Center for Appalachian Research in Environmental Sciences: Integrated Health Sciences Facility Core

Abstract The UK-CARES Career Development Award will enable Dr. Patrick Hannon to transition from a postdoctoral trainee to an independent research scientist in the field of reproductive toxicology. Dr. Hannon has extensive training in elucidating the effects of environmental toxicants on the ovary in rodent models, and during his postdoctoral training at the University of Kentucky he expanded his research training to translate these findings into human health and fertility. This research proposal and career development plan created by Dr. Hannon with the guidance of his mentoring team will provide Dr. Hannon with new experimental techniques and skills needed to establish an independent research program. In this research proposal, Dr. Hannon will elucidate the effects and mechanisms by which phthalates, a class of endocrine-disrupting chemicals, impair ovulation and fertility in humans and rodents. Women of reproductive age are exposed to phthalates on a daily basis because phthalates are incorporated in a myriad of common consumer, medical, building, and personal care products. However, little is known about the effects of environmentally relevant levels of phthalates on ovulation, especially in humans. This is concerning because defects in ovulation are the leading cause of infertility in women. Preliminary data for this proposal are the first to show that an environmentally relevant phthalate mixture decreases progesterone (P4) and prostaglandin (PG) levels and alters the mRNA levels of P4 receptor (PGR) and prostaglandin-endoperoxide synthase 2 (PTGS2) following human chorionic gonadotropin treatment (hCG; analogous to the midcycle luteinizing hormone surge) in human and mouse ovarian cells. P4,PG, PGR, and PTGS2 are known mediators of ovulation. Thus, these findings suggest that phthalate exposure may disrupt ovulation contributing to infertility. A primary human granulosa cell model and mice will be utilized to test the hypothesis that phthalates adversely impact ovulatory processes by altering the levels of ovulatory mediators leading to impaired ovulation and fertility. Specific Aim 1 will determine which ovulatory events are impaired by phthalate exposure. Specific Aim 2 will elucidate the mechanisms by which phthalates impair these ovulatory processes. Specific Aim 3 will establish that phthalate exposure causes impaired ovulation and infertility in vivo. These findings will establish the impact of phthalates on female fertility and reproductive health. Further, the attainment of a greater understanding of the mechanisms of action of phthalates in human samples will begin to provide avenues to intervene on phthalate-induced reproductive dysfunction and infertility.