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Archives of Toxicology (v.86, #6)

Arsenic: an ancient toxicant of continuous public health impact, from Iceman Ötzi until now by Hermann M. Bolt (pp. 825-830).

Mercury-based traditional herbo-metallic preparations: a toxicological perspective by Sushant U. Kamath; Brindha Pemiah; Rajan K. Sekar; Sridharan Krishnaswamy; Swaminathan Sethuraman; Uma Maheswari Krishnan (pp. 831-838).

This review aims to explore the toxicological aspects of mercury-based herbo-metallic preparations like cinnabar and “Rasasindura” that are primarily composed of mercuric sulfide (HgS). Cinnabar-containing preparations have been used extensively in Indian and Chinese systems of medicine for treatment of chronic ailments like syphilis, high fever, pneumonia, insomnia, nervous disorders, deafness, and paralysis of the tongue. Contrary to Western medicine, which does not promote the use of mercury due to its toxic effects, Indian and Chinese traditional practitioners believe that mercury-based formulations have potent therapeutic efficacy, while there is no toxicity due to the unique and repeated purification processes employed during preparation. However, lack of proper pharmacovigilance and widespread self-medication has resulted in undesirable effects to certain sections of the consumers of these preparations, which have contributed to the negative publicity for these forms of medicine. Variations in the quality of the preparations coupled with the lack of understanding of the differences in the recommended dosages and treatment strategies adopted by traditional medicine practitioners, further fuels concerns in the Western world on the safety and efficacy of traditional medicine. But in spite of these concerns, concerted efforts to understand the biological interactions and transformations of these preparations are yet to gain momentum. Although scattered reports on the toxicity of these preparations are available in literature, their mechanism of action has not been conclusively established. Long-term pharmacotherapeutic and in-depth toxicity studies are needed to address the apprehensions raised by these herbo-metallic preparations. This review highlights the lacunae in the studies conducted thus far, and assesses the need for further studies to provide significant data to establish the safety and efficacy of such preparations, as well as develop gold standards for stringent quality control of these preparations.

Keywords: Mercury; Cinnabar; Rasasindura ; Mercuric sulfide; Herbo-metallic preparations

Co-occurrence of arseniasis and fluorosis due to indoor combustion of high fluorine and arsenic content coal in a rural township in northwest China: epidemiological and toxicological aspects by Guo-fang Lin; Shi-you Gong; Cheng Wei; Ji-gang Chen; Klaus Golka; Jian-hua Shen (pp. 839-847).

A large number of fluorosis and arseniasis cases appeared in a mountainous area in northwest China. The residents relied on local inferior coal (“bone coal”) of high fluorine and arsenic content for domestic heating and cooking. For deep-inside information about this rare case of co-endemia of fluorosis and arseniasis in the population in this special exposure scenario, a field investigation in one of the hyperendemic townships was conducted. The resident population registered (n = 27,713) was enrolled in the investigation. All cases were diagnosed and assigned to three symptom severity groups, that is severe, medium, and mild according to Chinese National Standard Criteria GB 16396-96 and to the technical guideline WS/T208-01 or WS/T211-01 issued by the Chinese Ministry of Health. Gender difference was analyzed by standardized incidence ratio. Age trend and severity trend were tested by χ² analysis. Fluorosis was diagnosed in 56.7% of the residents. Over 95% of the diagnosed arseniasis cases were simultaneously diagnosed with fluorosis symptoms. Combined fluorosis-arseniasis represented 11.9% of the total fluorosis cases and 6.7% of the local population. No gender-related differences in the prevalence of skeletal, dental, or dermal symptoms inside all severity groups were detected. Symptom severity increased with age. The high frequency of superposition of arseniasis with fluorosis might be due to the fact that the local resident population has been exposed to very high levels of fluorine and arsenic via the same exposure route.

Keywords: Endemia; Arseniasis; Fluorosis; Indoor combustion; Coal

Inflammatory responses induced by fluoride and arsenic at toxic concentration in rabbit aorta by Yanqin Ma; Ruiyan Niu; Zilong Sun; Jinming Wang; Guangying Luo; Jianhai Zhang; Jundong Wang (pp. 849-856).

