Arsenic is found at high levels in almost half of all Superfund sites as well as many public and private water supplies in the northeastern and western regions of the United States. High levels of arsenic in drinking water are associated with an increased risk of skin, bladder, lung, and kidney cancer. Previous work in this and other laboratories has demonstrated that arsenic can have substantial effects on specific cytochrome P450s (CYPs) that are principally responsible for metabolism of drugs and other xenobiotics by the liver, lung and other organs. In particular, arsenic exposure decreases the induction of CYPs by chemicals that are subsequently metabolized by these CYPs. We hypothesize that arsenic-induced alterations in CYP mediated xenobiotic metabolism may have a significant impact on the response of humans and other organisms to other toxic chemicals, which might occur in Superfund sites containing arsenic in combination with other metals and organic contaminants. This is postulated to increase the bioaccumulation of other toxic chemicals, and therefore these effects may contribute to arsenic- induced cancer and vascular disease and/or enhance the toxicity of other chemicals. The overall goal of this project is to determine the effects of arsenic (III) and other selected metals on specific liver CYPs. Our previous studies have demonstrated in hepatocytes in culture that low concentrations of arsenic significantly decrease induction of several major CYPs. These arsenic mediated decreases are not due to the induction of heme oxygenase, depletion of heme, or oxidative damage as had been previously postulated. We hypothesize that these effects occur mainly at the post-transcriptional level.
Our specific aims will be to: 1) determine in intact rodents the effects of acute and chronic exposure to arsenic (III) on induction of CYPs, and the ability of arsenic to modulate accumulation and elimination of polychlorinated biphenyls and drugs; and 2) determine, in cultured hepatocytes, the post-transcriptional mechanisms by which arsenite specifically decreases synthesis of rat CYPA23 and chick CYP2H1. These studies may provide insight into effects of arsenic and other toxic metals, in combination with exposures to other toxic agents, that have not previously been appreciated. Since most Superfund sites and other waste sites contain complex mixtures of toxins, and over 60% of these sites contain toxic metals, understanding their effects when present in combinations will be important for our overall evaluation of the health effects of these agents.

Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
8
Fiscal Year
2002
Total Cost
$163,250
Indirect Cost
Name
Dartmouth College
Department
Type
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Taylor, V F; Buckman, K L; Seelen, E A et al. (2018) Organic carbon content drives methylmercury levels in the water column and in estuarine food webs across latitudes in the Northeast United States. Environ Pollut 246:639-649
Shi, Xiangming; Mason, Robert P; Charette, Matthew A et al. (2018) Mercury flux from salt marsh sediments: Insights from a comparison between 224Ra/228Th disequilibrium and core incubation methods. Geochim Cosmochim Acta 222:569-583
Andrew, Angeline S; Chen, Celia Y; Caller, Tracie A et al. (2018) Toenail mercury Levels are associated with amyotrophic lateral sclerosis risk. Muscle Nerve :
Eagles-Smith, Collin A; Silbergeld, Ellen K; Basu, Niladri et al. (2018) Modulators of mercury risk to wildlife and humans in the context of rapid global change. Ambio 47:170-197
Obrist, Daniel; Kirk, Jane L; Zhang, Lei et al. (2018) A review of global environmental mercury processes in response to human and natural perturbations: Changes of emissions, climate, and land use. Ambio 47:116-140
Farzan, Shohreh F; Howe, Caitlin G; Chen, Yu et al. (2018) Prenatal lead exposure and elevated blood pressure in children. Environ Int 121:1289-1296
Deyssenroth, Maya A; Gennings, Chris; Liu, Shelley H et al. (2018) Intrauterine multi-metal exposure is associated with reduced fetal growth through modulation of the placental gene network. Environ Int 120:373-381
Chen, Celia Y; Driscoll, Charles T; Eagles-Smith, Collin A et al. (2018) A Critical Time for Mercury Science to Inform Global Policy. Environ Sci Technol 52:9556-9561
Punshon, Tracy; Carey, Anne-Marie; Ricachenevsky, Felipe Klein et al. (2018) Elemental distribution in developing rice grains and the effect of flag-leaf arsenate exposure. Environ Exp Bot 149:51-58
Liu, Maodian; Zhang, Qianru; Luo, Yao et al. (2018) Impact of Water-Induced Soil Erosion on the Terrestrial Transport and Atmospheric Emission of Mercury in China. Environ Sci Technol 52:6945-6956

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