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Long-term exposure to arsenic may induce several human cancers, including non-melanoma skin cancer. The tissue inhibitor of metalloproteinase (TIMP)-3, encoded by the TIMP3 gene, may inhibit tumor growth, invasion, and metastasis of several cancer types. In this study, we aimed to investigate effects of the TIMP3 -1296 T > C (rs9619311) and -915 A > G (rs2234921) single-nucleotide polymorphisms (SNPs) on skin cancer risk in an arsenic-exposed population, and to evaluate the influence of allele-specific changes by an in silico analysis. In total, 1078 study participants were followed up for a median of 15 years for newly diagnosed skin cancer. New cases were identified through linkage to the National Cancer Registry of Taiwan. A Cox regression analysis was used to evaluate the effects of TIMP3 variants. Transcription factor (TF) profiling of binding sites of allele-specific changes in SNPs was conducted using the JASPAR scan tool. We observed borderline associations between TIMP3 genotypes and skin cancer risk. However, when combined with high arsenic exposure levels, the rs9619311 C allele, rs2234921 G allele, or C-G haplotype groups exhibited a greater risk of developing skin cancer compared to the respective common homozygous genotype group. The in silico analysis revealed several TF motifs located at or flanking the two SNP sites. We validated that the C allele of rs9619311 attenuated the binding affinity of BACH2, MEIS2, NFE2L2, and PBX2 to the TIMP3 promoter, and that the G allele of rs2234921 reduced the affinity of E2F8 and RUNX1 to bind to the promoter. Our findings suggest significant modifications of the effect of the association between arsenic exposure and skin cancer risk by the TIMP3 rs9619311 and rs2234921 variants. The predicted TFs and their differential binding affinities to the TIMP3 promoter provide insights into how TIMP3 interacts with arsenic through TFs in skin cancer formation. [ABSTRACT FROM AUTHOR]

Simple Summary: Epidemiological evidence has suggested that modifiable factors play an essential role in the risk of head and neck cancer (HNC). However, few studies have established HNC prediction models based on sex and tumor subsites. In this study, we establish sex- and subsite-specific HNC risk prediction models for the general Taiwanese population. Our study draws from a large sample size of 14,423 participants. The HNC prediction models may be applied in clinical risk assessments for health promotion programs. Epidemiological evidence has suggested that modifiable lifestyle factors play a significant role in the risk of head and neck cancer (HNC). However, few studies have established risk prediction models of HNC based on sex and tumor subsites. Therefore, we predicted HNC risk by creating a risk prediction model based on sex- and tumor subsites for the general Taiwanese population. This study adopted a case-control study design, including 2961 patients with HNC and 11,462 healthy controls. Multivariate logistic regression and nomograms were used to establish HNC risk prediction models, which were internally validated using bootstrap sampling. The multivariate logistic regression model indicated that age, education level, alcohol consumption, cigarette smoking, passive smoking, coffee consumption, and body mass index are common HNC predictors in both sexes, while the father's ethnicity, betel-nut-chewing habits, and tea consumption were male-specific HNC predictors. The risk factors of the prediction model for the HNC tumor subsite among men were the same as those for all patients with HNC. Additionally, the risks of alcohol consumption, cigarette smoking, and betel nut chewing varied, based on the tumor subsite. A c-index ranging from 0.93 to 0.98 indicated that all prediction models had excellent predictive ability. We developed several HNC risk prediction models that may be useful in health promotion programs. [ABSTRACT FROM AUTHOR]

