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National Institute of Environmental Health Sciences

 

Dartmouth College: Details

Superfund Research Program

Arsenic as an Endocrine Disrupter

Project Leader: Joshua W. Hamilton (Marine Biological Laboratory)
Grant Number: P42ES7373
Funding Period: 1995-2013
Grantee Website  

Summary

The overall objective of this research is to determine the mechanism by which inorganic arsenic (As) increases human disease risks. The specific goal of Dr. Hamilton's project is to determine the mechanism by which As acts as an endocrine disrupter, Dr. Hamilton and his team first reported the mechanism acting as the endocrine disrupter, and now he and his researchers have demonstrated what occurs when several nuclear hormone receptors, via a unique mechanism, are distinct from that of other known endocrine disrupters.

Researchers hypothesize that As-induced endocrine disruption is one of the principal means by which it (As) is able to influence a wide array of disease risks, including various cancers, diabetes, cardiovascular disease, and developmental problems to which it has been linked to in epidemiology studies. 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. Researchers continue to examine As effects on the glucocorticoid receptor (GR)-mediated gene expression in H4IIE and EDR3 rat hepatoma cells as a principal model that focuses on the differential effects of As on GR signaling at low and intermediate As doses.

Dr. Hamilton's objectives are:

  1. Determine the effects of very low dose As (0.01-1 µM, 0.75-75 ppb) to enhance GR-mediated gene regulation. The researchers 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 µM, 75-225 ppb) to suppress hormone receptor-mediated gene regulation. They 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.

Researchers are using a combination of confocal microscopy, molecular biology, biochemistry, and proteomic approaches to investigate these questions. The long-term goals of this project are to:

  • 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.