DRINKING WATER EXPOSURE TO ARSENIC, POLYMORPHISMS IN GSTT1, GSTM1 AND GSTP1 AND METHYLATION CAPACITY

Abstract

ISEE-291 Introduction: Individual differences in the biotransformation of arsenic have has been hypothesized to be a factor in arsenic related disease. Recently there has been a suggestion that the metabolism and methylation of arsenic is a toxification pathway rather than a detoxification pathway. The methylated metabolites of arsenic are thought to be more toxic than originally categorized. Aim: We examined whether polymorphisms in GSTT1, GSTP1 and GSTM1 were associated with primary (MMA monomethylarsonic acid / As III arsenite +As V arsenate) and secondary methylation capacity (DMA dimethylarsinic acid /MMA monomethylarsonic acid). We also examined the association between primary and secondary methylation capacity and development of arsenic related skin lesions and whether this relationship was modified by GSTT1, GSTM1, and GSTP1 polymorphisms. Methods: 592 cases and 597 controls, frequency matched on age and gender, were enrolled at Dhaka Community Hospital, Bangladesh in 2001-2002. Demographic data, toenail and water samples were collected for all subjects. Trained physicians diagnosed skin lesions. Nail and water arsenic levels were determined using ICP-MS EPA Method 200.8. Genotyping was done with multiplex PCR and TaqMan. Statistical analysis was done in SAS version 8.2 and plots in R. Results: While drinking water concentration of arsenic was related to secondary methylation capacity and individual metabolites MMA and DMA, it was not related to primary methylation capacity. Polymorphisms in GSTT1, GSTM1 and GSTP1 did not modify primary or secondary methylation capacity. Betel nut use was significantly associated with secondary methylation capacity. Individual metabolites, DMA and MMA, are associated with arsenic concentration of drinking water; however not associated with the polymorphisms. The odds of developing skin lesions is associated with an increase of secondary methylation capacity, but not primary methylation capacity. Conclusions: GSTT1, GSTM1 and GSTP1 polymorphisms do not impact primary or secondary methylation capacity in the metabolism of arsenic.