates that arsenic exposure inhibits stem cell differentiation. This study investigated whether arsenic disrupted the Wnt3a signaling pathway, critical in the formation of myotubes and neurons, during the differentiation in P19 mouse embryonic stem cells. Cells were exposed to 0, 0.1, or 0.5 μM arsenite, with or without exogenous Wnt3a, for up to 9 days of differentiation. Arsenic exposure alone inhibits the differentiation of stem cells into neurons and skeletal myotubes, and reduces the expression of both β-catenin and GSK3β mRNA to ∼55% of control levels. Co-culture of the arsenic-exposed cells with exogenous Wnt3a rescues the morphological phenotype, but does not alter transcript, protein, or phosphorylation status of GSK3β or β-catenin. However, arsenic exposure maintains high levels of Hes5 and decreases the expression of MASH1 by 2.2-fold, which are anti- and pro-myogenic and neurogenic genes, respectively, in the Notch signaling pathway. While rescue with exogenous Wnt3a reduced Hes5 levels, MASH1 levels stay repressed. Thus, while Wnt3a can partially rescue the inhibition of differentiation from arsenic, it does so by also modulating Notch target genes rather than only working through the canonical Wnt signaling pathway. These results indicate that arsenic alters the interplay between multiple signaling pathways, leading to reduced stem cell differentiation.
Abstract
Millions of people are exposed to arsenic through their drinking water and food, but the mechanisms by which it impacts embryonic development are not well understood. Arsenic [...]
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Interaction of p -benzoquinone with hemoglobin in smoker’s blood causes alteration of structure and loss of oxygen binding capacity
A. Ghosh, S. Banerjee, A. Mitra, M. Muralidharan, B. Roy, R. Banerjee, A. Mandal, I. Chatterjee

Toxicology Reports (2016). Vol. 3

Abstract
Cigarette smoke (CS) is an important source of morbidity and early mortality worldwide. Besides causing various life-threatening diseases, CS is also known to cause hypoxia. Chronic hypoxia would induce early aging and premature death. Continuation of smoking during pregnancy is a known risk for the unborn child. Although carbon monoxide (CO) is considered to be a cause of hypoxia, the effect of other component(s) of CS on hypoxia is not known. Here we show by immunoblots and mass spectra analyses that in smoker’s blood p -benzoquinone (p -BQ) derived from CS forms covalent adducts with cysteine 93 residues in both the β chains of hemoglobin (Hb) producing Hb-p -BQ adducts. UV–vis spectra and CD spectra analyses show that upon complexation with p -BQ the structure of Hb is altered. Compared to nonsmoker’s Hb, the content of α-helix decreased significantly in smoker’s Hb (p = 0.0224). p -BQ also induces aggregation of smoker’s Hb as demonstrated by SDS-PAGE, dynamic light scattering and atomic force microscopy. Alteration of Hb structure in smoker’s blood is accompanied by reduced oxygen binding capacity. Our results provide the first proof that p -BQ is a cause of hypoxia in smokers. We also show that although both p -BQ and CO are responsible for causing hypoxia in smokers, exposure to CO further affects the function over and above that produced by Hb-p -BQ adduct.
Abstract
Cigarette smoke (CS) is an important source of morbidity and early mortality worldwide. Besides causing various life-threatening diseases, CS is also known to cause hypoxia. [...]
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The possible role of intravenous lipid emulsion in the treatment of chemical warfare agent poisoning
A. Eisenkraft, A. Falk

Toxicology Reports (2016). Vol. 3

Abstract
Organophosphates (OPs) are cholinesterase inhibitors that lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and, without proper and early antidotal treatment, death. Most of these compounds are highly lipophilic. Sulfur mustard is a toxic lipophilic alkylating agent, exerting its damage through alkylation of cellular macromolecules (e.g., DNA, proteins) and intense activation of pro-inflammatory pathways. Currently approved antidotes against OPs include the peripheral anticholinergic drug atropine and an oxime that reactivates the inhibited cholinesterase. Benzodiazepines are used to stop organophosphate-induced seizures. Despite these approved drugs, efforts have been made to introduce other medical countermeasures in order to attenuate both the short-term and long-term clinical effects following exposure. Currently, there is no antidote against sulfur mustard poisoning. Intravenous lipid emulsions are used as a source of calories in parenteral nutrition. In recent years, efficacy of lipid emulsions has been shown in the treatment of poisoning by fat-soluble compounds in animal models as well as clinically in humans. In this review we discuss the usefulness of intravenous lipid emulsions as an adjunct to the in-hospital treatment of chemical warfare agent poisoning.
Abstract
Organophosphates (OPs) are cholinesterase inhibitors that lead to a characteristic toxidrome of hypersecretion, miosis, dyspnea, respiratory insufficiency, convulsions and, [...]
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Nrf2 activators as potential modulators of injury in human kidney cells
A. Atilano-Roque, X. Wen, L. Aleksunes, M. Joy

