Arsenic exposure not only disrupts the innate immune system, as the present study shows, it also disrupts the endocrine (hormonal) system in an unusually broad way, which Hamilton's laboratory discovered and first reported in 1998.

"Most chemicals that disrupt hormone pathways target just one, such as the estrogen pathway," he says. "But arsenic disrupts the pathways of all five steroid hormone receptors (estrogen, testosterone, progesterone, glucocorticoids, and mineralocorticoids), as well as several other hormone pathways. You can imagine that just this one effect could play a role in cancer, diabetes, heart disease, reproductive and developmental disorders “all the diseases that have a strong hormonal component."

At this point, Hamilton thinks arsenic disrupts the innate immune system and the endocrine system through different mechanisms. "Arsenic may ultimately be doing a similar thing inside the cell to make these effects happen, but the targets are likely different," he says. The proteins that mediate hormone response are different than the proteins that mediate the immune response. "We don't yet know how arsenic disrupts either system at the molecular level. But once we know how it affects one system, we will have a pretty good idea of how it affects the other systems as well."

Presently, Hamilton's lab is focused on understanding the unusual "biphasic" effect that arsenic has on the endocrine system. At very low doses, arsenic stimulates or enhances hormone responses, while at slightly higher doses (still within the range found in drinking water), it suppresses these same hormone responses.

"Why we see that dramatic shift (from hormone enhancement to suppression) over such a narrow dose range is quite fascinating and totally unknown," Hamilton says. "Our principal focus is to figure out this switch. We think that will help us understand why arsenic does what it does in the body."

mbl