Effects of Low-level Arsenic on Hormone Activity

Jack E. Bodwell, Ph.D. and Joshua W. Hamilton, Ph.D.
Dartmouth Medical School
R01ES011819 and P42ES007373

Arsenic is known to be acutely toxic at moderate to high doses and to cause a wide variety of adverse health outcomes at relatively low doses such as cancer, insulin-dependent diabetes, vascular damage, and reproductive and developmental effects. New research findings from the NIEHS Superfund Basic Research Program-supported laboratory of Josh Hamilton at Dartmouth Medical School shed light on a possible mechanism by which arsenic may produce its varied effects.

Previous research by this lab shows that arsenic disrupts glucocorticoid receptor mediated gene transcription in a biphasic manner: at drinking water levels near the current EPA standard (5-50 parts per billion) arsenic enhanced the hormone-stimulated gene expression, but at slightly higher doses (50-200 parts per billion) it had the opposite affect by almost completely blocking hormone-stimulated receptor gene expression. The new research findings mimic these results but in different hormone receptors; progesterone, a steroid hormone involved in female reproduction, and the mineralocorticoid hormones, also steroid hormones responsible for salt and water metabolism and balance.

Agents that disrupt steroid hormone receptor signaling are generally referred to as endocrine disruptors; however, arsenic does not act in the same fashion as most. Other results show that arsenic does not activate the receptors by mimicking the natural hormone as some endocrine disruptors do, nor does it block the natural hormone from binding to and activating its specific receptor. The investigators also determined that arsenic does not inhibit the movement of the hormone-activated receptor into the nucleus of the cell to bind to DNA and initiate gene expression. Further research is necessary to determine the specific cellular processes involved in the complex biological effects caused by arsenic exposure.

Citation: Bodwell JE, Gosse JA, Nomikos AP, Hamilton JW. Arsenic Disruption of Steroid Receptor Gene Activation: Complex Dose-Response Effects Are Shared by Several Steroid Receptors. Chem Res Toxicol. 2006 Dec 18;19(12):1619-1629.