We previously reported that the sustained exposure of human urothelial cells (HUCs) to low-dose sodium arsenite induces changes in the gene expression profile and neoplastic transformation. In this study, we used the HumanMethylation27 BeadChip to analyze genome-wide methylation profiles and 5-aza-2′-deoxycytidine to examine the involvement of promoter methylation in gene expression. Because the expression of lipocalin-2 (LCN2) was highly enhanced by promoter hypomethylation in inorganic arsenic (iAs)-HUCs cells as well as bladder cancer tissues, we further showed that mutations at the binding sequences for NF-κB and C/EBP-α significantly reduced LCN2 promoter activity. By chromatin immunoprecipitation assay, we demonstrated the significantly increased binding of RelA (p65) and NF-κB1 (p50) to the hypomethylated promoter of LCN2 in the iAs-HUCs. Furthermore, we also demonstrated that LCN2 overexpression was crucial for the neoplastic characteristics of the iAs-HUCs, such as enhanced anchorage-independent growth, resistance to serum deprivation and activation of NF-κB signaling. In addition, our results indicated that enhanced NF-κB activity in iAs-HUCs was via LCN2-mediated increase in intracellular iron and reactive oxygen species levels. Taken together, our results show that sustained low-dose arsenic exposure results in epigenetic changes and enhanced oncogenic potential via LCN2 overexpression. [ABSTRACT FROM AUTHOR]

Background: Associations of obesity and obesity-related metabolic factors (adiposity factors) with uterine corpus cancer (UCC) and ovarian cancer (OVC) risk have been described. Still, a cause-effect relationship and the underlying mediators remain unclear, particularly for low-incidence populations. We aimed to prospectively determine whether adiposity factors could predict the development of UCC and OVC in Taiwanese women. To explore the biological mediators linking adiposity factors to cancer risk, we examined the association of two adipokines, leptin and adiponectin, with the gynecological cancers. Methods: Totally, 11,258 women, aged 30–65, were recruited into the Community-Based Cancer Screening Program (CBCSP) study during 1991–1993, and were followed for UCC and OVC cases until December 31, 2011. Cox proportional hazard models were used to estimate hazard ratios (HRs). Adiposity factors and risk covariates were assessed at recruitment. Newly-developed cancer cases were determined from data in the government’s National Cancer Registry and Death Certification System. For adipokienes study, a nested case-control study was conducted within the cohort. Baseline plasma samples of 40 incident gynecological cancer cases and 240 age-menopause-matched controls were assayed for adipokines levels. Findings: There were 38 and 30 incident cases of UCC and OVC, respectively, diagnosed during a median 19.9 years of follow-up. Multivariate analysis showed that alcohol intake (HR = 16.00, 95% = 4.83–53.00), high triglyceride levels (HR = 2.58, 95% = 1.28–5.17), and years of endogenous estrogen exposure per 5-year increment (HR = 1.91, 95% = 1.08–3.38) were associated with increased UCC risk. High body mass index (BMI≥27 kg/m2, HR = 2.90, 95% = 1.30–6.46) was associated with increased OVC risk. Analysis further showed an independent effect of adipokines on UCC and OVC risk after adjustment of the risk covariates. Conclusion: We provided evidence that alcohol intake, high triglyceride levels and long endogenous estrogen exposure increase UCC risk, whereas obesity positively predicts OVC risk. Circulating adipokines may mediate the link of adiposity factors to gynecological cancer risk. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Heme oxygenase (HO)-1 is up-regulated as a cellular defense responding to stressful stimuli in experimental studies. A GT-repeat length polymorphism in the HO-1 gene promoter was inversely correlated to HO-1 induction. Here, we reported the association of GT-repeat polymorphism with blood pressure (BP) phenotypes, and their interaction on cardiovascular (CV) mortality risk in arsenic-exposed cohorts. Methods: Associations of GT-repeat polymorphism with BP phenotypes were investigated at baseline in a cross-sectional design. Effect of GT-repeat polymorphism on CV mortality was investigated in a longitudinal design stratified by hypertension. GT-repeat variants were grouped by S (<27 repeats) or L (≥27 repeats) alleles. Multivariate analyses were used to estimate the effect size after accounting for CV covariates. Results: Totally, 894 participants were recruited and analyzed. At baseline, carriers with HO-1 S alleles had lower diastolic BP (L/S genotypes, P =0.014) and a lower possibility of being hypertensive (L/S genotypes, P =0.048). After follow-up, HO-1 S allele was significantly associated with a reduced CV risk in hypertensive participants [relative mortality ratio (RMR) 0.27 (CI 0.11, 0.69), P =0.007] but not in normotensive. Hypertensive participants without carrying the S allele had a 5.23-fold increased risk [RMR 5.23 (CI 1.99, 13.69), P =0.0008] of CV mortality compared with normotensive carrying the S alleles. Conclusions: HO-1 short GT-repeat polymorphism may play a protective role in BP regulation and CV mortality risk in hypertensive individuals against environmental stressors. [Copyright &y& Elsevier]

