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Arsenic is a common environmental and occupational pollutant and a well-known human carcinogen that causes cancers in many human organs. The exact molecular mechanisms of arsenic carcinogenesis, however, are not well understood. It is generally acknowledged that arsenic does not act via a classic genotoxic or mutagenic mechanism, because it is not a direct mutagen. On the other hand, a growing amount of evidence has shown that arsenic shares many properties with tumor promoters by inducing intracellular signal transduction, activating transcription factors, and changing the expression of genes that are involved in promoting cell growth, proliferation, and malignant transformation. It is postulated that arsenic-induced mitogen-activated protein kinases (MAPKs) signal transduction, which leads to activation of transcription factors such as activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB) (which in turn alter gene expression), is associated with the carcinogenicity of arsenic. In this article, we review the recent findings in arsenic-induced MAPKs, AP-1 and NF-kappaB activation, and aberrant gene expression; their implications in arsenic carcinogenesis are discussed. The elucidation of arsenic-induced signal transduction pathways that lead to aberrant gene expression involved in the arsenic-triggered malignant transformation could help to identify novel molecular targets for the treatment of human cancers resulting from arsenic exposure.
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PMID:Arsenic-mediated cellular signal transduction, transcription factor activation, and aberrant gene expression: implications in carcinogenesis. 1251 Sep 62

Arsenic is well established as a human carcinogen, but its precise mechanism of action remains unknown. Arsenic does not directly damage DNA, but may act as a carcinogen through inhibition of DNA repair mechanisms, leading indirectly to increased mutations from other DNA damaging agents. The molecular mechanism underlying arsenic inhibition of nucleotide excision repair after UV irradiation (Hartwig et al., Carcinogenesis 1997;18:399-405) is unknown, but could be due to decreased expression of critical genes involved in nucleotide excision repair of damaged DNA. This hypothesis was tested by analyzing expression of repair genes and arsenic exposure in a subset of 16 individuals enrolled in a population based case-control study investigating arsenic exposure and cancer risk in New Hampshire. Toenail arsenic levels were inversely correlated with expression of critical members of the nucleotide excision repair complex, ERCC1 (r(2) = 0.82, p < 0.0001), XPF (r(2) = 0.56, p < 0.002), and XPB (r(2) = 0.75, p < 0.0001). The internal dose marker, toenail arsenic level, was more strongly associated with changes in expression of these genes than drinking water arsenic concentration. Our findings, based on human exposure to arsenic in a US population, show an association between biomarkers of arsenic exposure and expression of DNA repair genes. Although our findings need verification in a larger study group, they are consistent with the hypothesis that inhibition of DNA repair capacity is a potential mechanism for the co-carcinogenic activity of arsenic.
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PMID:Decreased DNA repair gene expression among individuals exposed to arsenic in United States drinking water. 1256 48

Arsenic is a known human carcinogen, but development of rodent models of inorganic arsenic carcinogenesis has been problematic. Since gestation is often a period of high sensitivity to chemical carcinogenesis, we performed a transplacental carcinogenicity study in mice using inorganic arsenic. Groups (n = 10) of pregnant C3H mice were given drinking water containing sodium arsenite (NaAsO(2)) at 0 (control), 42.5, and 85 ppm arsenite ad libitum from day 8 to 18 of gestation. These doses were well tolerated and body weights of the dams during gestation and of the offspring subsequent to birth were not reduced. Dams were allowed to give birth, and offspring were weaned at 4 weeks and then put into separate gender-based groups (n = 25) according to maternal exposure level. The offspring received no additional arsenic treatment. The study lasted 74 weeks in males and 90 weeks in females. A complete necropsy was performed on all mice and tissues were examined by light microscopy in a blind fashion. In male offspring, there was a marked increase in hepatocellular carcinoma incidence in a dose- related fashion (control, 12%; 42.5 ppm, 38%; 85 ppm, 61%) and in liver tumor multiplicity (tumors per liver; 5.6-fold over control at 85 ppm). In males, there was also a dose-related increase in adrenal tumor incidence and multiplicity. In female offspring, dose-related increases occurred in ovarian tumor incidence (control, 8%; 42.5 ppm, 26%; 85 ppm, 38%) and lung carcinoma incidence (control, 0%; 42.5 ppm, 4%; 85 ppm, 21%). Arsenic exposure also increased the incidence of proliferative lesions of the uterus and oviduct. These results demonstrate that oral inorganic arsenic exposure, as a single agent, can induce tumor formation in rodents and establishes inorganic arsenic as a complete transplacental carcinogen in mice. The development of this rodent model of inorganic arsenic carcinogenesis has important implications in defining the mechanism of action for this common environmental carcinogen.
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PMID:Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. 1258 88

