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Abstract: Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (<27 repeats) or L allele (≥27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16–0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure. [Copyright &y& Elsevier]

Abstract: Arsenic-contaminated well water has been shown to increase the risk of atherosclerosis. Because of involving S-adenosylmethionine, homocysteine may modify the risk by interfering with the biomethylation of ingested arsenic. In this study, we assessed the effect of plasma homocysteine level and urinary monomethylarsonic acid (MMAV) on the risk of atherosclerosis associated with arsenic. In total, 163 patients with carotid atherosclerosis and 163 controls were studied. Lifetime cumulative arsenic exposure from well water for study subjects was measured as index of arsenic exposure. Homocysteine level was determined by high-performance liquid chromatography (HPLC). Proportion of MMAV (MMA%) was calculated by dividing with total arsenic species in urine, including arsenite, arsenate, MMAV, and dimethylarsinic acid (DMAV). Results of multiple linear regression analysis show a positive correlation of plasma homocysteine levels to the cumulative arsenic exposure after controlling for atherosclerosis status and nutritional factors (P < 0.05). This correlation, however, did not change substantially the effect of arsenic exposure on the risk of atherosclerosis as analyzed in a subsequent logistic regression model. Logistic regression analyses also show that elevated plasma homocysteine levels did not confer an independent risk for developing atherosclerosis in the study population. However, the risk of having atherosclerosis was increased to 5.4-fold (95% CI, 2.0–15.0) for the study subjects with high MMA% (≥16.5%) and high homocysteine levels (≥12.7 μmol/l) as compared to those with low MMA% (<9.9%) and low homocysteine levels (<12.7 μmol/l). Elevated homocysteinemia may exacerbate the formation of atherosclerosis related to arsenic exposure in individuals with high levels of MMA% in urine. [Copyright &y& Elsevier]

Abstract: Background: Arsenic is a well-documented carcinogen of human urothelial carcinoma (UC) with incompletely understood mechanisms. Objectives: This study aimed to compare the genome-wide DNA methylation profiles of arsenic-induced UC (AsUC) and non-arsenic-induced UC (Non-AsUC), and to assess associations between site-specific methylation levels and cumulative arsenic exposure. Methods: Genome-wide DNA methylation profiles in 14 AsUC and 14 non-AsUC were analyzed by Illumina Infinium methylation27 BeadChip and validated by bisulfite pyrosequencing. Mean methylation levels ( ) in AsUC and non-AsUC were compared by their ratio ( ratio) and difference ( ). Associations between site-specific methylation levels in UC and cumulative arsenic exposure were examined. Results: Among 27,578 methylation sites analyzed, 231 sites had ratio >2 or <0.5 and 45 sites had >0.2 or <−0.2. There were 13 sites showing statistically significant (q<0.05) differences in between AsUC and non-AsUC including 12 hypermethylation sites in AsUC and only one hypermethylation site in non-AsUC. Significant associations between cumulative arsenic exposure and DNA methylation levels of 28 patients were observed in nine CpG sites of nine gens including PDGFD (Spearman rank correlation, 0.54), CTNNA2 (0.48), KCNK17 (0.52), PCDHB2 (0.57), ZNF132 (0.48), DCDC2 (0.48), KLK7 (0.48), FBXO39 (0.49), and NPY2R (0.45). These associations remained statistically significant for CpG sites in CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 in 20 non-smoking women after adjustment for tumor stage and age. Conclusions: Significant associations between cumulative arsenic exposure and methylation level of CTNNA2, KLK7, NPY2R, ZNF132 and KCNK17 were found in smoking-unrelated urothelial carcinoma. Arsenic exposure may cause urothelial carcinomas through the hypermethylation of genes involved in cell adhesion, proteolysis, transcriptional regulation, neuronal pathway, and ion transport. The findings of this study, which are limited by its small sample size and moderate dose–response relation, remain to be validated by further studies with large sample sizes. [Copyright &y& Elsevier]

