Superfund Research Program
Arsenic as an Endocrine Disrupter
The overall goal of this project is to determine the mechanistic basis for the preferential effects of the toxic and carcinogenic metals, arsenic(III) and chromium(VI), on inducible gene expression. Previously, low dose arsenic or chromium exposure was found to have significant but highly selective effects on expression of specific genes. The hypothesis of this project is that such selective effects on gene expression may be the basis for, or contribute to the tissue-specific toxic and carcinogenic properties of these metals in humans. A model gene system (PEPCK) was developed to examine the molecular basis for these effects. The primary specific aims are to determine whether specific DNA regulatory regions within a gene's promoter region, and/or functional alterations in specific transcriptional factors are responsible for these effects. Previous work has shown that the effects of arsenic on PEPCK expression are primarily mediated by the glucocorticoid receptor (GR)-regulated pathway for this gene. Mutation of GR-responsive sequences within the PEPCK promoter largely ablated the effects of arsenic, and model gene constructs containing the PEPCK promoter, or only GR-binding elements (GREs), were affected by arsenic in a similar manner as the native PEPCK gene. Arsenic appears to target GR itself, since it was shown to bind stoichiometrically to GR at low doses. Its effects appear to be allosteric, since it does not interfere with hormone binding or hormone-mediated activation or nuclear translocation of GR, but alters its ability to function as a transcription factor in the nucleus. The suppression of GR function by arsenic may in large part explain the patterns of arsenic-induced disease, i.e., skin and lung cancer, cardiovascular disease and diabetes, since loss of GR responsiveness has been shown to play a fundamental role in each of these disease states. Determining the mechanisms by which arsenic and chromium selectively alter gene expression would have important implications for understanding the molecular basis for the impact of these agents on normal and disease processes. Understanding these interactions at the molecular level is critical for an accurate assessment of the overall health effects of these agents on the human population.