Arsenic exposure, AS3MT polymorphism, and neuropsychological functioning among rural dwelling adults and elders: a cross-sectional study.
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ABSTRACT:
SUBMITTER: Edwards M
PROVIDER: S-EPMC4234288 | biostudies-literature | 2014 Mar
REPOSITORIES: biostudies-literature
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Arsenic exposure, AS3MT polymorphism, and neuropsychological functioning among rural dwelling adults and elders: a cross-sectional study.
Edwards Melissa M Hall James J Gong Gordon G O'Bryant Sid E SE
Environmental health : a global access science source 20140312 1
<h4>Background</h4>The aim was to examine the link between low-level arsenic exposure and cognitive functioning, and the potential role of a single nucleotide polymorphism (SNP A35991G, rs10748835) of the AS3MT gene in modifying this link.<h4>Methods</h4>Data were analyzed on 526 participants from Project FRONTIER. Hierarchical linear regressions were created with neuropsychological raw index scores as the outcome variable and arsenic exposure and AS3MT SNP as different predictor variables.<h4>R ...[more]
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Project description:BACKGROUND:Inorganic arsenic at high and prolonged doses is highly neurotoxic. Few studies have evaluated whether long-term, low-level arsenic exposure is associated with neuropsychological functioning in adults. OBJECTIVES:To investigate the association between long-term, low-level inorganic arsenic exposure and neuropsychological functioning among American Indians aged 64-95. METHODS:We assessed 928 participants in the Strong Heart Study by using data on arsenic species in urine samples collected at baseline (1989-1991) and results of standardized tests of global cognition, executive functioning, verbal learning and memory, fine motor functioning, and speed of mental processing administered during comprehensive follow-up evaluations in 2009-2013. We calculated the difference in neuropsychological functioning for a 10% increase in urinary arsenic with adjustment for sex, age, education, and study site. RESULTS:The sum of inorganic and methylated arsenic species (?As) in urine was associated with limited fine motor functioning and processing speed. A 10% increase in ?As was associated with a .10 (95% CI -.20, -.01) decrease on the Finger Tapping Test for the dominant hand and a .13 decrease (95% CI -.21, -.04) for the non-dominant hand. Similarly, a 10% increase in ?As was associated with a .15 (95% CI -.29, .00) decrease on the Wechsler Adult Intelligence Scale-Fourth Edition Coding Subtest. ?As was not associated with other neuropsychological functions. CONCLUSIONS:Findings indicate an adverse association between increased urinary arsenic fine motor functioning and processing speed, but not with other neuropsychological functioning, among elderly American Indians.
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Project description:Arsenic methylation, the primary biotransformation in the human body, is catalyzed by the enzyme As(III) S-adenosylmethionine (SAM) methyltransferases (hAS3MT). This process is thought to be protective from acute high-level arsenic exposure. However, with long-term low-level exposure, hAS3MT produces intracellular methylarsenite (MAs(III)) and dimethylarsenite (DMAs(III)), which are considerably more toxic than inorganic As(III) and may contribute to arsenic-related diseases. Several single nucleotide polymorphisms (SNPs) in putative regulatory elements of the hAS3MT gene have been shown to be protective. In contrast, three previously identified exonic SNPs (R173W, M287T, and T306I) may be deleterious. The goal of this study was to examine the effect of single amino acid substitutions in hAS3MT on the activity of the enzyme that might explain their contributions to adverse health effects of environmental arsenic. We identified five additional intragenic variants in hAS3MT (H51R, C61W, I136T, W203C, and R251H). We purified the eight polymorphic hAS3MT proteins and characterized their enzymatic properties. Each enzyme had low methylation activity through decreased affinity for substrate, lower overall rates of catalysis, or lower stability. We propose that amino acid substitutions in hAS3MT with decreased catalytic activity lead to detrimental responses to environmental arsenic and may increase the risk of arsenic-related diseases.
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