Abstract: Few studies investigated the association between chronic arsenic exposure and the mortality of cancers by estimating individual urinary arsenic methylation profiles. Therefore, we compared with the general population in Taiwan to calculate the standardized mortality ratio (SMR) in arseniasis-endemic area of Taiwan from 1996 to 2010 and evaluated the dose-response relationships between environmental arsenic exposure indices or urinary arsenic profiles and the mortality of cause-specific cancer. A cohort of 1563 residents was conducted and collected their urine sample and information regarding arsenic exposure from a questionnaire. All-cause death was identified using the National Death Registry of Taiwan. Urinary arsenic profiles were measured using high performance liquid chromatography–hydride generator–atomic absorption spectrometry. We used Cox proportional hazard models to evaluate the mortality risks. In results, 193 all-site cancer deaths, and 29, 71, 43 deaths respectively for liver, lung and bladder cancers were ascertained. The SMRs were significantly high in arseniasis-endemic areas for liver, lung, and bladder cancers. People with high urinary InAs% or low DMA% or low secondary methylation index (SMI) were the most likely to suffer bladder cancer after adjusting other risk factors. Even stopping exposure to arsenic from the artesian well water, the mortality rates of the residents were higher than general population. Finally, urinary InAs%, DMA% and SMI could be the potential biomarkers to predict the mortality risk of bladder cancer. [Copyright &y& Elsevier]

Abstract: Individual susceptibility to arsenic-induced carotid atherosclerosis might be associated with genetic variations in arsenic metabolism. The purpose of this study is to explore the interaction effect on risk of carotid atherosclerosis between arsenic exposure and risk genotypes of purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), and glutathione S-transferase omega 1 (GSTO1) and omega 2 (GSTO2). A community-based case-control study was conducted in northeastern Taiwan to investigate the arsenic metabolic-related genetic susceptibility to carotid atherosclerosis. In total, 863 subjects, who had been genotyped and for whom the severity of carotid atherosclerosis had been determined, were included in the present study. Individual well water was collected and arsenic concentration determined using hydride generation combined with flame atomic absorption spectrometry. The result showed that a significant dose–response trend (P=0.04) of carotid atherosclerosis risk associated with increasing arsenic concentration. Non-significant association between genetic polymorphisms of PNP Gly51Ser, Pro57Pro, As3MT Met287Thr, GSTO1 Ala140Asp, and GSTO2 A-183G and the risk for development of carotid atherosclerosis were observed. However, the significant interaction effect on carotid atherosclerosis risk was found for arsenic exposure (>50μg/l) and the haplotypes of PNP (p=0.0115). A marked elevated risk of carotid atherosclerosis was observed in subjects with arsenic exposure of >50μg/l in drinking water and those who carried the PNP A–T haplotype and at least either of the As3MT risk polymorphism or GSTO risk haplotypes (OR, 6.43; 95% CI, 1.79–23.19). In conclusion, arsenic metabolic genes, PNP, As3MT, and GSTO, may exacerbate the formation of atherosclerosis in individuals with high levels of arsenic concentration in well water (>50μg/l). [Copyright &y& Elsevier]

Abstract: Our previous study combining two arseniasis-endemic areas in Taiwan confirmed a dose–response association of lung cancer and arsenic exposure. We conducted current analysis to elucidate the dose–response relationship in lower exposure level, and to evaluate whether the association differs in different histological types. In addition, whether specific characteristics of well water consumptions increased lung cancer risk was examined in order to establish a complete risk profile for arsenic exposure. A total of 8086 residents in northeastern Taiwan were followed for 11 years and 6888 participants remained in the final analysis because 1198 residents with unknown arsenic concentration were excluded. The 178 incident lung cancers were ascertained through linkage with the national cancer registry profiles in Taiwan. All analyses were performed by Cox''s proportional hazards regression models. We found a significant dose–response trend (P=0.001) of lung cancer risk associated with increasing arsenic concentration. There was no apparent increased risk at concentrations between 10 and 100μg/L, but concentrations between 100 and 300μg/L showed evidence of excess risk (RR 1.54, 0.97–2.46). The relative risk was 2.25 (95% CI: 1.43, 3.55) for exposure to ≥300μg/L when compared to <10μg/L. The significant dose–response trends and the synergistic effect of arsenic exposure and cigarette smoking can be found in squamous and small cell carcinomas, but not in adenocarcinoma. Despite lacking statistical precision, when duration is accounted for, all levels of exposure including low concentration were in the direction of increased risk of lung cancer, and these associations tended to increase with longer durations of exposure. This study provides additional evidence linking arsenic to lung cancer, and the indications that arsenic may play a more important role in certain histological type may help with further research in carcinogenic effect of inorganic arsenic on lung cancer. [Copyright &y& Elsevier]

