Estrogen is a critically important hormone that guides the normal acquisition of structural and functional competence in mammals, with effects on the growth and differentiation of multiple organ systems, including the reproductive system. Currently, considerable attention is focused on the potential for disruption of normal estrogen function by several xenobiotic chemicals such as methoxychlor and 2, 3, 7, 8 tetrachlordibenzo-p-dioxin. These chemicals are hypothesized to cause infertility and cancer, among other effects, in wildlife and humans through a common mechanism of interfering with normal endocrine function. The overall goal of this research is to develop an understanding of the long-term consequences of disrupting estrogen function during development. The studies in this proposal address the hypothesis that exposure to endocrine disruptors during critical periods of fetal development causes """"""""reprogramming"""""""" of the hormone response system in target cells, resulting in aberrant responses to endogenous hormones or exogenous estrogen-like xenobiotics later in life. To test the hypothesis, the following specific aims will be completed: 1) characterize the physiological consequences from specifically timed prenatal disruption of the estrogen response system on the vagina, uterus, and ovary and 2) test whether prenatal disruption of the estrogen response system alters vaginal, uterine, and ovarian responsiveness to xenobiotics (i.e., methoxychlor and 2,3,7,8 tetrachlorodibenzo-p-dioxin) during postnatal life. Collectively, this research will determine whether prenatal estrogen disruption results in long-term effects on vaginal, uterine, and ovarian morphology and function that are manifest later in life. In addition, the proposed research will result in the characterization of a novel transgenic animal model that will be valuable for future studies on: the consequences of endocrine disruption on other developmental endpoints that are directed, regulated, or influenced by estrogen (e.g., brain, mammary gland, bones, and cardiovascular system), the physiological roles of ERalpha in the female reproductive system, and the effects of xenobiotics that interact with ERalpha on the female reproductive system. ? ?
