low-dose arsenic affects hormone receptors - hormesis

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Cell experiments show that arsenic interacts at extremely low levels with

several hormone receptors. The dose-response curves contradict classic

'dose makes the poison' toxicology. The pattern of gene alteration at low

doses is almost completely different than the pattern at high, overtly

toxic doses. These results indicate the epidemiological links between low

dose arsenic and a range of human health conditions, including cancer,

diabetes, developmental problems and cardiovascular disease, may result

from its ability to disrupt hormone mechanisms.

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Arsenic Disruption of Steroid Receptor Gene Activation: Complex

Dose-Response Effects Are Shared by Several Steroid Receptors

Chem. Res. Toxicol., 19 (12), 1619 -1629, 2006.

http://pubs.acs.org/cgi-bin/article.cgi/crtoec/2006/19/i12/html/tx060122q.html

Jack E. Bodwell et al.

Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire

03756, and Department of Pharmacology & Toxicology and Center for

Environmental Health Sciences, Dartmouth Medical School, Hanover, New

Hampshire 03755

Abstract:

Chronic intake of arsenic (As) has been associated with increased risk of

cancer, diabetes, developmental and reproductive problems, and

cardiovascular disease. Recent studies suggest increased health risks with

drinking water levels as low as 5-10 ppb. We previously reported that As

disrupts glucocorticoid receptor (GR) mediated transcription in a very

complex fashion. Low As levels (0.1-0.7 M) stimulated transcription,

whereas slightly higher levels (1-3 M) were inhibitory. The DNA binding

domain (DBD) was the minimal region of GR required for the response to As.

Mutations in the DBD that alter the conformation of the dimerization

domain (D-loop) to a DNA-bound GR conformation abolished the stimulatory

effect and enhanced the inhibitory response to As. Here we report that

receptors for progesterone (PR) and mineralocorticoids display a complex

As response similar to that of the GR, suggesting a common mechanism for

this effect. The complex response to As is not due to altered steroid or

receptor levels. Moreover, a well-characterized GR dimerization mutant

displayed a wild-type biphasic response to As for several divergent

reporter genes, suggesting that dimerization is not critical for the

response to As. Fluorescence polarization studies with purified PR and GR

demonstrated that the specific PR/GR-DNA interaction is not altered in the

presence of As. These results indicate that the numerous and diverse human

health effects associated with As exposure may be mediated, at least in

part, through its ability to simultaneously disrupt multiple hormone

receptor systems.