Nutritional Status Has Marginal Influence on the Metabolism of Inorganic Arsenic in Pregnant Bangladeshi Women

Worldwide, millions of people are exposed to inorganic arsenic (iAs), a documented potent human toxicant and carcinogen, via drinking water [International Agency for Research on Cancer (IARC) 2004; World Health Organization (WHO)/International Programme on Chemical Safety 2001]. The British Geological Survey (BGS 2001) estimated that about 50 million people in Bangladesh alone are drinking water from tube wells that exceeds the WHO drinking-water guideline value for As of 10 μg/L. There is a marked variation in susceptibility to As, which—at least in part—may be mediated via variation in As metabolism (Vahter 2002). iAs is metabolized by most mammals, including humans, via reduction and methylation reactions with S-adenosylmethionine (SAM) as the methyl donor (Hayakawa et al. 2005; Marafante and Vahter 1984; Vahter 2002). Dimethylarsinic acid (DMA) is the main As metabolite excreted in human urine, besides monomethylarsonic acid (MMA) and some remaining iAs, but there are major differences among individuals as well as between population groups (Vahter 2002). Usually, the proportions are 10–30% iAs, 10–20% MMA, and 60–80% DMA (Vahter 2002). The metabolism of As implies both detoxification and activation. The reduced trivalent forms, in particular MMA(III), are more toxic than the pentavalent forms (Bredfeldt et al. 2006; Schwerdtle et al. 2003; Styblo et al. 2002; Wang et al. 2007). A high concentration of MMA in the urine indicates a low capacity of further methylation to DMA and, probably, elevated concentrations of the highly toxic MMA(III) in the cells. There is increasing evidence of positive associations between urinary MMA and the prevalence of As-related bladder cancer (Chen et al. 2003b; Pu et al. 2007; Steinmaus et al. 2006), skin cancer (Chen et al. 2003a; Hsueh et al. 1997; Yu et al. 2000), other skin effects (Ahsan et al. 2007; Del Razo et al. 1997), structural chromosomal aberrations (Maki-Paakkanen et al. 1998), cardiovascular effects (Tseng et al. 2005), and increased retention of ingested As (Vahter 2002). Thus, it is essential to identify the mechanisms behind the wide interindividual variation in As metabolism. Because As is methylated through one-carbon metabolism (Figure 1), it is likely that the availability of methyl groups via intake of protein (Lammon and Hood 2004; Marafante and Vahter 1984; Vahter and Marafante 1987) and other factors involved in the methylation cycles [e.g. folate and vitamin B12 (Spiegelstein et al. 2003; Spiegelstein et al. 2005)] are critical for As methylation. There is also experimental evidence for the involvement of essential trace elements such as selenium and zinc (De Kimpe et al. 1999; Hong et al. 2000; Walton et al. 2003), although the mechanisms are not clear. Because of the marked species differences in As methylation (Vahter 1999), it is difficult to extrapolate the results to humans. However, there is growing evidence for a nutritional regulation of As methylation in humans (Gamble et al. 2005, 2006, 2007; Heck et al. 2007; Steinmaus et al. 2005). In the present study, we aimed to elucidate the modifying effects of macronutrient status, assessed by body mass index [BMI; body weight (kg) ÷ height (m2)], and micronutrient status, assessed by biomarkers of folate, vitamin B12, Zn, ferritin, and Se status, on As metabolism in pregnant Bangladeshi women with a wide range of nutritional status and As exposure via drinking water. Figure 1 Overview of one-carbon metabolism and the methylation of As. Abbreviations: 5,10-CH2-THF, methylene tetrahydrofolate; AS3MT, As methyltransferase; DMG, dimethylglycine; GAA, guanidinoacetate; MTHFR, 5,10-CH2-THF reductase; SAH, S-adenosylhomocysteine; ...