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

描述（由申请人提供）：目前科学界、政府和公众对接触可能通过干扰内分泌系统发挥作用的化学品的不良影响表示担忧。对实验室和家畜物种的研究以及有限的人类研究表明，暴露于一些环境干扰化学品（EDCs）可能会对卵母细胞和胚胎质量产生负面影响，从而影响生育力。在一组IVF患者中，我们发现尿BPA浓度与获得和受精的卵母细胞数量减少以及形成的高质量胚胎和囊胚比例降低之间存在显著的剂量反应相关性。此外，在最近的一项关于人类卵母细胞体外成熟的研究中，我们发现双酚A（BPA）与卵母细胞向中期II（MII）的进展减少、自发激活和变性的发生率增加以及成熟卵母细胞纺锤体异常和染色体排列增加之间存在剂量反应相关性。由于MII期卵母细胞中正常的纺锤体组织和染色体排列对于形成发育能力强的卵母细胞至关重要，因此该阶段任何化学诱导的扰动都会对生育力产生不利影响。与本申请特别相关的是，EDC改变减数分裂进展至MII的途径和潜在机制目前尚不清楚。卵母细胞的成熟和健康取决于卵母细胞和卵泡颗粒间室之间紧密协调的通信网络。创新研究提出，卵泡内的这种细胞间传递可能涉及分泌和摄取细胞外囊泡（如外来体）中携带的microRNA（miRNA）。外泌体存在于人类FF中，这提高了miRNA外泌体概况被内分泌干扰物干扰的可能性。我们拟定研究的目的是确定BPA和摩尔DEHP代谢物的尿液水平是否与FF分离的外泌体中的miRNA谱以及卵母细胞成熟和第3天胚胎质量相关。我们还将使用介导分析来估计BPA和摩尔DEHP代谢物对卵母细胞成熟和胚胎质量的间接影响，这些影响是通过FF分离的外泌体miRNA表达介导的。来自FF外泌体的miRNA可能在卵泡内卵母细胞控制中发挥作用的这一概念是新颖的，并且可以为理解成熟卵母细胞和有能力胚胎的发育提供重要的见解。我们希望这些结果将为未来研究内分泌干扰物，卵巢功能，卵母细胞发育，胚胎植入和胎儿健康之间的关系提供基础。

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.