The broad objective of this proposal is to understand the delayed epigenetic effect of endocrine disrupter methoxychlor (MXC) exposure during fetal/neonatal ovarian development. Epigenetic alterations (e.g., DNA methylation) cause aberrant gene expression, which can lead to major diseases such as cancer. Fetal/ neonatal exposure to estrogenic endocrine disrupters results in uterine and testicular abnormalities in the adult that are linked to DNA methylation changes. Whether similar epigenetic effects occur in the ovary is unknown. The HYPOTHESIS is that transient MXC exposure during fetal/neonatal development directly impairs adult ovarian function by altering early folliculogenesis, DNA methylation, and gene expression. There are 3 specific aims to test this hypothesis.
SPECIFIC AIM 1 is to identify the effect of MXC exposure during fetal/neonatal ovarian development on adult ovarian function, morphology, DNA methylation, and gene expression (adult effect). Rats will be treated with MXC perinatally. Pubertal age and adult ovarian functions such as response to gonadotropins, fertility, litter size, and early aging will be assessed. DNA methylation and critical gene expression (e.g., StAR, P450scc, LHR) for adult ovarian function will be examined.
SPECIFIC AIM 2 is to determine if the adult effect of MXC results from alterations in folliculogenesis, DNA methylation and gene expression in the fetal/neonatal ovary (fetal basis of adult effect). Early folliculogenesis, DNA methylation, and critical gene expression for ovarian development (bFGF, GDF-9, MIS) will be examined using organ culture.
SPECIFIC AIM 3 is to determine whether early MXC exposure directly affects the ovary using organ transplantation (direct effect). This proposal is to investigate whether transient perinatal exposure to the endocrine disrupter MXC directly alters adult ovarian function. The findings will improve our understanding of the fetal basis of epigenetic adult ovarian dysfunction. ? ?
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