Among the most serious issues confronting the global public health community is the long term consequence of arsenic ingestion in drinking water, a situation that has affected an estimated 100 million people worldwide, albeit disproportionately so in Bangladesh and West Bengal owing to the widespread provision of wells drawing arsenic-laced groundwater. Though arsenic is a well-known acute poison of oxidative phosphorylation when ingested in large quantities, chronic, low-level exposure leads to a variety of pathologies, among which are numerous forms of cancer. Mechanistically it has proven difficult to assign the specific cause of arsenic-induced cancer, though DNA and/or chromosomal aberrations typically accompany its appearance, and there has been much debate regarding whether or not arsenic can act as a complete carcinogen. Moreover, progress in these areas has been hampered by a relative lack of suitable animal models. Recently, the realization that metabolic methylation of arsenic may actually lead to a more potent carcinogen rather than to its presumed detoxification has prompted interest in the mechanism of methylation, the species formed, and the possibility that polymorphisms in the gene(s) involved in uptake, metabolism and excretion of arsenic may have profound effects on susceptibility of exposed individuals. To address some of these issues with a well-defined, genetically amenable, in vivo system we propose to create a Drosophila transgenic model, in which control, and precise analysis, of arsenic methylation (catalyzed by human gene variants that occur naturally in the population) can be married with a variety of in vivo assays investigating specific features of DNA metabolism (oxidative damage, strand breakage, recombination), cellular response (chromosomal aberrations, cell cycle aberrations), and carcinogenic potential via tumor formation in a transplantation assay. With the enormous versatility available in the Drosophila system, allowing controllable over- and underexpression of virtually any endogenous gene to be easily achieved, it is anticipated that critical molecular pathways intersected by arsenic and its methylated metabolites can be identified as a result of phenotypic variation occurring in one or more of the above assays when tested in such altered genetic backgrounds. Thus, we propose that a model higher eukaryotic organism, one that has consistently proved to be an unparalleled resource in uncovering critical molecular features of numerous human pathological conditions, can be harnessed to shed light on a vitally important toxicogenetic problem.
The long-term ingestion of arsenic via drinking water by human populations in many parts of the world has proven to be one of the largest global public health disasters of modern times owing to the variety of detrimental health consequences that ensue, including numerous forms of organ cancer. Though much of interest has been learned from studies in cultured cells, investigation of the mechanisms by which this toxic metal affects biological pathways (particularly in its ability to cause cancer) has been hampered by a relative lack of good animal models that duplicate the human pathologies.
We aim to develop a model for arsenic cellular toxicity and tumorigenesis by introducing critical human genes involved in arsenic metabolism into the fruit fly, Drosophila, where a combination of assays, allied to the unparalleled genetic manipulability of this organism, are anticipated to shed new light on questions related to how arsenic induces cancer and why individuals show widely variable susceptibility to its effects.
|States, J Christopher; Barchowsky, Aaron; Cartwright, Iain L et al. (2011) Arsenic toxicology: translating between experimental models and human pathology. Environ Health Perspect 119:1356-63|
|Muniz Ortiz, Jorge G; Shang, Junjun; Catron, Brittany et al. (2011) A transgenic Drosophila model for arsenic methylation suggests a metabolic rationale for differential dose-dependent toxicity endpoints. Toxicol Sci 121:303-11|