Mapping the cosmetic chemical exposome and its role in female fertility - PROJECT SUMMARY Infertility affects about 15% of couples, and ovulatory dysfunction is a primary cause with unclear etiology. Studies have found that certain chemicals are reproductive toxicants and impair female fertility. However, these studies are limited to a small number of known environmental chemicals, and there are major gaps in understanding of the impacts of simultaneous exposures to thousands of chemicals (i.e., the exposome) on ovarian function and female fertility. Thus, there is a critical need to evaluate how complex chemical exposures target reproductive organs, to determine potential underlying mechanistic pathways in the metabolome, and to identify important sources of exposures to inform opportunities for prevention and clinical intervention. This research project leverages an integrated exposomics–metabolomics approach to evaluate associations between cosmetic use, chemical exposure biomarkers, ovarian health biomarkers, and female fertility outcomes. Untargeted high-resolution mass spectrometry analysis will concurrently measure up to 100,000 environmental chemicals and endogenous metabolites in human samples of blood and follicular fluid, the latter of which is a localized reproductive biofluid that directly encapsulates oocytes in the ovaries. During the K99 phase, we completed a study evaluating the associations of the untargeted chemical exposome and metabolome in follicular fluid with the reproductive outcome of ovarian reserve (retrieved oocyte count) among a group of 82 patients undergoing egg retrieval for assisted reproduction in Atlanta, GA. During the R00 phase, we will continue our research progress on two studies. First, we will create an untargeted exposome annotation database that includes novel cosmetic ingredients and their biotransformation products and then will develop machine learning algorithms for classifying chemical signatures in the exposome that represent various cosmetic usage habits, based on blood samples from 4,188 women in the Sister Study. This will provide a key resource for other ‘omics health studies, including our own, to retrospectively assess cosmetic exposures in banked biologic samples. Second, we will leverage a sub-cohort of ~350 women in the EARTH study who underwent assisted reproduction in Massachusetts to investigate associations between cosmetic uses, the untargeted chemical exposome, the metabolome, and fertility/birth outcomes using longitudinal samples of both blood and follicular fluid. This study also offers an independent cohort for evaluating shared risk factors and metabolic pathways identified in the previous K99 fertility study. The research in the R00 phase will support the discovery of emerging chemical exposures contributing to infertility, identify their potential biologic pathways of action, improve our understanding of the distribution of chemicals into reproductive organs, identify product sources of harmful chemical exposures, and inform future grant proposals of understudied reproductive health conditions.
