Gene-environment interactions for arsenic metabolism and metal-related oxidatively generated DNA damage

Abstract: Over 100 million people around the world are exposed to high concentrations of arsenic (As) in drinking water, associated with a number of adverse health effects such as skin, lung and bladder cancer, vascular diseases and diabetes. In humans, As is metabolized via alternating reduction and methylation reactions, from inorganic As (iAs) into monomethylated (MMA) and dimethylated As (DMA). The most toxic metabolite is MMA, and the fraction of urinary MMA appears to be a marker for susceptibility to As-related toxic effects. The metabolism of As and thus the distribution of the As metabolites in urine demonstrate large inter-individual differences, which in part may be explained by genetic factors. A potential mechanism of the toxicity of As is the induction of oxidative stress, which can result in oxidatively generated DNA damage. Oxidatively generated DNA damage can be assessed by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in urine. Concurrent chronic mixed exposure to other metals, such as cadmium (Cd) and lead (Pb), can also induce oxidative stress, and there may also be a genetic influence on oxidative stress. The aims of this thesis were 1) to evaluate the impact of genetic factors on As metabolism and 2) to evaluate the impact of As exposure and metabolism, chronic mixed metal exposure and genetic factors on oxidatively generated DNA damage, here assessed by 8-oxodG in urine. This was evaluated in two populations, one from the Argentinean Andes and one from rural Bangladesh. Six non-coding polymorphisms in As (3+ oxidation state) methyltransferase (AS3MT) had a strong impact on As metabolism in both populations, and it was demonstrated that one functional influence of the AS3MT polymorphisms was alternation of gene expression. Increasing concentrations of As in urine and increasing fractions of MMA were associated with higher 8-oxodG concentrations. Increasing concentrations of urinary Cd were strongly associated with higher 8-oxodG concentrations, and there was a joint effect of As and Cd on 8-oxodG concentrations. A polymorphism in apurinic/apyrimidinic endonuclease 1 (APEX1) had an impact on 8-oxodG concentrations.