DNA methylation and histone modification promote changes in chromatin structure that may affect gene expression in a heritable manner without directly altering the genome. As such, these phenomena are considered to be epigenetic in nature and are believed to contribute to the normal processes of human development but also to aberrant disease states such as cancer. Epigenetic processes probably contribute mechanistically to toxicant-induced changes in gene expression and cancer. Nickel is a potent human carcinogen that has been shown to alter DNA methylation patterns and affect histone acetylation status. Both of these changes are associated with the proximity of the affected regions to heterochromatin. The two processes probably occur in concert in mammalian cells. However, in yeast cells, DNA methylation is absent, and nickel is capable of regulating gene expression through changes in acetylation of the lysine residues in the N terminal tail of histone H4. Arsenic is another important environmental carcinogen, and it is methylated during its metabolism. Hence, it has been proposed that arsenic metabolism may deplete intracellular methyl group stores and thereby lead to changes in DNA methylation that may be involved in carcinogenesis. However, the data concerning DNA methylation changes following arsenic exposure are equivocal, leading researchers to propose that DNA hypo- and hypermethylation are both important in the development of arsenic-induced cancers. Heightened awareness by toxicologists of the importance of epigenetics in normal human development and in carcinogenesis should lead to the identification of other toxicants that manifest their effects, at least in part, via epigenetic mechanisms.
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PMID:Epigenetics and the environment. 1272 20

Roxarsone is a veterinary drug used as a growth promoter and as an anticoccidial agent and for treatment of swine dysentery. Toxicology and carcinogenesis studies were conducted by administering roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, the diets fed to rats contained 0 or 100-1,600 ppm roxarsone, and those fed to mice contained 0 or 60-1,000 ppm. Deaths occurred in rats and mice that received the highest doses. Rats that received 800 or 1,600 ppm lost weight. Male mice that received 1,000 ppm and female mice that received 500 ppm lost weight. In the first 13-week studies, roxarsone was fed to rats and mice at dietary concentrations of 0 or 50-800 ppm. Decreases (more than 10%) in final mean body weights of dosed rats relative to those of controls were observed for males that received 200, 400, or 800 ppm and for females that received 400 or 800 ppm. Deaths occurred in groups that received 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats that received 800 ppm. Kidney lesions were observed in rats that received 800 ppm. These lesions were characterized by tubular necrosis and mineralization in the rats that died during the studies and by tubular dilatation and casts, interstitial inflammation, and tubular epithelial cell regeneration in the rats that lived to the end of the studies. Additional 13-week studies were conducted in rats at dietary concentrations of 0, 100, or 400 ppm to demonstrate the absorption of roxarsone from the gastrointestinal tract; to determine its distribution in liver, kidney, and blood; and to study its effects on various hematologic and clinical chemical values. No deaths occurred. Renal lesions of minimal severity observed in male rats that received 400 ppm were characterized by tubular epithelial cell degeneration and regeneration, tubular casts, and mineralization. Arsenic levels in urine, blood, kidney, and liver of dosed rats increased (140%-300%) with time on study and were proportional to the dietary concentrations of roxarsone. No compound-related hematologic or clinical chemical effects were observed in rats. In the first 13-week studies, final mean body weights of mice that received 800 ppm were 11%-18% lower than those of controls. Deaths occurred in males and females receiving 400 and 800 ppm. No compound-related gross or histopathologic lesions were observed. In the second 13-week studies in mice, no compound-related hematologic or clinical chemical effects were observed. At the end of the studies, arsenic concentrations in dosed mice ranged from 0.45 to 0.99 ug/g of liver and from 0.85 to 2.98 ug/g of kidney. No arsenic was detected in the liver or kidney of control mice. Because of kidney lesions, lower body weight gain, and increased mortality in rats and lower body weight gain and increased mortality in mice in the short-term studies, dietary concentrations of roxarsone selected for the 2-year studies were 0, 50, or 100 ppm for rats and 0, 100, or 200 ppm for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were generally within 5% of those of controls. No significant differences in survival were observed between any groups of rats of either sex, although survival in males was lower than usual (final survival--male: control, 24/50; low dose, 18/50; high dose, 18/50; female: 27/50; 35/50; 32/50). The average feed consumption by high dose rats was 95% that of controls for males and 88% for females. The average amount of roxarsone consumed per day was approximately 2 mg/kg for low dose rats and 4 mg/kg for high dose rats. Mean body weights of high dose male mice were generally 5%-8% higher than those of the controls, whereas those of female mice were generally 6%-15% lower than those of the controls. The survival of the control group of male mice was lower than that of the low dose group after month 22; survival for females was low (final survir than that of the low dose group after month 22; survival for females was low (final survival--male: 27/50; 40/50; 33/50; female: 14/50; 18/50; 17/50). The low survival in females was due in part to utero-ovarian infection, with more than 50&percnt; of the animals in each dose group having suppurative inflammation at this site. The average daily feed consumption by dosed mice was 105&percnt;-110&percnt; that by the controls. The average amount of roxarsone consumed per day was approximately 21 or 43 mg/kg for low dose or high dose male mice and 27 or 54 mg/kg for low dose or high dose female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Although the incidence of adenomas of the exocrine pancreas in high dose male rats was not statistically greater than that in the controls (control, 1/50; low dose, 1/50; high dose, 5/50), it was greater than that seen in any historical control group of male F344/N rats. The historical rate is 1/437 (0.2&percnt;) for the study laboratory and 5/1,871 (0.3&percnt;) throughout the Program. The incidences of hyperplasia were 2/50; 0/50; 3/50. No hyperplasia oradenomas were observed in the exocrine pancreas of female rats. Clitoral gland adenomas in female rats occurred with a marginally positive trend (1/44; 3/47; 6/48; P=0.049). One carcinoma was also observed in each of the groups. The incidences of adenomas or of adenomas or carcinomas (combined) in the dosed groups were not significantly different from those in the controls. This marginal effect was not considered to be related to roxarsone administration. No chemical-related increases in neoplastic or nonneoplastic lesions occurred in male or female mice. Lymphomas in female mice occurred with a negative trend; the incidences in the dosed groups were lower than that in the controls (13/50; 2/50; 3/50; P≤0.01). Genetic Toxicology: Roxarsone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. Roxarsone induced trifluorothymidine (Tft) resistance in mouse lymphoma L5178Y cells in the absence of metabolic activation; it was not tested with activation. Exposure of adult male Drosophila melanogaster to roxarsone by injection or by feeding did not cause an increase in sex--linked recessive lethal mutations. Audit: The data, documents, and pathology materials from the 2-year studies of roxarsone have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of roxarsone for male F344/N rats, as indicated by a marginally increased incidence of adenomas of the exocrine pancreas. There was no evidence of carcinogenic activity for female F344/N rats fed diets containing 50 or 100 ppm roxarsone for 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 100 or 200 ppm roxarsone for 2 years. Synonyms: 4-hydroxy-3-nitrophenylarsonic acid; 4-hydroxy-3-nitrobenzenearsonic acid; 2-nitro-1-hydroxybenzene-4-arsonic acid; nitrophenolarsonic acid; 3-nitro-4-hydroxybenzenearsonic acid; 3-nitro-4-hydroxyphenylarsonic acid Trade Names: Ristat; Ren-O-sal; 3-nitro; 3-nitro-10; 3-nitro-20; 3-nitro-50; 3-nitro-80
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PMID:NTP Toxicology and Carcinogenesis Studies of Roxarsone (CAS No. 121-19-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1272 87