Toxicology Reports (2016). Vol. 3

Abstract
Cisplatin is a chemotherapeutic agent used in the treatment of solid tumors, with clinical use often complicated by kidney toxicity. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) is a transcription factor involved in kidney protectant effects. The purpose of this study was to determine whether the Nrf2 activators oltipraz, sulforaphane, and oleanolic acid could protect human kidney cells against cisplatin-induced injury and to compare the protective effects between three Nrf2 activators. Human proximal tubule cells (hPTC) and human embryonic kidney 293 cells (HEK293) were exposed to cisplatin doses in the absence and presence of Nrf2 activators. Pre- and delayed-cisplatin and Nrf2 activator exposures were also assessed. Cell viability was enhanced with Nrf2 activator exposures, with differences detected between pre- and delayed-treatments. Both sulforaphane and oltipraz increased the expression of anti-oxidant genes GCLC and NQO1. These findings suggest potential human kidney protective benefits of Nrf2 activators with planned exposures to cisplatin.
Abstract
Cisplatin is a chemotherapeutic agent used in the treatment of solid tumors, with clinical use often complicated by kidney toxicity. Nuclear factor (erythroid-derived-2)-like [...]
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Acute toxicity of herbicide (glyphosate) in Clarias gariepinus juveniles
A. Sani, M. Idris

Toxicology Reports (2016). Vol. 3

Abstract
The constant discharge of agricultural waste into aquatic environment has led to accumulation of heavy chemicals and other variety of pollutants. Herbicides present in these wastes are washed down, carried by rains and flood to nearby aquatic environment. Glyphosate is one of the most popular herbicides used by farmers in Kano because of its active reaction on killing weeds without affecting the crops. A toxicity test of glyphosate was conducted using concentrations of 0, 0.004, 0.005, 0.006, 0.007 ml/l. The mortality rate of each concentration was determined and the physicochemical parameters (Dissolved oxygen and pH) were also determined. The result showed that high mortality occurs at 0.007 ml/l and less mortality was found at 0.004 ml/l. Hence, mortality is dose dependent. DO and pH decreases with increase in glyphosate concentration. Furthermore, the juveniles showed abnormal behaviour. The LC50 value at 96 h was 0.0072 ml/l. There was significant difference between the initial and final pH value (p < 0.05). On the other hand, the initial and final DO values showed no significant difference (p > 0.05). However, correlation between DO and pH showed no significant difference (p > 0.05). The findings of this study established that glyphosate has some level of toxicity on Clarias gariepinus juveniles. In addition, it was found that mortality, changes in behaviour, DO and pH are dose dependent. Therefore, it was suggested that an appropriate concentration that will not be detrimental to non-target organisms should be used by farmers. Alternatively, Biological method should be used as a substitute for chemical method of controlling weeds.
Abstract
The constant discharge of agricultural waste into aquatic environment has led to accumulation of heavy chemicals and other variety of pollutants. Herbicides present in these [...]
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Vanillin abrogates ethanol induced gastric injury in rats via modulation of gastric secretion, oxidative stress and inflammation
A. Asmari, H. Shahrani, N. Masri, A. Faraidi, I. Elfaki, M. Arshaduddin

Toxicology Reports (2016). Vol. 3

Abstract
Vanillin is commonly used as an additive in food, medicine and cosmetics, but its effect has not yet been studied in gastric injury. Therefore the effect of vanillin was studied in experimental gastric ulcer. Gastric secretion and acidity were studied in pylorus ligated rats. Ulcer index, levels of gastric mucus, malondialdehyde (MDA), myeloperoxidase activity (MPO), expression of nuclear factor kappa B (NF-κB) p65, and histopathological changes were determined in ethanol induced gastric ulcer. Pre treatment with vanillin significantly reduced gastric secretion (P < 0.001) and acidity (P < 0.0001) and gastric ulcer index scores (P < 0.001). and augmented the gastric mucosal defense. Vanillin significantly restored the depleted gastric wall mucus levels (P < 0.0001) induced by ethanol and also significantly attenuated ethanol induced inflammation and oxidative stress by the suppression of gastric MPO activity (P < 0.001), reducing the expression of NF-κB p65 and the increased MDA levels (P < 0.001). Vanillin was also effective in alleviating the damage to the histological architecture and the activation of mast cells induced by ethanol. Together the results of this study highlight the gastroprotective activity of vanillin in gastric ulcers of rats through multiple actions that include inhibition of gastric secretion and acidity, reduction of inflammation and oxidative stress, suppression of expression of NF-κB, and restoration of the histological architecture.
Abstract
Vanillin is commonly used as an additive in food, medicine and cosmetics, but its effect has not yet been studied in gastric injury. Therefore the effect of vanillin was studied [...]
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