Superfund Research Program
Arsenic as an Endocrine Disrupter
Chronic exposure to arsenic in drinking water is associated with increased risk of various cancers, type 2 diabetes, vascular and cardiovascular disease, and developmental and reproductive problems. The mechanisms by which arsenic contributes to these various disease processes is unknown. This project previously reported that arsenic acts as a potent endocrine disruptor, altering hormone-mediated cell signaling at extremely low doses that are directly relevant to human exposures of concern in New Hampshire and elsewhere in the U.S. from both naturally and anthropogenically contaminated drinking water and soil. This project is primarily examining potential mechanisms underlying this endocrine disruption, focusing in particular on the ability of low level arsenic to selectively alter the pattern of hormone-regulated gene expression. Dr. Hamilton’s research team also collaborates with Projects 1, 4 and 7 to develop and apply genomics and proteomics tools in these studies. They had previously demonstrated that arsenic alters hormone signaling by all five steroid receptors, as well as the retinoic acid receptor. Over the past year, they have also shown that arsenic alters thyroid hormone receptor signaling in a similar manner, indicating that it affects a broad class of nuclear receptors that are critical to many different normal and pathophysiological pathways. The research team recently demonstrated that arsenic substantially alters the pattern of changes in chromatin that are critical for hormone receptor signaling. They have also used genomics approaches to investigate the global patterns of gene expression changes in using mice exposed to arsenic in drinking water, in collaboration with Aaron Barchowsky of Dartmouth’s SBRP Project 1 and with Drs. Jay Gandolfi and Clark Lantz of the Arizona Superfund Basic Research Program. Project investigators have continued these studies and have shown that there is a small number of very specific changes that occur in lung and heart, and that these changes are tissue-, dose-, and time-point specific. The investigators have worked with Project 4 to examine effects of arsenic on expression of DNA repair genes in the New Hampshire population (see below) and have also worked with Project 7 to use genomics tools to develop potential biomarkers of toxic metal exposure and effect in the aquatic sentinel species, Daphnia pulex (see below). The researchers recent publication in Chemical Research in Toxicology received national attention since it demonstrated that exceedingly low concentrations of arsenic disrupt hormone signaling, even at levels well below the new drinking water MCL for arsenic.