Arsenic Alters the Function of the
Glucocorticoid Receptor as a Transcription Factor

Environmental Health Perspectives v.109, n.3, Mar01

Ronald C. Kaltreider, Alisa M. Davis, Jean P. Lariviere, and Joshua W. Hamilton

Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, USA

Abstract

Chronic human exposure to nonovertly toxic doses of arsenic is associated with an increased risk of cancer. Although its carcinogenic mechanism is still unknown, arsenic does not directly cause DNA damage or mutations and is therefore thought to act principally as a co-mutagen, co-carcinogen, and/or tumor promoter. Previous studies in our laboratory demonstrated that effects of low-dose arsenic (III) (arsenite) on expression of the hormone-regulated phosphoenolpyruvate carboxykinase (PEPCK) gene were strongly associated with the glucocorticoid receptor (GR)-mediated regulatory pathway. We therefore examined specifically the effects of arsenite on the biochemical function of GR in hormone-responsive H4IIE rat hepatoma cells. Completely noncytotoxic arsenite treatments (0.3-3.3 µM) significantly decreased dexamethasone-induced expression of transiently transfected luciferase constructs containing either an intact hormone-responsive promoter from the mammalian PEPCK gene or two tandem glucocorticoid response elements (GRE). Western blotting and confocal microscopy of a green fluorescent protein-tagged-GR fusion protein demonstrated that arsenite pretreatment did not block the normal dexamethasone-induced nuclear translocation of GR. These data indicate that nontoxic doses of arsenite can interact directly with GR complexes and selectively inhibit GR-mediated transcription, which is associated with altered nuclear function rather than a decrease in hormone-induced GR activation or nuclear translocation. Key words: arsenic, carcinogenesis, endocrine disruptor, gene regulation, glucocorticoid receptor, metal, transcription factor. Environ Health Perspect 109:245-251 (2001). [Online 26 February 2001] http://ehpnet1.niehs.nih.gov/docs/2001/109p245-251kaltreider/abstract.html

Address correspondence to J.W. Hamilton, Department of Pharmacology and Toxicology, 7650 Remsen, Dartmouth Medical School, Hanover, NH 03755-3835 USA. Telephone: (603) 650-1316. Fax: (603) 650-1129. E-mail: josh.hamilton@dartmouth.edu  We thank J. Bodwell (Dartmouth Medical School) for his technical assistance and intellectual support and A. Givan and K. Orndorff for technical assistance.

This work was supported by grant ES07373 to J.W. Hamilton from the National Institute of Environmental Health Sciences (NIEHS). J.W.H. was also partially supported by the Norris Cotton Cancer Center Core grant CA23108 from the National Cancer Institute, and R.C. Kaltreider was supported by a fellowship from NIEHS ES07373. Support for the Dartmouth College Molecular Biology Core Facility was provided by NIEHS ES07373 and the Norris Cotton Cancer Center Core grant CA23108. Support for the Dartmouth College Cell Imaging Core Facility was provided by the Norris Cotton Cancer Center Core grant CA23108.

Received 25 August 2000; accepted 13 October 2000.
Last Updated: February 26, 2001