Novel Biomarkers for the Risk Assessment of Exposure to Arsenic in Drinking Water

Currier, Jenna

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March 22, 2019

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Currier, Jenna
- Affiliation: School of Medicine, Curriculum in Toxicology

Abstract

The toxic methylated trivalent metabolites of inorganic arsenic (iAs), methylarsonite (MAsIII) and dimethylarsinite (DMAsIII), play an important role in the etiology of As-induced diseases, including diabetes mellitus. However, the rapid oxidation of DMAsIII and, to a lesser extent, MAsIII leads to difficulties in the analysis of these metabolites in biological samples and assessment of the risk associated with As exposure. The goal of this project was to determine if a recently optimized analytical technique, hydride generation-cryotrapping-atomic absorption spectroscopy (HG-CT-AAS), can be used to quantitate trivalent As species in complex biological matrices, and determine whether concentrations of these species in biological systems can predict susceptibility to the diabetogenic effects of As exposure. First, we established that HG-CT-AAS is suitable for the quantification of MAsIII and DMAsIII and that these species are relatively stable in cells and tissues. We then used HG-CT-AAS to compare As speciation in tissues of wild-type (WT) mice that methylate As and mice null for As (3+ oxidation state) methyltransferase (As3mt-KO), the key enzyme in the pathway for As methylation, focusing on tissues regulating glucose homeostasis, including liver, pancreas, skeletal muscle, and adipose tissue. In WT mice, MAsIII and DMAsIII were extensively retained in these tissues, while iAsIII and iAsV were predominantly retained in tissues of As3mt-KO mice. Lastly, we used HG-CT-inductively coupled plasma-mass spectrometry, which provides lower detection limits, to examine concentrations of tri- and pentavalent As species retained in bladder exfoliated cells (BECs) recovered from individuals exposed to iAs in drinking water, and determined associations between the concentrations of As species in BECs and urine and the individual risk of developing diabetes. As species retained in BECs were positively correlated with other markers of exposure. More importantly, iAsIII and MAsIII retained in BECs were positively associated with risk of diabetes. Taken together, this work demonstrates the robustness of the optimized HG-CT-based techniques for the oxidation state specific analysis of As species in a variety of biological samples, and provides the first evidence that measurements of trivalent arsenicals in these samples can provide sensitive markers for assessment of health risks associated with iAs exposure.

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