Superfund Research Program
The Human Genetics of Arsenic Biotransformation
Background: Once inside the human body, arsenic can be metabolized into at least five different chemical forms - each with very different toxic potencies and biologic targets. Understanding arsenic metabolism (the creation and removal of arsenic species) is essential to understanding both the impacts of arsenic exposure on human health and the well-documented observations of individual variation in susceptibility to arsenic-caused diseases. The significance of studying human arsenic metabolism is underscored by studies demonstrating an association between levels of urinary arsenic metabolites and arsenic-related disease in humans. Researchers believe that genetic variation in metabolic pathways could be a determinant of individual variation in arsenic metabolism and related toxicities.
SBRP-funded researchers at the University of Arizona have performed the most comprehensive genetic study of human arsenic metabolism to date, testing three genes with documented involvement in arsenic metabolism to determine whether person-to-person genetic variation associates with the way that arsenic is metabolized in some people.
Advances: Dr. Walt Klimecki and his colleagues at the University of Arizona SBRP are working to identify potential genetic determinants of arsenic metabolism. They conducted a screen for genetic association with urinary arsenic metabolite levels in 135 residents of Sonora, Mexico (ages 7-79) whose drinking water sources contain arsenic concentrations ranging from 5.5 to 43.3 ppb.
To date, three genes have been identified as being involved in arsenic biotransformation:
- Purine nucleoside phosphorylase (PNP) – involved in the reduction of arsenate [As(V)] to arsenite [As(III)]
- Glutathione-S-transferase omega (GSTO) – involved in the reduction of monomethylarsenic(V) [MMA(V)] to monomethylarsenic(III) [MMA(III)]
- Arsenic(III) methyltransferase (CYT19; recently designated AS3MT) – proposed to be capable of the entire gamut of arsenic biotransformations that begin with arsenite and end with dimethylarsenic(V) [DMA(V)]
The researchers performed genetic association analysis to screen for the presence of statistically significant effects of genotypes on arsenic metabolism, as indirectly reflected by urinary arsenic metabolite levels. Dr. Klimecki’s research team first developed polymorphism catalogs for GSTO, PNP, and AS3MT, within ethnically defined human populations. From these catalogs, the researchers selected 23 polymorphic sites within these three genes to test in the study population. They determined phenotypes for each study participant, noting standard demographic characteristics, the ratio of As(III) to As(V) in urine and the ratio of urinary dimethylarsenic(V) to monomethylarsenic(V) (D:M) in urine.
Three polymorphic sites in the AS3MT gene were found to be significantly associated with D:M ratios in the total population. To the researchers’ surprise, subsequent analysis of this association revealed that the association signal for the entire population was actually caused by an extremely strong association in only the children (7-11 years of age) between AS3MT genotype and D:M levels. The stratified analysis of the adults (>18 years of age) failed to produce any statistically significant genetic association.
The children in general had an overall higher D:M ratio than the adults, supporting previously reported findings for arsenic-exposed children in Bangladesh. But within the children, the highest D:M ratios were strongly associated with genetic variations in AS3MT. Dr. Klimecki’s team is currently expanding this work to confirm the finding in other populations, an essential element of genetic association testing. However, the observation of high D:M ratios in two independent, widely separated populations of children exposed to different arsenic levels suggests that there is a bona fide developmental component to arsenic metabolism in humans. Thus, it should not be entirely surprising that there is a genetic association with arsenic metabolism that is influenced by developmental stage.
Significance: Dr. Klimecki’s findings raise the possibility that a particular subset of exposed children may have increased susceptibility to arsenic toxicity by virtue of metabolism that is skewed toward enhanced accumulation of toxic species. Further research that integrates these findings with mechanistic studies of arsenic toxicity will be needed to explore this possibility.
Understanding the individual variation in arsenic metabolism is critical to understanding how arsenic affects populations. This knowledge would allow a more rational, quantitative approach to adjusting the dose-response assessment phase of the toxicological risk assessment process for inter-individual variability than the currently employed 10-fold uncertainty factors. Thus, this research will begin to determine real estimates of inter-individual variability that will form the basis of more accurate and more cost-beneficial toxicological risk assessments.
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To learn more about this research, please refer to the following sources:
- Meza MM, Yu L, Rodriguez YY, Guild M, Thompson D, Gandolfi A, Klimecki WT. 2005. Developmentally restricted genetic determinants of human arsenic metabolism: association between urinary methylated arsenic and CYT19 polymorphisms in children. Environ Health Perspect 113(6):775-781. PMID:15929903
- Chowdhury UK, Rahman MM, Sengupta MK, Lodh D, Chanda CR, Roy S, Quamruzzaman Q, Tokunaga H, Ando M, Chakraborti DK. 2003. Pattern of excretion of arsenic compounds [arsenite, arsenate, MMA(V), DMA(V)] in urine of children compared to adults from an arsenic exposed area in Bangladesh. J Environ Sci Health A Tox Hazard Subst Environ Eng 38(1):87-113. PMID:12635821
- Yu L, Kalla K, Guthrie E, Vidrine A, Klimecki WT. 2003. Genetic variation in genes associated with arsenic metabolism: GST-Omega and Purine Nucleoside Phosphorylase polymorphisms in European and Indigenous Americans. EHP Toxicogenomics 111(11):1421-1428.
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