Neonatal Endocrine Disruption and Ovarian Senescence

Wichita State University, Wichita KS

Investigators

Abstract

DESCRIPTION (provided by applicant): The developing mammalian female reproductive tract is particularly sensitive to actions of environmental toxicants referred to as endocrine disruptors. Fetal/neonatal exposure to endocrine disruptors such as diethylstilbestrol (DES) can permanently alter structure and function of reproductive organs including the uterus, oviduct, and ovary. A key morphological manifestation of neonatal DES exposure is the induction of numerous polyovular follicles (POF) in the neonatal ovary, indicative of abnormal germ cell: somatic cell association during primordial follicle genesis. It is hypothesized that the induction of POF by DES reduces the ovarian complement of primordial follicles, which accelerates ovarian senescence. This hypothesis will be tested by comparing primordial follicle content temporally in the ovaries of hamsters exposed to neonatally to DES relative to non-treated controls. Primordial follicle content of ovaries during the normal reproductive period in the adult hamster and in the aging ovary will be determined and the impact of a broad low-dose range of DES will be tested. To address potential gene targets of DES action, the expression of the oocyte-specific factor growth differentiation 9 (GDF-9) will be monitored. GDF-9 is expressed in the neonatal hamster ovary in primordial follicles and is expressed during the period of primordial follicle genesis. Hence, GDF-9 may be an endocrine disruptor target. It is hypothesized that neonatal DES exposure modifies GDF-9 expression, which alters the normal course of primordial follicle formation. The temporal impact of neonatal DES exposure upon GDF-9 mRNA content and localization in the neonatal ovary will be assessed by semi-quantitative RT/PCR and in situ hybridization, respectively. GDF-9 protein expression will be assessed via immunohistochemistry. In the adult and aging ovary, GDF-9 mRNA expression will be determined and correlated to the primordial follicle content determined above to assess whether GDF-9 reflects the existing oocyte pool and thus, can be used as a convenient marker. These studies will provide new and important information regarding the impact of a prototypic endocrine disruptor upon a key parameter of ovarian function and will establish a useful method to assess the impact of other environmentally important endocrine disruptors.