Arsenic as an Endocrine Disrupter

Project Leader:
Joshua Hamilton, Ph.D.
Senior Scientist
Chief Academic & Scientific Officer
Marine Biological Laboratory

Arsenic exposure has been linked in human epidemiology studies to a wide variety of serious illnesses. Long-term exposure of people to elevated levels in food and drinking water--levels that were previously considered relatively low--has now been linked to an increased risk of a number of different cancers, including those of the liver, lung, kidney, bladder, and skin; vascular and heart disease, type 2 diabetes, and other metabolic disorders; low birth weights in babies and other reproductive and developmental disorders; neurological and cognitive problems; immune deficiencies; and a growing list of other serious adverse health outcomes. In fact, arsenic is considered the number one environmental chemical of concern for human health effects both in the U.S. and worldwide, in part because of this large list of serious health effects, and in part because so many people are exposed to it daily in food and water.

One of the central questions in arsenic research is how one simple chemical can be linked to so many adverse outcomes. There is no other chemical with so many diverse health effects, and it has been difficult to envision a single mechanism by which arsenic could affect all of these different diseases. One part of the answer may be that arsenic is a potent endocrine disruptor, but does so in a way unlike any other chemical. The focus of this project is to understand the biological basis for these effects and also to understand the implications of this effect for human health.

Joshua Hamilton and colleagues have been investigating this problem since the beginning of the Dartmouth Superfund Research Program in 1995. In 1998 they first discovered and reported that arsenic is an endocrine disruptor, a novel finding for arsenic or any other metal at the time. The Hamilton lab was one of the founding research groups of the Dartmouth program, working initially at the Dartmouth Medical School in the Department of Pharmacology and Toxicology. In 2008, Dr. Hamilton moved with his research program to the Marine Biological Laboratory in Woods Hole, MA where he continues these studies as a member of the Dartmouth Superfund Research Program. The two principal avenues of research within this project are 1) to understand at the cellular and molecular level precisely how arsenic can act as an endocrine disruptor, and 2) to understand the adverse consequences of arsenic exposure as a result of this endocrine disruption.

The concept that environmental chemicals might be able to disrupt hormone-regulated processes first gained attention with the publication of Silent Spring by Rachel Carson in 1962. She brought to light the emerging realization by scientists that chemical pollutants could perturb the physiology of animals (and presumably humans) by mimicking natural hormones in inappropriate ways. Since then, this class of chemicals has been termed “endocrine disruptors,” and many chemicals of concern have been identified that may act this way. However, to date each chemical identified this way has tended to mimic a single hormone. For example, a pesticide that structurally mimics estrogen can disrupt that signaling pathway in the animal. Such mimics typically can do so either by acting like the hormone itself and turning on estrogen-dependent signaling in the body (acting as an “agonist”) or by mimicking the hormone enough to bind to the hormone receptor and prevent it from interacting with its normal hormone (that is, acting like an “antagonist”).

Over the past decade this research has shown two ways in which arsenic is unique. First, it disrupts a whole host of hormone pathways rather than one: in fact, all five steroid receptors (for estrogen, progesterone, testosterone, corticosteroids, and mineralocorticoids) and a growing list of other, unrelated hormone receptors including those for retinoic acid, thyroid hormone, and peroxisome proliferators are all affected in essentially the same way. Second, it does this by a unique mechanism: it does not act as an agonist (mimicking a hormone) or antagonist (blocking normal hormone binding). Actually, it does not appear to target the hormone receptors directly at all, but rather appears to target the common cellular machinery they all share, which explains its broad effects. Our current project focus is to more fully understand how arsenic is able to do this at the cellular level, to understand the health consequences of this disruption, and also to understand how this effect might be blocked or reversed in exposed populations.

This research has demonstrated that very low levels of arsenic exposure can severely affect embryonic, fetal and post-natal developmental processes, in frogs, fish and mice. And this endocrine disruption can also affect metabolic balance and other hormone-dependent physiological processes in adult animals as well. Recent research results from this project showed that arsenic has another effect related to this: it can act as a powerful immuno-suppressive agent, significantly altering the ability of the innate immune system to fight off infectious challenges. In the most dramatic experiment, mice drinking arsenic at very low levels for only five weeks were unable to fight off a flu infection in their lungs and actually died, at a viral exposure in which the control animals not drinking arsenic recovered fully from a normal and relatively mild flu disease course similar to that of most human flu infections. Another recent and unexpected discovery is that pregnant mice given arsenic at the current U.S. drinking water standard of 10 parts per billion had significant changes in their metabolism, and this resulted in severe growth and development deficiencies in their offspring. Current research for this project continues to examine these and other adverse effects of arsenic on human health, both in animal models and in collaboration with our program project on epidemiology and biomarkers and with other epidemiology and human health experts.

Recent Publications

Josh Hamilton Pubmed