Epidemiological and experimental studies have demonstrated the atherogenic effects of environmental toxicant arsenic and fluoride. Inflammatory mechanism plays an important role in the pathogenesis of atherosclerosis. The aim of the present study is to determine the effect of chronic exposure to arsenic and fluoride alone or combined on inflammatory response in rabbit aorta. We analyzed the expression of genes involved in leukocyte adhesion [P-selectin (P-sel) and vascular cell adhesion molecule-1(VCAM-1)], recruitment and transendothelial migration of leukocyte [interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1)] and those involved in pro-inflammatory cytokines [interleukin-6 (IL-6)]. We found that fluoride and arsenic alone or combined increased the expression of VCAM-1, P-sel, MCP-1, IL-8, and IL-6 at the RNA and protein levels. The gene expressions of inflammatory-related molecules were attenuated when co-exposure to the two toxicants compared with just one of them. We also examined the lipid profile of rabbits exposed to fluoride and (or) arsenic. The results showed that fluoride slightly increased the serum lipids but arsenic decreased serum triglyceride. We showed that inflammatory responses but not lipid metabolic disorder may play a crucial role in the mechanism of the cardiovascular toxicity of arsenic and fluoride.

Keywords: Inflammatory responses; Atherosclerosis; Arsenic; Fluoride

Association of glutathione S-transferase Ω 1-1 polymorphisms (A140D and E208K) with the expression of interleukin-8 (IL-8), transforming growth factor beta (TGF-β), and apoptotic protease-activating factor 1 (Apaf-1) in humans chronically exposed to arsenic in drinking water by D. M. Escobar-García; L. M. Del Razo; L. C. Sanchez-Peña; P. B. Mandeville; C. Lopez-Campos; Claudia Escudero-Lourdes (pp. 857-868).

Human exposure to arsenicals is associated with inflammatory-related diseases including different kinds of cancer as well as non-cancerous diseases like neuro-degenerative diseases, atherosclerosis, hypertension, and diabetes. Interindividual susceptibility has been mainly addressed by evaluating the role of genetic polymorphism in metabolic enzymes in inorganic arsenic (iAs) metabolism. Glutathione S-transferase omega 1-1 (GSTO1-1), which had been associated with iAs metabolism, is also known to participate in inflammatory and apoptotic cellular responses. The polymorphism A140D of GSTO1-1 has been not only associated with distinct urinary profile of arsenic metabolites in populations chronically exposed to iAs in drinking water, but also with higher risk of childhood leukemia and lung disease in non-exposed populations, suggesting that GSTO1-1 involvement in other physiologic processes different from toxics metabolism could be more relevant than is thought. We evaluated the association of the presence of A140D and E208K polymorphisms of GSTO1-1 gene with the expression of genes codifying for proteins involved in the inflammatory and apoptotic response in a human population chronically exposed to iAs through drinking water. A140D polymorphism was associated with higher expression of genes codifying for IL-8 and Apaf-1 mainly in heterozygous individuals, while E208K was associated with higher expression of IL-8 and TGF-β gene, in both cases, the association was independently of iAs exposure level; however, the exposure to iAs increased slightly but significantly the influence of A140D and E208K polymorphisms on such genes expression. These results suggest an important role of GSTO1-1 in the inflammatory response and the apoptotic process and indicate that A140D and E208K polymorphisms could increase the risk of developing inflammatory and apoptosis-related diseases in As-exposed populations.

Keywords: GSTO1-1; Polymorphisms; A140D; E208K; Arsenic; Inflammation; Apoptosis

Elevated risk of hypertension induced by arsenic exposure in Taiwanese rural residents: possible effects of manganese superoxide dismutase (MnSOD) and 8-oxoguanine DNA glycosylase (OGG1) genes by Shiuan-Chih Chen; Chun-Chieh Chen; Chung-Yih Kuo; Chun-Huang Huang; Chin-Hsiu Lin; Zi-Yun Lu; Yi-Yu Chen; Hong-Shen Lee; Ruey-Hong Wong (pp. 869-878).

