Risk Factors of IVF Success: Examining Extracellular Vesicle microRNAs in Ovarian Follicles as a Mechanistic Link

Infertility is influenced by a broad range of physical, hormonal, genetic and environmental stressors. Little attention, however, has been devoted to understanding how exposures, such as phthalates and phenols, and modifiable lifestyles factors, such as smoking and body mass index (BMI), can influence IVF outcomes on a mechanistic level. Follicular fluid, a crucial microenvironment for oocyte development and maturation, contains many biomolecules, including extracellular vesicles (EVs). EVs have been detected in almost every biofluid and can act as a vehicle carrying microRNAs (evmiRNAs). Recently, studies have suggested that evmiRNAs may act as a non-invasive biomarker of oocyte health and fertility outcomes. The objective of this current research is to determine whether evmiRNAs in follicular fluid are associated with phenols or phthalate metabolites, body mass index or smoking status, and outcomes of IVF, fertilization status and day three embryo quality. In Chapter 1, seven evmiRNAs were associated with different phenols and phthalate metabolites: hsa-miR-125b with mEHP, hsa-let-7c and hsa-miR-374a with mEOHP, mEHHP, and DEHP, hsa-miR-24 with mBP, hsa-miR-1180 and hsa-miR-375 with ethyl paraben, and hsa-miR-455 with butyl paraben. In Chapter 2, 18 evmiRNAs were associated with higher BMI and hsa-miR-328 remained significant after false-discovery rate (FDR) adjustments. Principal component analyses found the first component, accounting for 40% of the variation in our dataset, was significantly associated with BMI after FDR adjustments. Additionally, we detected five and six evmiRNAs associated with being an former smoker or current smoker respectively, compared to never smokers. In Chapter 3, we found that two evmiRNAs (hsa-miR-130b and hsa-miR-92a) associated with fertilization status and three (hsa-miR-214, hsa-miR-454, and hsa-miR-888) associated with day-three embryo quality. From our significant evmiRNAs, we identified pathways relevant to follicle and oocyte development, maturation and quality, yielding a better understanding of potential mechanistic roles these evmiRNAs play. This current research expands the growing understanding of how evmiRNAs may play a role in inter-cellular communication within human follicular fluid. Gaining knowledge of the roles of these evmiRNAs and how they might interact with pathways of oocyte function, development, and quality will help expand our understanding of the physiology of fertilization.