The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an anti-tumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome end-to-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.
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PMID:Oxidative stress contributes to arsenic-induced telomere attrition, chromosome instability, and apoptosis. 1276 76

Previous studies demonstrated that tobacco and arsenic exposure are risk factors for bladder cancer. A case-case study was conducted to compare p53 mutations in 147 bladder tumors from South American patients by tobacco and arsenic exposure. Information on residential history and lifestyle factors was collected. The prevalence of p53 mutations and protein expression was examined in relation to tumor stage, grade, patient age, gender, tobacco and arsenic exposure. Smokers were grouped as ever/never smokers and by pack years of exposure (0, 1-20, >20). Patients were also grouped into four arsenic exposure categories based on the average of the five highest years arsenic concentration in their drinking water: group 1, non-detectable to <10 microg/l (n = 50); group 2, 10-99 microg/l (n = 31); group 3, 100-299 microg/l (n = 35); group 4, >300 microg/l (n = 30). The proportion of tumor samples with p53 mutations and P53 immunopositivity increased strongly with both stage and grade, but not with arsenic exposure or smoking. The prevalence of tumors containing mutational transitions increased markedly with tumor stage (from 14 to 52%, P(trend) = 0.005) and grade (from 11 to 48%, P(trend) = 0.004) and was higher in smokers than in non-smokers (34 versus 18%, respectively, P = 0.10). An increasing trend was observed with pack years of smoking (P = 0.09). The majority of mutations in tumors from both smokers and non-smokers were G-->A transitions, however, in smokers a preference for G-->A transitions at CpG sites was observed (P = 0.07, two-tailed) and a positive trend was observed with pack years of exposure (P = 0.04). A hotspot was found at codon 273 in 12% of the tumors from smokers but was not observed in never smokers (P = 0.05) and a positive trend was observed with pack years of tobacco exposure (P = 0.001). Neither stage nor grade demonstrated a preference for CpG site mutation, suggesting that these changes may be early exposure-related events in carcinogenesis and are not related to tumor progression. Arsenic exposure was not associated with an increased prevalence of p53 mutation or P53 immunopositivity and there was no evidence of interaction between arsenic and smoking with these outcome variables.
Carcinogenesis 2003 Nov
PMID:P53 alterations in bladder tumors from arsenic and tobacco exposed patients. 1291 57

