Environmental Factor, January 2008, National Institute of Environmental Health Sciences
Low Dose Arsenic Is an Endrocrine Disruptor
By Robin Arnette
The U.S. drinking water supply contains several naturally occurring contaminants, such as potassium, arsenic, manganese and radium, as well as a number of organic contaminants including chlorination by-products and groundwater contaminants. The federal government established acceptable limits of these substances to protect the health and well-being of its citizens. But in a new Superfund study, researchers at Dartmouth Medical School have discovered that even low levels of one of these contaminants-arsenic-can disrupt hormone pathways that are involved in normal human development.
The corresponding author of the study, Joshua W. Hamilton, Ph.D., is director of the Center for Environmental Health Sciences at Dartmouth and a professor in the Department of Pharmacology and Toxicology at Dartmouth Medical School. The article appeared in the October 26 online edition of Environmental Health Perspectives. (http://ehp03.niehs.nih.gov/article/fetchArticle.action?articleURI=info:doi/10.1289/ehp.10131)
Hamilton and his colleagues knew from their previous work that low levels of arsenic prevented the ability of steroid hormone receptors (SR) to bind molecules of hormone in whole animal models and in cell culture. This disruption occurred in several SRs, including glucocorticoid, androgen, progesterone, mineralcorticoid and estrogen. The team wanted to know if the same was true for the retinoic acid (RA) receptor (RAR) and the thyroid hormone (TH) receptor (TR), two members of the nuclear hormone receptor super-family that are essential for normal vertebrate development.
They used two lines of experimentation to study the effects of arsenic on receptor-mediated gene transcription. In one approach, they constructed artificial RAR response elements or TR response elements and transfected them into cell lines. Human embryonic NT2 cells received the RAR construct and rat pituitary GH3 cells received the TR construct. The cells were then treated with low, non-cytotoxic doses (0.01-5.0 ?M) of sodium arsenite for 24 hours, in the presence or absence of RA or TH, respectively. In both cases, arsenic suppressed RAR- and TR-dependent gene transcription.
In the second approach, the team used frog tail shrinkage or resorption as an example of the hormone-dependent developmental transition that amphibians experience to study the effects of arsenic on TR. Frog tail shrinkage is tightly controlled by TH through TR, so they measured the area of the tail fin over a four-day period in the presence or absence of varying doses of arsenic (0.1-4.0 ?M). The TH-dependent tail shrinkage was inhibited by arsenic in a dose-dependent manner.
The study concluded that low dose arsenic prevented TH from functioning and metamorphosis did not occur. These findings are important because the TH spike in amphibians during metamorphosis is analogous to the TH spike in plasma levels in humans during the perinatal period. Thus, inhibiting TH action in humans could potentially lead to birth defects in arsenic-exposed populations in the U.S. and in many parts of the world.
"The two most important implications of this work with respect to possible human health effects are that human embryonic, neonatal and childhood development is critically dependent on the proper regulation of key developmental processes by thyroid hormone, retinoic acid hormone, and other hormones," Hamilton explained, "and that these endocrine disrupting effects were observed at or below the current U.S. and WHO arsenic drinking water standard of 10 ppb."
Hamilton's research was funded by NIEHS through the Superfund Basic Research Program (SBRP) (http://www.niehs.nih.gov/research/supported/srp/index.cfm) and is a great example of the collaborative effort that SBRP grantees play in addressing the challenges of environmental contamination. "The opportunity to regularly interact with many other researchers doing complementary research on other mechanisms of arsenic's actions as a toxicant on the one hand, and on endocrine disruption by other chemicals on the other," he says, "has provided us with important and timely insights that have been directly applied to our own research."