The Relationship Between Urinary Arsenic Metabolites, Drinking Water, and Genetic Polymorphisms in Glutathione S-transferase M1 and T1

Abstract

MM1-O-04 Introduction: Inorganic arsenic (As3 and As5) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and glutathione S-transferase (GST) acts as the electron donor. In humans, this process is incomplete and all species are excreted in urine. Genetic polymorphisms are thought to contribute to the large interindividual differences in excreted metabolites. This study investigates the associations between GST M1 and T1, 2 deletion polymorphisms and urinary arsenic metabolites. Methods: This analysis uses drinking water and first void urine samples collected from 197 individuals every 3 months for 1 year (January 2002 to March 2003) from an ongoing longitudinal study in Pabna, Bangladesh. Total inorganic arsenic in drinking water was measured using inductively coupled plasma mass spectrometry. Urinary arsenic metabolites were measured using high-performance liquid chromatography and hydride generated atomic absorption spectrometry. Separate log-log linear mixed-effects models evaluated the relationship between drinking water arsenic, GSTM1, GSTT1, on the following outcomes: total urinary arsenic, primary methylation index [MMA/(As3 + As5)] and secondary methylation index (DMA/MMA). A random intercept was included in the models to account for autocorrelation among repeated measures on a single participant. Results: Median drinking water and total urinary arsenic concentrations were 5.5 μg/L (IQR, 132 μg/L) and 31.0 μg/L (IQR, 32.7 μg/L). Drinking water arsenic concentrations were positively associated with total urinary arsenic concentrations but not primary or secondary methylation indexes. In models adjusted for age, gender, season, body mass index, and creatinine, every 10-fold increase in drinking water arsenic resulted in a 1.3-fold increase in total urinary arsenic. Also, a significant gene-environment interaction was observed, which found that for every 10-fold increase in drinking water arsenic individuals possessing the GSTT1 null genotype had a 1.51-fold increase in total urinary arsenic, whereas individuals possessing the GSTT1 wild-type had a 1.23-fold increase in total urinary arsenic. Additionally, individuals with GSTT1 null genotypes had 34% higher primary methylation index and an 18% lower secondary methylation index compared with GSTT1 wild-type. No association was observed for GSTM1 in any model. Conclusions: Drinking water arsenic exposure is associated with the total concentration of arsenic in the urine but not the relative percentages of each metabolite. GSTT1 is involved in arsenic metabolism and individuals who are unable to produce this enzyme excrete more total urinary arsenic at any given exposure. Additionally, this enzyme appears to influences the relative concentrations of methylated arsenic metabolites. Folding: Supported by ES 04957 and ES 00002.