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.

Public Health Relevance

Over the last several decades a decline in human fertility has coincided with widespread human exposure to synthetic chemicals. Phthalates and bisphenol A are widely used chemicals that adversely affect fertility in experimental animals and in humans. The proposed study will determine their impact on epigenetic profiles measured in follicular fluid and on the health of the oocyte among women undergoing IVF.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
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Dilworth, Caroline H
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Harvard University
Public Health & Prev Medicine
Schools of Public Health
United States
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Machtinger, Ronit; Gaskins, Audrey J; Racowsky, Catherine et al. (2018) Urinary concentrations of biomarkers of phthalates and phthalate alternatives and IVF outcomes. Environ Int 111:23-31
Machtinger, Ronit; Berman, Tamar; Adir, Michal et al. (2018) Urinary concentrations of phthalate metabolites, bisphenols and personal care product chemical biomarkers in pregnant women in Israel. Environ Int 116:319-325
Martinez, Rosie M; Liang, Liming; Racowsky, Catherine et al. (2018) Extracellular microRNAs profile in human follicular fluid and IVF outcomes. Sci Rep 8:17036
Machtinger, Ronit; Rodosthenous, Rodosthenis S; Adir, Michal et al. (2017) Extracellular microRNAs in follicular fluid and their potential association with oocyte fertilization and embryo quality: an exploratory study. J Assist Reprod Genet 34:525-533
Machtinger, Ronit; Gaskins, Audrey J; Mansur, Abdallah et al. (2017) Association between preconception maternal beverage intake and in vitro fertilization outcomes. Fertil Steril 108:1026-1033
Machtinger, Ronit; Laurent, Louise C; Baccarelli, Andrea A (2016) Extracellular vesicles: roles in gamete maturation, fertilization and embryo implantation. Hum Reprod Update 22:182-93