Prenatal Programming of Reproductive Health and Disease

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Strong epidemiological evidence suggests that the nutritional, metabolic and hormonal environment to which the fetus is exposed during gestation permanently "programs" the development and subsequent expression of its physiology and behavior during adulthood. In mammals, prenatal programming of the reproductive system is striking. For example, female rats can be masculanized in utero by the mere presence of male littermates sharing the same uterine horn. Similarly, it is well documented that exposure to excess androgens in utero can lead to sterility in monkeys and sheep. The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. At risk is the fetus whose mother has been exposed to exogenous steroids for a variety of reasons: she has had failed contraception and continued exposure to contraceptive steroids; she is on anabolic steroids; she is inadvertently being exposed to environmental compounds that have estrogenic or androgenic activity. Experimental manipulation of the prenatal steroid environment provides a powerful investigative tool for unraveling mechanisms that underlie programming of the reproductive axis. Our studies in sheep reveal that experimental exposure to excess androgen from 30-90 days of gestation culminates in a suite of adult disorders that include: hypergonadotropism, hyperinsulinemia, multifollicular ovarian morphology, increased follicular atresia, aberrant reproductive behaviors, and a number of ovarian cycle defects that culminate in reproductive failure. This multi-investigator proposal will test the hypothesis that "Androgens and estrogens program the reproductive physiology and behavior. Exposure of female fetuses to increased sex steroids during critical periods of fetal development produces changes in postnatal neuroendocrine and ovarian physiology culminating in disrupted reproductive and behavioral responses in postnatal life. Central to this hypothesis is altered responses to postnatal steroids, responses that ultimately reduce fertility as a consequence of increased susceptibility to endogenous and exogenous sex steroid actions." The proposal targets key elements of strategic plans that emanated from workshops convened by the NICHD in 2000-01 by focusing on fours targeted areas: fetal antecedents of disease, reproductive health for the 21st century, developmental biology and biobehavioral development. The findings will be relevant to research on fetal origin of adult diseases, infertility, aging, and gender identity. The results of this research effort will demonstrate the added value gained by an integrative approach to solving reproductive and behavioral problems.