In Vitro to In Vivo Extrapolation of Toxicant Effects on Ovarian Function

PROJECT SUMMARY Approximately 7.5 million American women are unable to become pregnant or carry a baby to term (impaired fecundity). The ovary is considered a critical target organ in infertility cases based on the large number of women seeking infertility treatment who are unable to release a viable egg from their ovaries. Folliculogenesis is the process through which ovarian follicles, the functional units of the ovary, develop into a form capable of sustaining hormone production and ovulating a healthy egg for fertilization. Any environmental exposure that causes damage to the ovarian follicle has the potential to impair fecundity in women. Most of what is known about toxicity to ovarian follicles has been uncovered in laboratory rodents, but there is little available data on toxicant exposure and related mechanistic toxicology studies in the nonhuman primate, the closest laboratory animal model to humans. There is, therefore, a critical need to develop alternative approaches and tools that synergize the accessibility and versatility of laboratory rodents with the physiological relevance of the nonhuman primate to deliver high quality ovarian follicle toxicity data. To meet this need, this proposal will support the formation of a virtual research consortium with expertise in mouse and nonhuman primate ovarian biology, toxicology and computational modeling. The proposed consortium will generate lab-based data on the physiological and toxicant-induced behavior of ovarian follicles in both species, using phthalate as a model toxicant, to create computational models capable of effectively predicting ovarian follicle responses to chemical insults in nonhuman primates. The experimental measures captured in the in vitro and in vivo model will be specifically chosen to align with the needs of the modelers. To achieve this goal, the proposed consortium will complete three specific aims. Specifically, the ovarian biology/toxicology team will quantify the physiological and toxicant-induced behavior of computationally useful markers of in vivo and in vitro folliculogenesis in mice (Aim 1) and nonhuman primates (Aim 2), while the computational modeling team will construct in silico models that match the physiological behavior of folliculogenesis in each species and predict follicular responses to phthalate insults in both species. Our virtual consortium includes researchers from five institutions and will create a transdisciplinary group that includes both experimental and computational expertise. The tight coupling of these two domains will provide the needed communication pathways to develop translational models for IVIVE as well as cross-species extrapolations in reproductive toxicology.