Dartmouth Medical School investigators are learning more about how low doses of arsenic, such as the levels found in drinking water in many areas of the United States, affect human physiology. In a paper published online on Dec. 2 in the journal Chemical Research in Toxicology, the researchers report that three different steroid hormones all show similar responses to arsenic, suggesting a broader effect and a common mechanism of arsenic on how these hormones function.
"Since most of the health consequences of exposure to arsenic - various cancers, diabetes, heart and vascular disease, reproductive and developmental effects, etc. - involve these same steroid receptors, we think that disruption of their normal function could explain, in large part, how arsenic can influence so many disease risks," says Joshua Hamilton, one of the authors on this study and the director of the Center for Environmental Health Sciences at Dartmouth and Dartmouth's Superfund Basic Research Program on Toxic Metals.
Hamilton's laboratory had earlier found that arsenic disrupts the activity of the glucocorticoid receptor, and this follow up study considered the progesterone and mineralocorticoid receptors, which regulate a wide range of biological processes. This work was done in collaboration with Jack Bodwell, the lead author on this paper and a research associate professor of physiology at Dartmouth Medical School.
Hamilton, Bodwell, and their team found that arsenic appears to suppress the ability of all three of these critical receptors to respond to their normal hormone signals. Chemicals that disrupt steroid hormone receptor signaling are called endocrine disruptors, and this study provides further evidence that arsenic, a metal, does not behave like other endocrine disruptors such as pesticides.
"Arsenic does not activate these receptors, as some endocrine disruptors do, by mimicking the natural hormone, nor does it block the ability of the normal hormones to activate their specific receptor, as most other endocrine disruptors do," says Hamilton, who is also a professor of pharmacology and toxicology at Dartmouth Medical School. "Nor does it affect the ability of the hormone-activated receptor to move to the nucleus of the cell or to bind to DNA to initiate gene expression. Yet, somehow arsenic still strongly affects the ability of these hormone-activated receptors to regulate gene expression. There's still a lot more to learn."
The study also looked into the effects of different levels of arsenic on these receptors. At very low doses (comparable to what is found in drinking water at the current and previous U.S. regulatory limits, in the range of 5-50 ppb) arsenic enhances hormone-stimulated gene expression, by two- to three-fold. At slightly higher doses (in the range of 50-200 ppb, commonly found in drinking water from contaminated wells in New Hampshire and elsewhere in the U.S.) arsenic has the exact opposite effect, strongly and almost completely inhibiting hormone-stimulated gene expression by these receptors. This non-conventional dose-response suggests that arsenic might have very different biological effects at the lower and higher doses.
"Elucidating these complex biological effects of arsenic on hormone signaling at different doses will be critical to our overall understanding of how arsenic influences human health, and should be considered as an important component of determining the overall disease risk of people who are exposed to arsenic in their drinking water, " says Hamilton.
The work is funded by grants to Dartmouth collaborators Hamilton and Bodwell from the National Institute of Environmental Health Sciences, a component of the National Institutes of Health. Both researchers are members of the NIEHS-funded Superfund Basic Research Program at Dartmouth and Dartmouth's Center for Environmental Health Sciences. Co-authors on the study include Julie A. Gosse, and Athena P. Nomikos, both of Dartmouth and both recipients of training fellowships from Dartmouth's Superfund Basic Research Program.
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