Arsenic as an Endocrine Disruptor: Arsenic
Disrupts Retinoic Acid Receptor– and Thyroid Hormone
Receptor–Mediated Gene Regulation and Thyroid
Hormone–Mediated Amphibian Tail Metamorphosis Jennifer C. Davey, Athena P. Nomikos,
Manida Wungjiranirun, Jenna R. Sherman, Liam Ingram, Cavus
Batki, Jean P. Lariviere, and Joshua W. Hamilton Department of Pharmacology & Toxicology,
and Center for Environmental Health Sciences, Dartmouth Medical
School, Hanover,
New Hampshire, USA Abstract Background: Chronic exposure to excess arsenic in drinking water has been strongly associated with increased risks of multiple cancers, diabetes, heart disease, and reproductive and developmental problems in humans. We previously demonstrated that As, a potent endocrine disruptor at low, environmentally relevant levels, alters steroid signaling at the level of receptor-mediated gene regulation for all five steroid receptors. Objectives: The goal of this study was to determine whether As can also disrupt gene regulation via the retinoic acid (RA) receptor (RAR) and/or the thyroid hormone (TH) receptor (TR) and whether these effects are similar to previously observed effects on steroid regulation. Methods and results: Human embryonic NT2 or rat pituitary GH3 cells were treated with 0.01–5 µM sodium arsenite for 24 hr, with or without RA or TH, respectively, to examine effects of As on receptor-mediated gene transcription. At low, noncytotoxic doses, As significantly altered RAR-dependent gene transcription of a transfected RAR response element–luciferase construct and the native RA-inducible cytochrome P450 CYP26A gene in NT2 cells. Likewise, low-dose As significantly altered expression of a transfected TR response element–luciferase construct and the endogenous TR-regulated type I deiodinase (DIO1) gene in a similar manner in GH3 cells. An amphibian ex vivo tail metamorphosis assay was used to examine whether endocrine disruption by low-dose As could have specific pathophysiologic consequences, because tail metamorphosis is tightly controlled by TH through TR. TH-dependent tail shrinkage was inhibited in a dose-dependent manner by 0.1– 4.0 µM As. Conclusions: As had similar effects on RAR- and TR-mediated gene regulation as those previously observed for the steroid receptors, suggesting a common mechanism or action. Arsenic also profoundly affected a TR-dependent developmental process in a model animal system at very low concentrations. Because RAR and TH are critical for both normal human development and adult function and their dysregulation is associated with many disease processes, disruption of these hormone receptor–dependent processes by As is also potentially relevant to human developmental problems and disease risk. Key words: arsenic (As) , CYP26A, deiodinase (DIO1) , endocrine, retinoic acid (RA) , steroid, thyroid (TH) . Environ Health Perspect 116: 165–172 (2008) . doi:10.1289/ehp.10131 available via http://dx.doi.org/ [Online 26 October 2007] Address correspondence to J.W. Hamilton, Department of Pharmacology & Toxicology, 7650 Remsen Building, Room 514, Dartmouth Medical School, Hanover NH 03755-3835 USA. Telephone: (603) 650-1316. Fax: (603) 650-1129. E-mail: josh.hamilton@dartmouth.edu Supplemental Material is available online at http://www.ehponline.org/members/2007/10131/suppl.pdf We thank J. Bodwell, J. Gosse, and B. Stanton for their useful comments and suggestions. We also acknowledge the assistance of B. Jackson and A. LaCroix-Fralish of the Dartmouth Trace Elements Analysis (TEA) Core Facility for their assistance in the trace analysis of our samples. This work was supported by grant P42 ES07373 to J.W.H. [Superfund Basic Research Program (SBRP) Project, Project 2 ; National Institute of Environmental Health Sciences, National Institutes of Health]. A.P.N. was supported by a graduate fellowship (P42 ES07373 ; SBRP, Training Core) . The TEA Core is partially supported by grant P42 ES07373 (SBRP, Core B) and by an instrument grant from the National Science Foundation (MRI-0215913) . The authors declare they have no competing financial interests. Received 1 February 2007 ; accepted 25 October 2007. The full version of this article is available for free in HTML or PDF formats. |