, 2005b). Folic acid supplementation of 130 participants of the HEALS cohort with low blood folate levels RGFP966 mouse reduced blood levels of MMA by 22.2% and total blood arsenic levels by 13.6%, and increased DMA in urine by 10.2% (Gamble et al., 2007). A high prevalence of hyperhomocysteinemia (63% in men and 26% in women) has been reported in Araihazar, Bangladesh,

compared to in the United States (9%) (Gamble et al., 2005a). Plasma total homocysteine was positively correlated with %MMA (r = 0.21) and inversely correlated with %DMA (r = −0.14) in urine, and only weakly correlated with water arsenic concentration (r = 0.05) ( Gamble et al., 2005b). Thus, the elevated prevalence of hyperhomocysteinemia is largely associated with factors other than arsenic water exposure. Environmental factors, most notably smoking status but also betel nut chewing in Bangladesh, have also been reported to reduce folate status, increase homocysteine levels, and affect susceptibility to arsenic toxicity (Chen et al., 2011, Gamble et al., 2005a, Pilsner et al., 2009 and Tungtrongchitr et al., 2003). Cigarette smoking can increase arsenic toxicity by impacting arsenic methylation capacity (likely through folate depletion), as shown for smokers

in Chile compared to non-smokers BIRB 796 in vivo (Hopenhayn-Rich et al., 1996). Cigarette smoking may also contribute additional iAs exposure (ATSDR, 2007 and Feki-Tounsi et al., 2013). Smoking has been reported to have an apparent synergistic effect on arsenic-induced heart disease mortality (Chen et al., 2011), as well as skin lesions in Bangladesh (Chen et al., 2006a) and lung cancer in Taiwan (Chen et al., 2004). Evidence of synergism with smoking is generally

at higher arsenic doses at which arsenic toxicity is occurring, including increased oxidative stress and impairment in DNA repair (Cohen et al., 2013). Duration of and cumulative betel nut use in the HEALS cohort was prospectively associated with increased risk of subclinical atherosclerosis (higher carotid intima-media thickness), including a synergistic effect with smoking (McClintock et al., 2014). many The available evidence reviewed does not indicate that populations in the U.S. would be genetically more sensitive than the Bangladeshi population studied (Islam and Majumder, 2013 and McNulty et al., 2012), particularly at low doses. For a common genetic polymorphism affecting a key enzyme of one-carbon metabolism, methylenetetrahydrofolate reductase (MTHFR, Fig. 2), some evidence suggests that North American populations are not at increased risk of CHD, unlike in other parts of the world, and that a gene-environment interaction (i.e., low folate) determines when an increased risk is expressed (McNulty et al., 2012). Research on polymorphisms in other genes affecting one-carbon metabolism and CVD risk likewise indicates the potential importance of gene-environment interactions regarding nutritional status in elderly U.S. non-Hispanic white men (Normative Aging Study) (Wernimont et al.