Heavy metals, including arsenic and lead, may lead to cellular oxidative damage that is linked to hypertension. Manganese superoxide dismutase (MnSOD) is a scavenger of reactive oxygen species, and 8-oxoguanine DNA glycosylase (OGG1) is the major glycosylase that repairs DNA lesions. Interestingly, whether there is an elevated risk of hypertension with arsenic or lead exposure in individuals with genetic variations in MnSOD or OGG1 has not yet been investigated. Questionnaires were administered to 240 Taiwanese rural residents. Blood pressure and biochemical indicators were assessed in each subject. Urinary levels of arsenic and lead were measured with atomic absorption spectrometry; and MnSOD and OGG1 genotypes were identified via polymerase chain reaction. There was a dose–response relationship between urinary arsenic levels and risk of hypertension (P = 0.021, test for trend). However, there was no association between urinary lead levels and hypertension risk. Individuals with high urinary arsenic levels and the MnSOD Val–Ala/Ala–Ala genotypes had a greater risk of hypertension than those with low urinary arsenic levels and the MnSOD Val–Val genotype (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 1.7–10.3). Subjects with a high urinary arsenic level and the OGG1 Cys–Cys genotype also had a greater risk of hypertension than those with a low urinary arsenic level and the OGG1 Ser–Ser/Ser–Cys genotypes (OR = 3.4, 95% CI = 1.1–10.7). Thus, both MnSOD and OGG1 genotypes may be prone to an increased risk of hypertension associated with arsenic exposure.

Keywords: Hypertension; Arsenic; Lead; MnSOD gene; OGG1 gene

Arsenic modulates heme oxygenase-1, interleukin-6, and vascular endothelial growth factor expression in endothelial cells: roles of ROS, NF-κB, and MAPK pathways by Lisu Wang; Mei-Chun Kou; Ching-Yi Weng; Ling-Wei Hu; Ying-Jan Wang; Ming-Jiuan Wu (pp. 879-896).

Chronic arsenic exposure has been linked to an increased risk of vascular diseases. To clarify the molecular mechanisms through which arsenic causes injuries to blood vessels, we analyzed the effects of arsenic trioxide on the cytotoxicity, intracellular reactive oxygen species (ROS), the expression of related genes, and signaling pathways involved in the SVEC4-10 mouse endothelial cells. Arsenic dose-dependently caused SVEC4-10 cell death, which is completely inhibited by α-lipoic acid (LA), a thioreductant, but partially ameliorated by Tiron, a potent superoxide scavenger. The mRNA levels of heme oxygenase-1 (HO-1), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) were significantly increased by arsenic. The up-regulation of these can be blocked by LA instead of Tiron, suggesting ROS is not important in their increase. HO-1 competitive inhibitor zinc protoporphyrin improved the cytotoxicity of arsenic in an inverted-U dose–response curve, indicating the biphasic hormetic effect of HO-1. HO-1 siRNA decreased VEGF expression in response to arsenic. Arsenic exposure also enhanced NF-E2-related factor 2 (Nrf2) expression and increased activation of nuclear factor-κB (NF-κB). NF-κB inhibitor Bay 11-7082 reduced arsenic-mediated expression of HO-1 and IL-6. Selective blocking of the MAPK pathways with p38 inhibitor SB203580 significantly decreased arsenic-induced HO-1 and VEGF expression, while JNKs inhibitor SP600125 increased IL-6 expression. These results suggest that in arsenic-treated SVEC4-10 cells, HO-1 expression is mediated through Nrf2-, NF-κB-, and p38 MAPK-dependent signaling pathways and serves as an upstream regulator of VEGF. IL-6 expression is regulated by NF-κB and JNKs. In conclusion, oxidative stress may be associated with arsenic-induced cytotoxicity and endothelial gene up-regulation, but signaling transduction dominates the direct effects of ROS.

Keywords: Arsenic; α-Lipoic acid; HO-1; IL-6; VEGF; MAPK

Differential modulation of aryl hydrocarbon receptor regulated enzymes by arsenite in the kidney, lung, and heart of C57BL/6 mice by Anwar Anwar-Mohamed; Ghada Abdelhamid; Issa E. A. Amara; Ayman O. S. El-Kadi (pp. 897-910).

