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ToxSci Advance Access originally published online on February 5, 2007
Toxicological Sciences 2007 98(1):75-86; doi:10.1093/toxsci/kfm013
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

HIGHLIGHTED ARTICLE

Arsenic as an Endocrine Disruptor: Effects of Arsenic on Estrogen Receptor–Mediated Gene Expression In Vivo and in Cell Culture

Jennifer C. Davey*,{dagger}, Jack E. Bodwell{dagger},{ddagger}, Julie A. Gosse*,{dagger} and Joshua W. Hamilton*,{dagger},1

* Department of Pharmacology & Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835 {dagger} Center for Environmental Health Sciences, Dartmouth Medical School, Hanover, New Hampshire 03755-3851 {ddagger} Department of Physiology, Dartmouth Medical School, Lebanon New Hampshire 03756-0001

1 To whom correspondence should be addressed at Department of Pharmacology & Toxicology, 7650 Remsen Building, Room 514, Dartmouth Medical School, Hanover NH 03755-3835. Fax: (603) 650-1129. E-mail: josh.hamilton{at}dartmouth.edu.

Received December 12, 2006; accepted January 8, 2007


  Abstract

Arsenic (As) contamination of drinking water is considered a serious worldwide environmental health threat that is associated with increased disease risks including skin, lung, bladder, and other cancers; type 2 diabetes; vascular and cardiovascular diseases; reproductive and developmental effects; and neurological and cognitive effects. Increased health risks may occur at as low as 10–50 ppb, while biological effects have been observed in experimental animal and cell culture systems at much lower levels. We previously reported that As is a potent endocrine disruptor, altering gene regulation by the closely related glucocorticoid, mineralocorticoid, progesterone, and androgen steroid receptors (SRs) at concentrations as low as 0.01µM (~ 0.7 ppb). Very low doses enhanced hormone-mediated gene transcription, whereas slightly higher but still noncytotoxic doses were suppressive. We report here that As also disrupts the more distally related estrogen receptor (ER) both in vivo and in cell culture. At noncytotoxic doses (1–50 µmol/kg arsenite) As strongly suppressed ER-dependent gene transcription of the 17ß-estradiol (E2)–inducible vitellogenin II gene in chick embryo liver in vivo. In cell culture, noncytotoxic levels (0.25–3µM, ~ 20–225 ppb) of As significantly inhibited E2-mediated gene activation of an ER-regulated reporter gene and the native ER-regulated GREB1 gene in human breast cancer MCF-7 cells. While the effects of As on ER-dependent gene regulation were generally similar to As effects on the other SRs, there were specific differences, particularly the lack of significant enhancement at the lowest doses, that may provide insights into possible mechanisms.

Key Words: arsenic (As); estrogen receptor (ER); steroid receptors (SR); GREB1.


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