Abstract: Chronic arsenic exposure has been documented to be associated with various cardiovascular diseases. We aimed to investigate 1) the increased risk of QT prolongation in chronic arsenic exposure, and 2) the relationships of cardiac repolarization (QT interval duration) with ischemic heart disease and carotid atherosclerosis. We studied 280 men and 355 women living in the endemic area of arseniasis in southwestern Taiwan. QT intervals in electrocardiogram and carotid intima–media thickness (IMT) by ultrasonography were measured. Ischemic heart disease was diagnosed by history or abnormal electrocardiogram. Significant associations of the corrected QT interval (QTc) duration with ischemic heart disease and carotid intima–medium thickness and plaque were observed after adjustment for various risk factors in the multiple linear regression analysis (all p values <0.05). Three indices of chronic arsenic exposure were all significantly associated with the risk of QTc prolongation showing dose–response relationships (p <0.001). Chronic arsenic exposure was dose-dependently associated with the risk of QTc prolongation. Ischemic heart disease and carotid atherosclerosis were significantly associated with QTc intervals in chronic arsenic exposure. QTc prolongation might be suggested as an early biomarker for ischemic heart disease or carotid atherosclerosis in population with previous exposure to arsenic. [Copyright &y& Elsevier]

Abstract: Cardiovascular disease is the leading cause of mortality worldwide. Arsenic is a ubiquitous metalloid in the crust of the earth. Chronic arsenic poisoning is becoming an emerging epidemic in Asia. Epidemiological studies have shown that chronic arsenic poisoning through ingestion of arsenic-contaminated water is associated with various cardiovascular diseases in dose–response relationships. These cardiovascular disorders include carotid atherosclerosis detected by ultrasonography, impaired microcirculation, prolonged QT interval and increased QT dispersion in electrocardiography, and clinical outcomes such as hypertension, blackfoot disease (a unique peripheral vascular disease endemic in southwestern Taiwan), coronary artery disease and cerebral infarction. Chronic arsenic poisoning is an independent risk factor for cardiovascular disease. The adverse cardiovascular effects of long-term arsenic exposure may be persistent and/or irreversible. Arsenic-induced cardiovascular diseases in human population may result from the interaction among genetic, environment and nutritional factors. The major adverse cardiovascular effect of chronic arsenic poisoning has been established qualitatively and quantitatively in the high arsenic exposure areas, but the low-dose effect of arsenic on cardiovascular diseases remains to be explored. Cardiovascular death is the major cause of mortality worldwide, and a small increased risk may imply a large quantity of excess mortality. [Copyright &y& Elsevier]

Abstract: Long-term exposure to ingested arsenic from drinking water has been well documented to be associated with an increased risk of diabetes mellitus and hypertension in a dose-response relationship among residents of arseniasis-endemic areas in southwestern Taiwan and Bangladesh. An increased risk of self-reported hypertension but not diabetes was reported in a community-based study of residents who consumed drinking water with a low level of arsenic. Increased glycosylated hemoglobin level and systolic blood pressure were observed in workers occupationally exposed to arsenic. Inconsistent findings of arsenic and diabetes in occupational studies may result from the healthy worker effect and the variation in exposure measurement, age composition, number of patients, accuracy in diagnosis and classification of underlying causes of death, competing causes of death, and method to detect diabetes. The dose-response relationship and toxicological mechanisms of arsenic-induced diabetes and hypertension need further elucidation. [Copyright &y& Elsevier]

Abstract: Long-term exposure to inorganic arsenic from drinking water has been documented to induce cancers and vascular diseases in a dose-response relationship. A series of molecular environmental epidemiological studies have been carried out to elucidate biomarkers of exposure, effect, and susceptibility for arsenic-related health hazards in Taiwan. Arsenic levels in urine, hair, and nail are biomarkers for short-term (&#60;1 year) internal dose, skin hyperpigmentation and palmoplantar hyperkeratosis are for long-term (many years) internal dose, and percentage of monomethylarsonic acid in total metabolites of inorganic arsenic in urine may be considered as an exposure marker for biologically effective dose. The biomarkers of early biological effects of ingested inorganic arsenic included blood levels of reactive oxidants and anti-oxidant capacity, genetic expression of inflammatory molecules, as well as cytogenetic changes including sister chromatid exchange, micronuclei, and chromosome aberrations of peripheral lymphocytes. Both mutation type and hot spots of p53 gene were significantly different in arsenic-induced and non-arsenic-induced TCCs. The frequency of chromosomal imbalances analyzed by comparative genomic hybridization and the frequency of loss of heterozygosity were significantly higher in arsenic-induced TCC than non-arsenic-induced TCC at specific sites. Biomarkers of susceptibility to arsenic-induced health hazards included genetic polymorphisms of enzymes involved in xenobiotic metabolism, DNA repair, and oxidative stress, as well as serum level of carotenoids. Gene–gene and gene–environment interactions are involved in arsenic-induced health hazards through toxicological mechanisms including genomic instability and oxidative stress. [Copyright &y& Elsevier]