During the last couple of decades, efforts have been made to study the toxic effects of individual aryl hydrocarbon receptors (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or heavy metals typified by arsenic As(III). However, little is known about the combined toxic effects of TCDD and As(III) in vivo. Previous reports from our laboratory and others have demonstrated that As(III), by itself or in the presence of AhR ligands, such as TCDD, is capable of differentially altering the expression of various phase I and phase II AhR-regulated genes in in vitro systems. Thus, the objective of the current study was to investigate whether or not similar effects would occur at the in vivo level. Therefore, we examined the effect of exposure to As(III) (12.5 mg/kg) in the absence and presence of TCDD (15 μg/kg) on the AhR-regulated genes using C57Bl/6 mice. Our results demonstrated that As(III) alone inhibited Cyp1a1 and Cyp1a2 in the kidney, while it induced their levels in the lung and did not affect their mRNA levels in the heart. As(III) also induced Nqo1 and Gsta1 in all tested tissues. Upon co-exposure to As(III) and TCDD, As(III) inhibited the TCDD-mediated induction of Cyp1a1 in the kidney and heart, Cyp1a2 in the kidney and heart, while it potentiated TCDD-mediated induction of Cyp1a1 in the lung, and Nqo1 and Gsta1 in the kidney and lung. In conclusion, the present study demonstrates for the first time that As(III) modulates constitutive and TCDD-induced AhR-regulated genes in a time-, tissue-, and AhR-regulated enzyme-specific manner.

Keywords: AhR; Arsenite; Cyp1a1; Cyp1a2; Nqo1; Gsta1

Characterization of the role of protein–cysteine residues in the binding with sodium arsenite by Yu-Ying Chang; Tai-Chih Kuo; Chun-Hua Hsu; Duen-Ren Hou; Yung-Hsi Kao; Rong-Nan Huang (pp. 911-922).

To better characterize the interaction of protein–cysteines with sodium arsenite, arsenic-binding proteins were identified from the arsenic-resistant Chinese hamster ovary cell line SA7 using a p-aminophenylarsine oxide (PAO)-agarose matrix in combination with proteomic techniques. Twenty of the isolated arsenic-binding proteins were further peptide-mapped by MALDI-Q-TOF-MS. The binding capacity of PAO-agarose-retained proteins was then verified by re-applying Escherichia coli overexpressed recombinant proteins with various numbers of cysteine residues onto the PAO-agarose matrix. The results showed that recombinant heat shock protein 27 (HSP27, with one cysteine residue), reticulocalbin-3 (RCN3, with no cysteine residue), galectin-1 (GAL1, with six cysteine residues), but not peroxiredoxin 6 (Prdx6, with one cysteine residue but not retained by the PAO-agarose matrix), were bound to the PAO-agarose matrix. The six free cysteine residues in GAL1 were individually or double-mutated to alanine by means of site-directed mutagenesis and subjected to CD and ICP-MS analysis. The binding capacity of GAL1 for sodium arsenite was significantly attenuated in C16A, C88A and all double mutant clones. Taken together, our current data suggest that the cysteine residues in GAL1 may play a critical role in the binding of arsenic, but that in the case of RCN3 and Prdx6, this interaction may be mediated by other factors.

Keywords: Sodium arsenite; Arsenic-binding protein; Galectin-1; Heat shock protein 27; Reticulocalbin-3

Arsenic induces apoptosis in myoblasts through a reactive oxygen species-induced endoplasmic reticulum stress and mitochondrial dysfunction pathway by Yuan-Peng Yen; Keh-Sung Tsai; Ya-Wen Chen; Chun-Fa Huang; Rong-Sen Yang; Shing-Hwa Liu (pp. 923-933).

A pool of myoblasts available for myogenesis is important for skeletal muscle size. The decreased number of skeletal muscle fibers could be due to the decreased myoblast proliferation or cytotoxicity. Identification of toxicants that regulate myoblast apoptosis is important in skeletal muscle development or regeneration. Here, we investigate the cytotoxic effect and its possible mechanisms of arsenic trioxide (As₂O₃) on myoblasts. C2C12 myoblasts underwent apoptosis in response to As₂O₃ (1–10 μM), accompanied by increased Bax/Bcl-2 ratio, decreased mitochondria membrane potential, increased cytochrome c release, increased caspase-3/-9 activity, and increased poly (ADP-ribose) polymerase (PARP) cleavage. Moreover, As₂O₃ triggered the endoplasmic reticulum (ER) stress indentified through several key molecules of the unfolded protein response, including glucose-regulated protein (GRP)-78, GRP-94, PERK, eIF2α, ATF6, and caspase-12. Pretreatment with antioxidant N-acetylcysteine (NAC, 0.5 mM) dramatically suppressed the increases in reactive oxygen species (ROS), lipid peroxidation, ER stress, caspase cascade activity, and apoptosis in As₂O₃ (10 μM)-treated myoblasts. Furthermore, As₂O₃ (10 μM) effectively decreased the phosphorylation of Akt, which could be reversed by NAC. Over-expression of constitutive activation of Akt (c.a. Akt) also significantly attenuated As₂O₃-induced myoblast apoptosis. Taken together, these results suggest that As₂O₃ may exert its cytotoxicity on myoblasts by inducing apoptosis through a ROS-induced mitochondrial dysfunction, ER stress, and Akt inactivation signaling pathway.

