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Dartmouth Medical School (DMS)
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.
Dartmouth researchers (from left) Athena Nomikos, Jack Bodwell, Josh Hamilton,
and Julie Gosse have found that very low doses of arsenic (comparable to what
is found in drinking water at the current and previous U.S. regulatory limits)
enhances hormone-stimulated gene expression by two- to three-fold. (Photo by
Joseph Mehling '69)
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"Since most of the health consequences of exposure to arsenic-various
cancers, diabetes, heart and vascular disease, reproductive and developmental
effects-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 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
DMS.
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 DMS. "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 United States) arsenic has the exact opposite effect, strongly and
almost completely inhibiting hormone-stimulated gene expression by these
receptors. This nonconventional 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. Coauthors on the study include Julie A. Gosse, postdoctoral fellow,
and Athena P. Nomikos, graduate student in pharmacology and toxicology, both
recipients of training fellowships from Dartmouth's Superfund Basic Research
Program.
By SUSAN KNAPP
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