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A transgenic Drosophila model for arsenic methylation suggests a metabolic rationale for differential dose-dependent toxicity endpoints.

ABSTRACT: The mechanisms by which exposure to arsenic induces its myriad pathological effects are undoubtedly complex, while individual susceptibility to their type and severity is likely to be strongly influenced by genetic factors. Human metabolism of arsenic into methylated derivatives, once presumed to result in detoxification, may actually produce species with significantly greater pathological potential. We introduce a transgenic Drosophila model of arsenic methylation, allowing its consequences to be studied in a higher eukaryote exhibiting conservation of many genes and pathways with those of human cells while providing an important opportunity to uncover mechanistic details via the sophisticated genetic analysis for which the system is particularly well suited. The gene for the human enzyme, arsenic (+3 oxidation state) methyltransferase, was introduced into nonmethylating Drosophila under inducible control. Transgenic flies were characterized for enzyme inducibility, production of methylated arsenic species, and the dose-dependent consequences for chromosomal integrity and organismal longevity. Upon enzyme induction, transgenic flies processed arsenite into mono and dimethylated derivatives identical to those found in human urine. When induced flies were exposed to 9 ppm arsenite, chromosomal stability was clearly reduced, whereas at much higher doses, adult life span was significantly increased, a seemingly paradoxical pair of outcomes. Measurement of arsenic body burden in the presence or absence of methylation suggested that enhanced clearance of methylated species might explain this greater longevity under acutely toxic conditions. Our study clearly demonstrates both the hazards and the benefits of arsenic methylation in vivo and suggests a resolution based on evolutionary grounds.

SUBMITTER: Muniz Ortiz JG

PROVIDER: S-EPMC3098963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of AS3MT have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, p16, which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of AS3MT in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the AS3MT gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed.

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A transgenic Drosophila model for arsenic methylation suggests a metabolic rationale for differential dose-dependent toxicity endpoints.

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