Urinary arsenic profile affects the risk of urothelial carcinoma even at low exposure

Department of Urology, National Taiwan University College of Medicine, Taipei, Taiwan.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 02/2007; 218(2):99-106. DOI: 10.1016/j.taap.2006.09.021
Source: PubMed


Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the association between individual risk and urinary arsenic profile in subjects without evident exposure, 177 UC cases and 313 age-matched controls were recruited between September 2002 and May 2004 for a case-control study. Urinary arsenic species including the following three categories, inorganic arsenic (As(III)+As(V)), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), were determined with high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Arsenic methylation profile was assessed by percentages of various arsenic species in the sum of the three categories measured. The primary methylation index (PMI) was defined as the ratio between MMA(V) and inorganic arsenic. Secondary methylation index (SMI) was determined as the ratio between DMA(V) and MMA(V). Smoking is associated with a significant risk of UC in a dose-dependent manner. After multivariate adjustment, UC cases had a significantly higher sum of all the urinary species measured, higher percent MMA(V), lower percent DMA(V), higher PMI and lower SMI values compared with controls. Smoking interacts with the urinary arsenic profile in modifying the UC risk. Differential carcinogenic effects of the urinary arsenic profile, however, were seen more prominently in non-smokers than in smokers, suggesting that smoking is not the only major environmental source of arsenic contamination since the UC risk differs in non-smokers. Subjects who have an unfavorable urinary arsenic profile have an increased UC risk even at low exposure levels.

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Available from: M. H. Yang, Feb 05, 2015
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    • "Several studies showed that individuals excreting high % uMMA are more susceptible to develop arsenic-induced diseases (as they have low methylation capacity) compared to individuals with high methylation efficiency that excrete low % uMMA (Chen et al., 2003; Pu et al., 2007; Steinmaus et al., 2003; Tseng et al., 2005). Individuals with the minor allele in 7388 intronic polymorphism and higher BMI had lower % uMMA excretion capability; while in contrast, minor allele in M287T exonic polymorphism and lower BMI had higher % uMMA excretion capability (Agusa et al., 2011; Drobná et al., 2004; Gomez- Rubio et al., 2011; Valenzuela et al., 2009). "
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    ABSTRACT: Exposure to chronic arsenic toxicity is associated with cancer. Although unstable genome is a characteristic feature of cancer cells, the mechanisms leading to genomic instability in arsenic-induced carcinogenesis are poorly understood. While there are excellent reviews relating to genomic instability in general, there is no comprehensive review presenting the mechanisms involved in arsenic-induced genomic instability. This review was undertaken to present the current state of research in this area and to highlight the major mechanisms that may involved in arsenic-induced genomic instability leading to cancer. Genomic instability is broadly classified into chromosomal instability (CIN), primarily associated with mitotic errors; and microsatellite instability (MIN), associated with DNA level instability. Arsenic-induced genomic instability is essentially multi-factorial in nature and involves molecular cross-talk across several cellular pathways, and is modulated by a number of endogenous and exogenous factors. Arsenic and its metabolites generate oxidative stress, which in turn induces genomic instability through DNA damage, irreversible DNA repair, telomere dysfunction, mitotic arrest and apoptosis. In addition to genetic alteration; epigenetic regulation through promoter methylation and miRNA expression alters gene expression profiling leading to genome more vulnerable and unstable towards cancer risk. Moreover, mutations or silencing of pro-apoptotic genes can lead to genomic instability by allowing survival of damaged cells that would otherwise die. Although a large body of information is now generated regarding arsenic-induced carcinogenesis; further studies exploring genome-wide association, role of environment and diet are needed for a better understanding of the arsenic-induced genomic instability.
    Environment international 01/2013; 53C:29-40. DOI:10.1016/j.envint.2012.12.004 · 5.56 Impact Factor
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    • ", we invited the residents of cohort and collected repeatedly the second urine samples of 204 residents, who voluntarily participated in the study (Huang et al., 2009). Their individual average levels of total urinary arsenic decreased from 74.9 to 57.1 mg/L, which was still higher than that of other populations (26 mg/L) not living in arseniasis-endemic area in Taiwan (Pu et al., 2007). Our recent study further analyzed the effect of the change in urinary arsenic profiles on cancer risk, with a 15-year follow-up (1988–2004) (Chung et al., 2009). "
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    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.
    Environmental Research 12/2012; 122. DOI:10.1016/j.envres.2012.11.007 · 4.37 Impact Factor
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    • "In addition, cigarette smoking has been identified as a risk factor of UC (Strope and Montie, 2008). There has also been shown to be a significantly interaction between cigarette smoking and arsenic on the risk for bladder cancer (Pu et al., 2007; Wang et al., 2012) Furthermore, Chen et al. found a significant interaction between environmental tobacco smoking Table 1 Sequences of flanking primers, annealing temperature, restricted enzyme, and fragment size of CYP1A1, SULT1A1, EPHX1, GSTT1 and GSTM1. "
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    ABSTRACT: Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene-environment interaction in the carcinogenesis of UC. A hospital-based case-control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain risk factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene-environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene-environmental interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination.
    Toxicology and Applied Pharmacology 11/2012; 266(2). DOI:10.1016/j.taap.2012.11.005 · 3.71 Impact Factor
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