title: 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.
authors: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
authors: Jorge G
authors: JG
authors: Muñiz Ortiz
authors: Junjun
authors: J
authors: Shang
authors: Brittany
authors: B
authors: Catron
authors: Julio
authors: J
authors: Landero
authors: Joseph A
authors: JA
authors: Caruso
authors: Iain L
authors: IL
authors: Cartwright
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D001151:Arsenic / Q000633:toxicity*; D018053:Arsenites / Q000378:metabolism*; D001822:Body Burden; D002875:Chromosomes / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004330:Drosophila / Q000235:genetics*; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D023421:Models, Animal
chemical_list: D018053:Arsenites; D008780:Methyltransferases; C505756:AS3MT protein, human; C015001:arsenite; D001151:Arsenic