Keywords: Arsenic; Myoblasts; Apoptosis; Reactive oxygen species

NADPH oxidase-produced superoxide mediates EGFR transactivation by c-Src in arsenic trioxide-stimulated human keratinocytes by Hong-Yu Tseng; Zi-Miao Liu; Huei-Sheng Huang (pp. 935-945).

Arsenic is a well-known poison and carcinogen in humans. However, it also has been used to effectively treat some human cancers and non-carcinogenic ailments. Previously, we demonstrated in keratinocytes that arsenic trioxide (ATO)-induced p21 WAF1/CIP1 (p21) expression leading to cellular cytotoxicity through the c-Src/EGFR/ERK pathway and generation of reactive oxygen species (ROS). In this study, we found that EGFR-Y845 and EGFR-Y1173 could be phosphorylated by ATO. Using confocal microscopy and flow cytometry, we found that pretreatment with apocynin, DPI, and tiron could remove ATO-induced ROS production. Furthermore, to increase NADPH oxidase activity, ATO could induce cytosolic p67 phox expression and translocation to membrane. In addition, knockdown of p67 phox could abolish ATO-induced ROS production. Therefore, we suggest that NADPH oxidase-produced superoxide was a major source of ATO-induced ROS production. Conversely, ATO-induced NADPH oxidase activation and superoxide generation could be inhibited by the c-Src inhibitor PP1, but not by the EGFR inhibitor PD153035. In addition, overexpression of c-Src as well as treatment with ATO could stimulate EGFR-Y845/ERK phosphorylation, p21 expression, and cellular arrest/apoptosis, which could be attenuated by pretreatment with apocynin or knockdown of p67 phox. Collectively, we suggest that NADPH oxidase was involved in the ATO-induced arrest/apoptosis of keratinocytes, which was regulated by c-Src activation.

Keywords: Arsenic trioxide; Psoriasis; ROS; NADPH oxidase; Superoxide

Blockade of p53 by HIF-2α, but not HIF-1α, is involved in arsenite-induced malignant transformation of human bronchial epithelial cells by Yuan Xu; Yuan Li; Ying Pang; Min Ling; Lu Shen; Rongrong Jiang; Yue Zhao; Jianwei Zhou; Xinru Wang; Qizhan Liu (pp. 947-959).

Hypoxia-inducible factors (HIFs), which consist of α and β subunits, are transcription factors involved in regulation of a variety of cellular functions. By blocking the function of the tumor suppressor p53, over-expressions of HIFs are linked to carcinogenesis and tumor progression. Inorganic arsenic, a ubiquitous environmental contaminant, is associated with an increased risk of cancer. Although there are several hypotheses regarding arsenic-induced carcinogenesis, the mechanism of action remains obscure. We have shown that long-term exposure of human bronchial epithelial (HBE) cells to a low level of arsenite increases their proliferation rate and anchorage-independent growth. When introduced into nude mice, the transformed cells are tumorigenic. The present report demonstrates that, with increased time of exposure to arsenite, there is more increased expression of HIF-2α, but not HIF-1α. These factors are known to have different functions, and, in some cases, opposite effects. Arsenite induces accumulation of HIF-2α by inhibiting its degradation through the ubiquitin-mediated proteasome pathway. HIF-2α knockdown, but not HIF-1α knockdown, increases the activation of p53. Finally, inhibition of HIF-2α blocks arsenite-induced proliferation and malignant transformation. Thus, our studies show that blockade of p53 function by inhibiting the ubiquitin-mediated proteasome degradation of HIF-2α, but not that of HIF-1α, is involved in arsenite-induced proliferation and neoplastic transformation of HBE cells.