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: To evaluate the joint effects between genetic polymorphisms of glutathione S-transferase M1, T1, P1, and p53, and arsenic exposure through drinking well water on the risk of carotid atherosclerosis, 605 residents including 289 men and 316 women were recruited from a northeastern area of Taiwan. Carotid atherosclerosis was diagnosed by either a carotid artery intima-media thickness (IMT) of >1.0mm, a plaque score of ≥1, or stenosis of >50%. A significant age- and gender-adjusted odds ratio of 3.3 for the development of carotid atherosclerosis was observed among the high-arsenic exposure group who drank well water containing arsenic at levels >50μg/L. The high-arsenic exposure group with GSTP1 variant genotypes of Ile/Val and Val/Val, and with the p53 variant genotypes of Arg/Pro and Pro/Pro had 6.0- and 3.1-fold higher risks of carotid atherosclerosis, respectively. In addition, the high-arsenic exposure group with one or two variant genotypes of GSTP1 and p53 had 2.8- and 6.1-fold higher risks of carotid atherosclerosis, respectively, and showed a dose-dependent relationship. A multivariate-adjusted odds ratio of 3.4 for the risk of carotid atherosclerosis among study subjects with the two variant genotypes of GSTP1 and p53 was also found. Our study showed the joint effects on the risk of carotid atherosclerosis between the genetic polymorphisms of GSTP1 and p53, and 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]

Long-term arsenic exposure is associated with an increased risk of vascular diseases including ischemic heart disease, cerebrovascular disease, and carotid atherosclerosis. The pathogenic mechanisms of arsenic atherogenicity are not completely clear. A fundamental role for inflammation in atherosclerosis and its complications has become appreciated recently. To investigate molecular targets of inflammatory pathway possibly involved in arsenic-associated atherosclerosis, we conducted an exploratory study using cDNA microarray and enzyme-linked immunosorbent assay to identify genes with differential expression in arsenic-exposed yet apparently healthy individuals. As an initial experiment, array hybridization was performed with mRNA isolated from activated lymphocytes of 24 study subjects with low (0–4.32 μg/L), intermediate (4.64–9.00 μg/L), and high (9.60–46.5 μg/L) levels of blood arsenic, with each group comprising eight age-, sex-, and smoking frequency-matched individuals. A total of 708 transcripts of known human genes were analyzed, and 62 transcripts (8.8%) showed significant differences in the intermediate or high-arsenic groups compared with the low-level arsenic group. Among the significantly altered genes, several cytokines and growth factors involving inflammation, including interleukin-1 beta, interleukin-6, chemokine C-C motif ligand 2/monocyte chemotactic protein- 1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncongene beta, CD14 antigen, and matrix metalloproteinase 1 (interstitial collagnase) were upregulated in persons with increased arsenic exposure. Multivariate analyses on 64 study subjects of varying arsenic exposure levels showed that the association of CCL2/MCP1 plasma protein level with blood arsenic remained significant after adjustment for other risk factors of cardiovascular diseases. The results of this gene expression study indicate that the expression of inflammatory molecules may be increased in human subjects after prolonged exposure to arsenic, which might be a contributory factor to the high risk of atherosclerosis in arseniasis-endemic areas in Taiwan. Further multidisciplinary studies, including molecular epidemiologic investigations, are needed to elucidate the role of arsenic-associated inflammation in the development of atherosclerosis and subsequent cardiovascular disease. [ABSTRACT FROM AUTHOR]

