title: Target organ specific activity of drosophila MRP (ABCC1) moderates developmental toxicity of methylmercury.
abstract: Methylmercury (MeHg) is a ubiquitous and persistent neurotoxin that poses a risk to human health. Although the mechanisms of MeHg toxicity are not fully understood, factors that contribute to susceptibility are even less well known. Studies of human gene polymorphisms have identified a potential role for the multidrug resistance-like protein (MRP/ABCC) family, ATP-dependent transporters, in MeHg susceptibility. MRP transporters have been shown to be important for MeHg excretion in adult mouse models, but their role in moderating MeHg toxicity during development has not been explored. We therefore investigated effects of manipulating expression levels of MRP using a Drosophila development assay. Drosophila MRP (dMRP) is homologous to human MRP1-4 (ABCC1-4), sharing 50% identity and 67% similarity with MRP1. A greater susceptibility to MeHg is seen in dMRP mutant flies, demonstrated by reduced rates of eclosion on MeHg-containing food. Furthermore, targeted knockdown of dMRP expression using GAL4>UAS RNAi methods demonstrates a tissue-specific function for dMRP in gut, Malpighian tubules, and the nervous system in moderating developmental susceptibility to MeHg. Using X-ray synchrotron fluorescence imaging, these same tissues were also identified as the highest Hg-accumulating tissues in fly larvae. Moreover, higher levels of Hg are seen in dMRP mutant larvae compared with a control strain fed an equivalent dose of MeHg. In sum, these data demonstrate that dMRP expression, both globally and within Hg-targeted organs, has a profound effect on susceptibility to MeHg in developing flies. Our findings point to a potentially novel and specific role for dMRP in neurons in the protection against MeHg. Finally, this experimental system provides a tractable model to evaluate human polymorphic variants of MRP and other gene variants relevant to genetic studies of mercury-exposed populations.
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box EHSC, Rochester, New York 14642.
authors.forename: Lisa
authors.initials: L
authors.lastname: Prince
authors.affiliation: Canadian Light Source Inc. 44 Innovation Boulevard, Saskatoon, SK S7N 2V3, Canada Department of Anatomy and Cell Biology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Korbas
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box EHSC, Rochester, New York 14642 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box EHSC, Rochester, New York 14642.
authors.forename: Philip
authors.initials: P
authors.lastname: Davidson
authors.affiliation: Institute of Environmental Medicine, Box 210, Karolinska Institute, Stockholm, Sweden, 171-77.
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
authors.affiliation: Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box EHSC, Rochester, New York 14642 matthew_rand@urmc.rochester.edu.
authors.forename: Matthew Dearborn
authors.initials: MD
authors.lastname: Rand
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004330:Drosophila / Q000254:growth & development; D055785:Gene Knockdown Techniques; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D008767:Methylmercury Compounds / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D013723:Teratogens / Q000633:toxicity*
chemical_list: D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D008767:Methylmercury Compounds; D013723:Teratogens
keywords: Drosophila; Malpighian tubule; X-ray synchrotron fluorescence; fat body; methylmercury; multidrug resistance-like protein