Telomeres are critical in maintaining chromosome and genomic stability. Arsenic, a human carcinogen as well as an anticancer agent, is known for its clastogenicity. To better understand molecular mechanisms of arsenic actions, we investigated arsenite effects on telomere and telomerase and determined cell growth and apoptosis in HL-60 and HaCaT cells in vitro. Low concentrations (0.1-1 microM in HaCaT and 0.1-0.5 microM in HL-60) of arsenite increased telomerase activity, maintained or elongated telomere length, and promoted cellular proliferation. High concentrations (>1-40 microM) of arsenite decreased telomerase activity, telomere length and induced apoptosis. Results from the studies comparing cell lines with and without telomerase activity suggested that telomerase was involved in arsenic-induced apoptosis. The spin trap agent, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) was effective in protecting the arsenite-induced telomere attrition and apoptosis, suggesting that reactive oxygen species may play an important role in the shortening of telomeres and apoptosis induced by arsenic. These findings suggest the carcinogenic effects of arsenic may be partly attributed to increase in telomerase activity leading to promotion of cell proliferation and its anticancer effects by exerting oxidative stress and leading to telomeric DNA attrition and apoptosis.
Carcinogenesis 2003 Nov
PMID:Effects of arsenic on telomerase and telomeres in relation to cell proliferation and apoptosis in human keratinocytes and leukemia cells in vitro. 1291 60

Arsenic is a notorious environmental toxicant known to be carcinogenic for the skin, lung and urinary bladder in human beings. The carcinogenicity of trimethylarsine oxide (TMAO), one organic metabolite of inorganic arsenics in humans and experimental animals, was investigated here in male Fischer 344 rats in a 2-year carcinogenicity test. TMAO was administered to a total of 129 male rats ad libitum at concentrations of 0 (Control), 50 or 200 p.p.m. in the drinking water. In animals that died or were killed from the 87th week until the end of 104th week, incidences of hepatocellular adenomas were 14.3, 23.8 and 35.6% in the 0, 50 and 200 p.p.m.-treated groups, respectively; the multiplicities were 0.21, 0.33 and 0.53. Both were significantly increased in the 200 p.p.m.-treated group. While a variety of other tumors developed in various organs, they were present in all groups, including the controls, and were histologically diagnosed as those known to occur spontaneously in F344 rats. To test the contribution of reactive oxygen species (ROS) to TMAO tumorigenicity in the liver, 8-hydroxydeoxyguanosine (8-OHdG) formation was assessed by high performance liquid chromatography. The 8-OHdG values for the 200 p.p.m. TMAO group were significantly higher than those for the control group. Furthermore, as assessed by the proliferating cell nuclear antigen index, cell proliferation in the normally appearing parenchyma was elevated by the TMAO treatment. These results indicate that TMAO exerts liver tumorigenicity with possible mechanistic roles for oxidative DNA damage and enhanced cell proliferation.
Carcinogenesis 2003 Nov
PMID:Liver tumorigenicity of trimethylarsine oxide in male Fischer 344 rats--association with oxidative DNA damage and enhanced cell proliferation. 1291 61

Arsenic is a well-known carcinogen that possibly promotes tumors and the development of various types of cancer in individuals chronically exposed to arsenic in their work or living environment. Many studies have demonstrated the activation of mitogen-activated protein kinase (MAPK) in several cell types by using lethal concentrations of arsenic in the range of 50-500 micro M. Since the exposure of humans to arsenic is normally at a much lower level in the workplace or in daily life, it is more relevant to study the effects of arsenic at this lower exposure level. In the present study we aimed at redefining the role of signal transduction pathways in arsenic-induced malignant transformation as well as apoptosis using our established in vitro rat lung epithelial cell model system. Our results indicate a molecular mechanism by which MAPK pathways might differentially contribute to cell growth regulation and cell death in response to different dosages of arsenite. A low level (2 micro M) of arsenite stimulated extracellular signal-regulated kinase (ERK) signaling pathway and enhanced cell proliferation, and this arsenite-induced ERK activity was blocked by MEK inhibitor, PD98059. In contrast, a high level (40 micro M) of arsenite stimulated the c-Jun N-terminal kinase (JNK) signaling pathway and induced cell apoptosis, and this arsenite-induced JNK activity was blocked by JNK inhibitor II, SP600125. The implications of these findings are that a high concentration of arsenic exposure causes apoptosis, whereas a low concentration of arsenic exposure is carcinogenic and may result in aberrant cell accumulation.
Carcinogenesis 2004 Jan
PMID:Opposed arsenite-induced signaling pathways promote cell proliferation or apoptosis in cultured lung cells. 1451 59

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