Arsenic is a notorious environmental toxicant known as both a carcinogen and an atherogen in human beings, but the pathogenic mechanisms are not completely understood. In cell culture studies, trivalent arsenic enhanced oxidative stress in a variety of mammalian cells, and this association may be closely associated with the development of arsenic-related diseases. To investigate the effect of arsenic exposure on oxidative stress in humans, we conducted a population study to determine the relationships of blood arsenic to reactive oxidants and antioxidant capacity at the individual level. We recruited 64 study subjects ages 42-75 years from residents of the Lanyang Basin on the northeast coast of Taiwan, where arsenic content in well water varies from 0 to ≥ 3,000 µg/L. We used a chemiluminescence method, with lucigenin as an amplifier for measuring Superoxide, to measure the plasma level of reactive oxidants. We used the azino-diethyl-benzthiazoline sulphate method to determine the antioxidant capacity level in plasma of each study subject. We determined arsenic concentration in whole blood by hydride formation with an atomic absorption spectrophotometer. The average arsenic concentration in whole blood of study subjects was 9.60 ± 9.96 µg/L (± SD) with a range from 0 to 46.50 µg/L. The level of arsenic concentration in whole blood of study subjects showed a positive association with the level of reactive oxidants in plasma (r = +0.41, p = 0.001) and an inverse relationship with the level of plasma antioxidant capacity (r = -0.30, p = 0.014). However, we found no significant association (p = 0.266) between levels of plasma reactive oxidants and antioxidant capacity. Our results also show that the lower the primary arsenic methylation capability, the lower the level of plasma antioxidant capacity (p = 0.029). These results suggest that ingestion of arsenic-contaminated well water may cause deleterious effects by increasing the... [ABSTRACT FROM AUTHOR]

Studies evaluating the association between age-related macular degeneration (AMD) risk and HCV infection are scant. In this population-based cohort study, 13,300 patients newly diagnosed as having HCV (HCV cohort) and 26,600 propensity score-matched patients without HCV (non-HCV cohort) were identified from the Taiwan National Health Insurance Research Database between 2000 and 2013. Furthermore, 1,983 patients with HCV who received pegylated interferon and ribavirin treatment (HCV-treated cohort) and propensity score-matched patients with HCV (matched at a ratio of 1:2) who did not receive this treatment (HCV-untreated cohort) were selected from the HCV cohort. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) associated with the risk of AMD in the HCV and non-HCV cohorts. The adjusted HR (aHR) for AMD in the HCV cohort was 1.22 (95% CI = 1.09–1.35). This significant association was observed only for nonexudative AMD (aHR = 1.22, 95% CI = 1.09–1.37). Compared with the HCV-untreated cohort, the HCV-treated cohort showed no significant association with any type of AMD (aHR = 1.07, 95% CI = 0.81–1.43). Age and sex did not modify AMD development after the exposure and treatment of chronic HCV infection. Our findings revealed that patients with chronic HCV infection had an increased risk of AMD. [ABSTRACT FROM AUTHOR]

The induction of heme oxygenase-1 (HO-1) has been shown to have therapeutic potential in experimental models of hepatitis and liver fibrosis, which are closely related to liver cancer. In humans, HO-1 induction is transcriptionally modulated by the length of a GT-repeat [(GT)n] in the promoter region. We aimed to investigate the effect of HO-1 (GT)n variants on liver cancer in a human population. We determined the HO-1 genotype in 1153 study subjects and examined their association with liver cancer risk during a 15.9-year follow-up. Allelic polymorphisms were classified as short [S, <27 (GT)n] or long [L, ≥27 (GT)n]. Newly developed cancer cases were identified through linkage to the National Cancer Registry of Taiwan. Multivariate Cox regression analysis was used to evaluate the effect of the HO-1 (GT)n variants. Alpha-fetoprotein (AFP) and cirrhosis history were also examined. The S/S genotype was found to be significantly associated with liver cancer risk, compared to the L/S and L/L genotypes. The S/S genotype group also had a higher percentage of subjects with abnormal AFP levels than other groups. There were significant percentages of cirrhosis among groups who carried S-alleles. Our findings indicate that short (GT)n variants in the HO-1 gene may confer susceptibility to rather than protection from liver cirrhosis/cancer. [ABSTRACT FROM AUTHOR]

Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01-8.83; OR = 2.04, 95% CI = 0.99-4.27; OR = 1.74, 95% CI = 1.00-3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated. [ABSTRACT FROM AUTHOR]

This population-based retrospective cohort study investigated the effectiveness of erythropoietin (EPO) treatment in reducing the risk of age-related macular degeneration (AMD) in hemodialysis patients, using the National Health Insurance Research Data of Taiwan. From the database, we identified 147,318 end-stage renal disease (ESRD) patients on hemodialysis who had been diagnosed in 2000–2014 to establish the propensity-score-matched EPO user cohort and non-EPO user cohort with equal sample size of 15,992. By the end of 2016, the cumulative incidence of AMD in EPO users was about 3.29% lower than that in non-EPO users (Kaplan–Meier survival p < 0.0001). The risk of AMD was 43% lower in EPO users than in non-EPO users, with an adjusted hazard ratio (aHR) of 0.57 (95% confidence interval (CI) = 0.51–0.64) estimated in the multivariate Cox model. A significant negative dose–response relationship was identified between the EPO dosage and the risk of AMD (p < 0.0001). Another beneficial effect of EPO treatment was a reduced risk of both exudative AMD (aHR = 0.48, 95% CI = 0.40–0.61) and non-exudative AMD (aHR = 0.61, 95% CI = 0.53–0.69), also in similar dose–response relationships (p < 0.0001). Our findings suggest that EPO treatment for hemodialysis patients could reduce AMD risk in a dose–response relationship. [ABSTRACT FROM AUTHOR]

Abstract: Arsenic exposure and cigarette smoking are environmental risk factors for urothelial carcinoma (UC). Vascular endothelial growth factor (VEGF) is the key regulator of angiogenesis in various malignancies. This study investigates the joint effect of arsenic exposure, cigarette smoking, and VEGF polymorphisms on UC risk. This was a hospital-based case–control study consisting of 730 histopathologically confirmed UC cases, including 470 bladder cancers, 260 upper urinary tract UCs (UUTUCs), and 850 age-matched controls, recruited from September 1998 to December 2009. UC risk was estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. Ever smokers with high arsenic exposure had significantly increased risks of 5.7 and 6.4 for bladder cancer and UUTUC, respectively. Moreover, ever smokers with high arsenic exposure carrying 1 or 2 risk genotypes of the VEGF gene had a significantly increased risk of 6.6 for bladder cancer and a strikingly higher risk of 9.9 for UUTUC. Additionally, UUTUC cases with high arsenic exposure carrying 1 or 2 risk genotypes of the VEGF gene had a non-significant increased risk of advanced tumor stage. Our findings suggest that arsenic exposure, cigarette smoking, and risk genotypes of VEGF contribute to a higher risk of UUTUC than of bladder cancer. [Copyright &y& Elsevier]

