PROJECT SUMMARY Cutaneous wound healing is a complex process that involves several physiological and molecular changes surrounding the damaged skin tissue. Environmental contaminants that impede wound healing place individuals at risk for infection and suffering. Steroid hormones, and estrogen in particular, positively influence cellular and tissue processes involved in wound healing, leading to changes in skin structure and physiology and increased shifts in the rate and capacity for wounds to close and heal, but contaminants that interfere with estrogen signaling may impede healing. Inorganic arsenic is an environmental contaminant that interferes with estrogen signaling processes. While there are several potential routes for human exposure to arsenic, in many parts of the world water resources provide a significant exposure route. This risk is real for many Native Americans living in tribal communities where challenges to accessing drinking water with arsenic levels meeting current USEPA standards exist. Health effects resulting from high arsenic exposure are well documented, but recent studies find that even moderate levels of arsenic exposure, such as those identified in some Southwestern Native American communities, are associated with negative health-related outcomes. Much of this exposure is not removed through current water treatment processes on Native lands. Given that Native Americans are at particularly high risk of diabetes and, therefore, diabetes-related wounds determining whether hormonal therapies can improve wound outcomes has the potential to provide translational outcomes useful both to this vulnerable population, and to others experiencing wounds in arsenic contaminated regions globally. The overarching hypothesis of this proposal is that environmentally relevant levels of arsenic will act to inhibit wound healing processes as well as steroid signaling processes. Furthermore, exogenous administration of estradiol will reverse the effects of arsenic exposure. Aim 1 determines the full dose response of arsenic on an in vitro model for cutaneous wound healing, Aim 2 determines whether estrogen exposure reverses the effects of arsenic exposure using the same in vitro model, and Aim 3 determines not only whether an in vivo model of wound healing validates the results found in the in vitro aims, but also determines whether estrogen treatment in a pre-clinical model supports the use of topical hormone therapy on wounds for individuals exposed to arsenic in their food and water resources. !