The overall objective of this research is to determine the mechanism by which inorganic arsenic (As) increases human disease risks. The specific goal is to determine the mechanism by which As acts as an endocrine disrupter, which our laboratory first reported and has now demonstrated occurs with several nuclear hormone receptors via a unique mechanism distinct from that of other known endocrine disrupters. We hypothesize that As-induced endocrine disruption is one of the principal means by which it is able to influence the wide array of disease risks including various cancers, diabetes, cardiovascular disease and developmental problems to which it has been linked in epidemiology studies, and that these effects are a result of As targeting one or more critical regulatory steps that are shared by these receptors, leading in turn to a variety of patho-physiological consequences. We will examine As effects on glucocorticoid receptor (GR)-mediated gene expression in H4IIE and EDR3 rat hepatoma cells as our principal model system, focusing on the differential effects of As on GR signaling at low and intermediate As doses.
Our Specific Aims are to: 1) Determine the effects of very low dose As (0.01-1 u.M, 0.75-75 ppb) to enhance GR-mediated gene regulation. We hypothesize that these effects are a result of As targeting the early steps in receptor activation between binding of hormone and activation of transcription. 2) Determine the effects of intermediate dose As (1-3 |aM, 75-225 ppb) to suppress hormone receptor-mediated gene regulation. We hypothesize that these effects are distinct from the enhancement seen at lower doses, and involve the intermediate to later steps of receptor-mediated transcription. 3) Determine the effects of endocrine disruption by As on two hormone-regulated and As-affected genes, TAT and GREB1, that are likely to be involved in As-associated disease processes. We will use a combination of confocal microscopy, molecular biology, biochemistry, and proteomics approaches to investigate these questions. The long-term goals of this project are to provide mechanistic insights that can be used for more effective science-based risk assessments, for predicting the specific patho-physiological consequences of As exposure, for assessing gene-environment, agent-agent and other interactions, for assessing specifically sensitive sub-populations at elevated risk, and for developing effective interventions for these As-exposed populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
5P42ES007373-16
Application #
8056101
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
16
Fiscal Year
2010
Total Cost
$346,603
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

Showing the most recent 10 out of 372 publications