Phthalate Exposure and Female Reproductive Aging

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The female reproductive system ages before any other physiological system, making it the most sensitive indicator of aging. Most women experience reproductive senescence around age 51, but many women experience early reproductive aging (early menopause). This is a serious public health problem because early reproductive aging is associated with early onset of infertility and increased risk of several diseases and early death. Further, the consequences of early reproductive senescence are significant in women who delay childbirth for personal and professional reasons. Despite the profound impact of early reproductive aging on women’s health, little is known about the mechanisms underlying early reproductive aging. Our published and preliminary data indicate that acute exposure to the environmental chemicals, di-(2-ethyhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), during adulthood increases several key indicators of early reproductive aging in female mice. Further, published data indicate that activation of the inflammasome and inflammation are hallmarks of reproductive aging and our preliminary data indicate that DEHP exposure increases inflammatory macrophages in the hypothalamus, DEHP and DiNP exposure increase expression of inflammatory pathways in the ovary, and DEHP activates resident macrophages in the peritoneal cavity. In addition, published studies indicate that the aryl hydrocarbon receptor (AhR) plays an important role in regulating reproductive aging and our preliminary data indicate that DEHP and its metabolite (MEHP) induce expression of the known AhR targets in the pituitary and the ovary and that a specific AhR antagonist rescues ovarian follicles from phthalate-induced inhibition of follicle growth. These impacts of phthalate exposure are of concern because phthalates are one of the top contaminants present in human tissues and they are present in a myriad of consumer products, personal care products, pesticides, wood finishes, adhesives, solvents, lubricants, defoaming agents, and medical devices. Given our preliminary data, the importance of reproductive aging for reproductive health, and the ubiquitous exposure of humans to phthalates, we propose to use mice to test the hypothesis that environmentally relevant doses of DEHP and DiNP interact with the AhR pathway to cause inflammation and facilitate early reproductive aging. To test this hypothesis, we will complete the following specific aims:1) compare the effects of acute versus chronic exposure to environmentally relevant doses of DEHP and DiNP on the onset and characteristics of reproductive aging, 2) determine if environmentally relevant phthalate exposure causes inflammation, leading to early reproductive aging, and 3) determine if phthalates work through the AhR pathway to cause early reproductive aging. Collectively, the proposed studies will greatly improve our understanding of the mechanisms by which phthalate exposure causes early female reproductive aging. In turn, this work will set the foundation for the identification and development of novel targets for the treatment of phthalate-induced diseases, including early reproductive aging.