Environmental Chemicals, Exosomal miRNAs in Ovarian Follicles, and IVF Success

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DESCRIPTION (provided by applicant): There is currently scientific, government and public concern regarding adverse effects from exposure to chemicals that may act through disruption of the endocrine system. Studies with laboratory and domestic animal species, and limited human studies, have shown that exposure to some environmental disrupting chemicals (EDCs) may negatively affect oocyte and embryo quality, therefore impacting fertility. In a cohort of IVF patients, we have shown a significant dose-response association between urinary BPA concentrations and decreased numbers of oocytes retrieved and fertilized, as well as decreased proportions of high quality embryos and blastocysts formed. Furthermore, in a recent study on in vitro maturation in human oocytes, we showed a dose response association between bisphenol A (BPA) and a decreased progression of oocytes to metaphase II (MII), an increased incidence of both spontaneous activation and degeneration and, of those oocytes that did mature, an increase in spindle abnormalities and chromosome alignment. As normal spindle organization and chromosome alignment in MII oocytes are critical for formation of a developmentally competent oocyte, any chemically-induced perturbations at this stage will adversely affect fertility. Of specific relevance to this application, the pathways and potential mechanisms by which EDCs alter meiotic progression to MII are currently unknown. Oocyte maturity and health are dependent upon a tightly coordinated communication network between the oocyte and follicular granulosa compartment. Innovative studies have proposed that such intercellular transmission within the follicle may involve secretion and uptake of microRNAs (miRNAs) carried in extracellular vesicles such as exosomes. Exosomes are present in human FF, which raises the possibility that miRNA exosome profiles are perturbed by endocrine disruptors. The objective of our proposed study is to determine if urinary levels of BPA and molar DEHP metabolites are associated with miRNA profile in FF-isolated exosomes and with oocyte maturation and day 3 embryo quality. We will also use mediation analysis to estimate the indirect effects of BPA and molar DEHP metabolites on oocyte maturation and embryo quality that are mediated through FF isolated exosomes miRNA expression. This concept, that miRNAs from FF exosomes may play a role in intra-follicular oocyte control is novel and may provide important insights for the understanding of the development of a mature oocyte and a competent embryo. We expect the results will provide the basis for future research investigating the associations among endocrine disrupting chemicals, ovarian function, oocyte development, embryo implantation and fetal health.