Long-term arsenic exposure results in atherosclerosis and cancers, along with aberrant immune responses. Animal-based and epidemiological studies indicate that arsenic exposure increases susceptibility to viral and bacterial infections. This study aimed to assess whether arsenic exposure is associated with the development of fungal infection, which is substantially attributed to as a cause of aberrant immunity. Based on two well-established cohorts from two basins in southwestern (SW; high arsenic area) and northeastern (NE; low arsenic area) Taiwan (n = 297 and 2738, respectively), the arsenic exposure in well water was estimated using HPLC-ICP-MS. Fungal infections were defined via clinical and mycological assessments (PCR of fungal 18S rRNA) of nail samples. Individuals in SW cohort with cumulative arsenic exposure > 10,000 μg/L ∗ years had a higher risk of developing fungal infections (OR = 1.57, 95% CI = 1.08–1.92) after adjusting for diabetes and occupation. In NE cohort, female sex, alcohol consumption, and chronic kidney diseases were associated with toenail infections. In contrast, fingernail infections (OR = 1.33, 95% CI = 1.05–1.68) were highly associated with arsenic exposure in a dose-dependent manner. We are the first to report palmar and plantar hyperkeratosis upon low arsenic exposure in 3.9% and 6.7% individuals, respectively. This is the first large-scale study showing arsenic exposure is associated with fungal infections in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

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]

Highlights: [•] This study estimated arsenic-associated urothelial carcinoma and lung cancer risk. [•] 8086 residents in the arseniasis-endemic area of northeastern Taiwan were enrolled. [•] Lifetime urothelial carcinoma and lung cancer risk increased with arsenic exposure. [•] Arsenic exposure and cigarette smoking had synergistic effect on these two cancers. [Copyright &y& Elsevier]

Highlights: [•] We evaluate the association of diabetes mellitus with subsequent internal malignancies in the arsenic-exposed area in Taiwan. [•] Diabetes is associated with an increased cancer risk of liver, pancreatic, stomach, colon and lungs. [•] The association of diabetes with lung cancer as well as urinary cancers seems to be confined to arsenic-related DM patients. [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]

Hyperpigmentation, hyperkeratoses, and Bowen's disease are hallmarks of chronic arsenic exposure. The association between arsenic-induced skin lesions and subsequent internal cancers is examined by using a community-based prospective study. The cohort was enrolled from an arseniasis-endemic area in southwestern Taiwan, where 2,447 residents participated in skin examinations during the late 1980s. The number of participants diagnosed with hyperpigmentation was 673; with hyperkeratosis, 243; and with skin cancer (Bowen's disease or non–melanoma skin cancer), 378. Newly diagnosed internal cancers were ascertained through linkage with National Cancer Registry profiles. Cox regression was performed to estimate hazard ratios with 95% confidence intervals for potential risk predictors. Compared with participants without skin lesions, patients affected with skin cancers had a significantly increased risk of lung cancer (hazard ratio = 4.64, 95% confidence interval: 2.92, 7.38) and urothelial carcinoma (hazard ratio = 2.02, 95% confidence interval: 1.23, 3.30) after adjustment for potential confounders and cumulative arsenic exposure. Hyperkeratosis is significantly associated with an increased lung cancer risk (hazard ratio = 2.76, 95% confidence interval: 1.35, 5.67). A significant interactive effect on lung cancer risk between hyperkeratosis and cigarette smoking was identified, which suggests that patients with hyperkeratosis who have been exposed to arsenic should cease smoking. [ABSTRACT FROM PUBLISHER]

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]

