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Characterization of the molecular mechanism by which arsenic and chromium alter inducible gene expression.

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Call No.	RA1231.A7 K35 2000
Author	Kaltreider, Ronald C.
Title	Characterization of the molecular mechanism by which arsenic and chromium alter inducible gene expression.
Date	2000
Abstract	Metals are ubiquitous in our environment. Through evolution, many biological processes have taken advantage of and have become dependent on specific metals for various biochemical functions. Metals can also be toxic to biological systems at elevated concentrations, and can represent significant human health risks as a result of occupational exposure or environmental contamination. It had previously been reported that arsenic and chromium significantly altered the expression of several inducible genes while having no effect on non-inducible or constitutive gene expression at low, environmentally relevant doses that caused no overt toxicity. We hypothesize that arsenic(III) and chromium(VI) each selectively alter inducible gene expression by targeting specific, but distinct, trans-activation pathways. These studies were designed to test this hypothesis in detail. Our data demonstrate that non-overtly toxic doses of arsenic and chromium are able to significantly alter the function of specific transcription factors that regulate expression of several metal-sensitive inducible genes, in a metal-, dose-, and time-dependent manner. In particular, chromium and arsenic differentially altered the function of the glucocorticoid receptor (GR) as a nuclear transcription factor at very low doses, although through different mechanisms. Arsenic binds stoichiometrically to GR and we hypothesize that this leads to alteration in GR interactions with critical transcriptional co-factors. Chromium''s effect appears to be mediated through an extracellular signaling event, leading to alterations in GR function. Taken together, these studies provide a greater understanding of the mechanisms by which arsenic and chromium alter inducible gene expression. These results also suggest a direct role for GR in arsenic- and chromium-associated disease states such as cancer.
Description	1 online resource (xiv, 217 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Hamilton, Joshua W.
Subject	Arsenic -- Mechanism of action. ; Arsenic -- Toxicology. ; Chromium -- Mechanism of action. ; Chromium -- Toxicology. ; Gene expression.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org/10.1349/ddlp.2772

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Characterization of the molecular mechanism by which arsenic and chromium alter inducible gene expression.

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