Superfund Research Program
Arsenic as an Endocrine Disrupter
This project (2005 is its eleventh year) is focused on two aspects of arsenic molecular toxicology, based on previous research discoveries by this group. The first aspect is to investigate the molecular basis for the ability of arsenic to act as a potent endocrine disruptor. In particular, Dr. Hamilton previously discovered that extremely low levels of arsenic exposure (in dose ranges equivalent to 1-100 parts per billion (ppb) which is the range of exposures typically found in U.S. drinking water supplies) had profound effects on the function of all five steroid hormone receptors as well as the receptors for thyroid hormone and retinoic acid. Given the myriad of functions that these receptors and their hormones modulate in normal human biology, as well as the many diseases in which they have been shown to play a fundamental role, it is hypothesized that this is one of the major pathways by which arsenic increases the risk of various cancers, heart and vascular disease, reproductive and developmental problems, diabetes, and other diseases associated with arsenic exposure. These results also predict that there will be human health effects at drinking water levels of arsenic at or below the current U.S. drinking water standard of 10 ppb.
Current work in Dr. Hamilton’s lab is focusing on how arsenic perturbs the interaction of these receptors with the partner proteins that are required for modulating hormone-induced gene transcription. The other area of their research focuses on use of toxicogenomics to examine patterns of gene expression associated with endocrine disruption as well as other gene expression effects that might provide clues to arsenic’s mechanism of action. The Hamilton group’s cell culture studies using normal human lung cells (a a target for arsenic toxicity and carcinogenesis) are focusing on the long term effects of arsenic on gene expression, as well as examining the possible role of adaptation in modulating the arsenic response and the possible reversal of effects following cessation of exposure. Their mouse studies are focusing on the role of different sources of arsenic and pathways of exposure on resulting toxicogenetic endpoints, and also examining the role of adaptation.