Keywords: Hypoxia-inducible factor-2α; Hypoxia-inducible factor-1α; p53 function; Tumorigenesis; Arsenite

Barium inhibits arsenic-mediated apoptotic cell death in human squamous cell carcinoma cells by Ichiro Yajima; Noriyuki Uemura; Saika Nizam; Md. Khalequzzaman; Nguyen D. Thang; Mayuko Y. Kumasaka; Anwarul A. Akhand; Hossain U. Shekhar; Tamie Nakajima; Masashi Kato (pp. 961-973).

Our fieldwork showed more than 1 μM (145.1 μg/L) barium in about 3 μM (210.7 μg/L) arsenic-polluted drinking well water (n = 72) in cancer-prone areas in Bangladesh, while the mean concentrations of nine other elements in the water were less than 3 μg/L. The types of cancer include squamous cell carcinomas (SCC). We hypothesized that barium modulates arsenic-mediated biological effects, and we examined the effect of barium (1 μM) on arsenic (3 μM)-mediated apoptotic cell death of human HSC-5 and A431 SCC cells in vitro. Arsenic promoted SCC apoptosis with increased reactive oxygen species (ROS) production and JNK1/2 and caspase-3 activation (apoptotic pathway). In contrast, arsenic also inhibited SCC apoptosis with increased NF-κB activity and X-linked inhibitor of apoptosis protein (XIAP) expression level and decreased JNK activity (antiapoptotic pathway). These results suggest that arsenic bidirectionally promotes apoptotic and antiapoptotic pathways in SCC cells. Interestingly, barium in the presence of arsenic increased NF-κB activity and XIAP expression and decreased JNK activity without affecting ROS production, resulting in the inhibition of the arsenic-mediated apoptotic pathway. Since the anticancer effect of arsenic is mainly dependent on cancer apoptosis, barium-mediated inhibition of arsenic-induced apoptosis may promote progression of SCC in patients in Bangladesh who keep drinking barium and arsenic-polluted water after the development of cancer. Thus, we newly showed that barium in the presence of arsenic might inhibit arsenic-mediated cancer apoptosis with the modulation of the balance between arsenic-mediated promotive and suppressive apoptotic pathways.

Keywords: Anticancer effects; Arsenic; Barium; Apoptosis; XIAP

Tumors and proliferative lesions in adult offspring after maternal exposure to methylarsonous acid during gestation in CD1 mice by Erik J. Tokar; Bhalchandra A. Diwan; David J. Thomas; Michael P. Waalkes (pp. 975-982).

Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the biological methylation of inorganic arsenic, could be a key carcinogenic species. Thus, pregnant CD1 mice were provided drinking water containing MMA3+ at 0 (control), 12.5, or 25 parts per million (ppm) from gestational days 8 to 18. Tumors were assessed in groups of male or female (initial n = 25) offspring up to 2 years of age. In utero treatment had no effect on survival or body weights. Female offspring exhibited increases in total epithelial uterine tumors (control 0%; 12.5 ppm 26%; 25 ppm 30%), oviduct hyperplasia (control 4%; 12.5 ppm 35%; 25 ppm 43%), adrenal cortical adenoma at 25 ppm (control 0%; 12.5 ppm 9%; 25 ppm 26%), and total epithelial ovarian tumors (control 0%; 12.5 ppm 39%; 25 ppm 26%). Male offspring showed dose-related increases in hepatocellular carcinoma (control 0%; 12.5 ppm 12%; 25 ppm 22%), adrenal adenoma (control 0%; 12.5 ppm 28%; 25 ppm 17%), and lung adenocarcinoma (control 17%; 12.5 ppm 44%). Male offspring had unusual testicular lesions, including two rete testis carcinomas, two adenomas, and three interstitial cell tumors. Overall, maternal consumption of MMA3+ during pregnancy in CD1 mice produced some similar proliferative lesions as gestationally applied inorganic arsenic in the offspring during adulthood.

Keywords: Methylated arsenical; Carcinogenesis; Mice; Transplacental exposure

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Archives of Toxicology (v.86, #6)