Context: Arsenic has been documented as a lung carcinogen in humans in only a few follow-up studies, which were limited by a small number of cases or the lack of information on cigarette smoking.Objectives: To elucidate the dose-response relationship between ingested arsenic and lung cancer and to assess the effect of cigarette smoking on the arsenic-lung cancer association.Design, Setting, and Participants: A total of 2503 residents in southwestern and 8088 in northeastern arseniasis-endemic areas in Taiwan were followed up for an average period of 8 years. Information on arsenic exposure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire interview.Main Outcome Measures: The incidence of lung cancer was ascertained through linkage with national cancer registry profiles in Taiwan (January 1985-December 2000). The joint effect of arsenic and cigarette smoking was estimated by both etiologic fraction and synergy index.Results: There were 139 newly diagnosed lung cancer cases during a follow-up period of 83,783 person-years. After adjustment for cigarette smoking and other risk factors, there was a monotonic trend of lung cancer risk by arsenic level in drinking water of less than 10 to 700 microg/L or more (P<.001). The relative risk was 3.29 (95% confidence interval, 1.60-6.78) for the highest arsenic level compared with the lowest. The etiologic fraction of lung cancer attributable to the joint exposure of ingested arsenic and cigarette smoking ranged from 32% to 55%. The synergy indices ranged from 1.62 to 2.52, indicating a synergistic effect of ingested arsenic and cigarette smoking on lung cancer.Conclusions: There was a significant dose-response trend of ingested arsenic on lung cancer risk, which was more prominent among cigarette smokers. The risk assessment of lung cancer induced by ingested arsenic should take cigarette smoking into consideration. [ABSTRACT FROM AUTHOR]

Context Arsenic has been documented as a lung carcinogen in humans in only a few follow-up studies, which were limited by a small number of cases or the lack of information on cigarette smoking. Objectives To elucidate the dose-response relationship between ingested arsenic and lung cancer and to assess the effect of cigarette smoking on the arsenic-lung cancer association. Design, Setting, and Participants A total of 2503 residents in southwestern and 8088 in northeastern arseniasis-endemic areas in Taiwan were followed up for an average period of 8 years. Information on arsenic exposure, cigarette smoking, and other risk factors was collected at enrollment through standardized questionnaire interview. Main Outcome Measures The incidence of lung cancer was ascertained through linkage with national cancer registry profiles in Taiwan (January 1985-December 2000). The joint effect of arsenic and cigarette smoking was estimated by both etiologic fraction and synergy index. Results There were 139 newly diagnosed lung cancer cases during a follow-up period of 83 783 person-years. After adjustment for cigarette smoking and other risk factors, there was a monotonic trend of lung cancer risk by arsenic level in drinking water of less than 10 to 700 µg/L or more (P<.001). The relative risk was 3.29 (95% confidence interval, 1.60-6.78) for the highest arsenic level compared with the lowest. The etiologic fraction of lung cancer attributable to the joint exposure of ingested arsenic and cigarette smoking ranged from 32% to 55%. The synergy indices ranged from 1.62 to 2.52, indicating a synergistic effect of ingested arsenic and cigarette smoking on lung cancer. Conclusions There was a significant dose-response trend of ingested arsenic on lung cancer risk, which was more prominent among cigarette smokers. The risk assessment of lung cancer induced by ingested arsenic should take cigarette smoking into consideration. [ABSTRACT FROM AUTHOR]

This retrospective cohort study aims to investigate interferon (IFN)-associated retinopathy incidence in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon (PegIFN) plus ribavirin (RBV). We selected 1688 patients undergoing PegIFN/RBV therapy for HCV (HCV-treated cohort), 3376 patients not receiving HCV treatment (HCV-untreated cohort) and 16,880 controls without HCV (non-HCV cohort) from the Taiwan Longitudinal Health Insurance Database. The patients were frequency-matched by age, sex, and index date at a 1:2:10 ratio, and followed up until the end of 2013. Cox proportional hazard regression models were used to compare the incidences of any retinal vascular events, including subtypes, among the three cohorts. Compared with the non-HCV cohort, the HCV-treated cohort had a significantly increased risk of retinopathy (hazard ratio (HR) = 4.98, 95% confidence interval (CI): 2.02–12.3). The risk was particularly prominent for retinal hemorrhage (HR = 12.7, 95% CI: 3.78–42.9). When the HCV-untreated cohort was used as the reference, the aforementioned HRs increased to 9.02 (95% CI: 3.04–26.8) and 32.3 (95% CI: 3.94–265), respectively. This study suggested that PegIFN/RBV therapy significantly increased the risk of retinal hemorrhage but not retinal vascular occlusions in the HCV-treated cohort. [ABSTRACT FROM AUTHOR]