Endocrine Disrupting Chemicals and Female Reproductive Health - The ovary is a particularly important reproductive organ because it is essential for the production of oocytes and sex steroid hormones. Unfortunately, exposure to environmental endocrine disrupting chemicals (EDCs) can damage the ovary. EDC-induced ovarian damage leads to female reproductive dysfunction, which cannot be prevented or treated by eliminating EDC exposures. It is extremely important to understand the mechanisms by which EDCs damage the ovary so that we can develop strategies to prevent and/or treat EDC-induced reproductive toxicity. Towards this end, the overall goals of the proposed RIVER program are to: 1) unravel the intricate mechanisms underlying EDC-induced ovarian damage and female reproductive dysfunction, 2) decode the multigenerational effects of EDCs on ovarian function and female reproductive capacity, and 3) bridge the gap to human health by elucidating how EDC exposure is associated with ovarian function and reproductive aging in a prospective cohort of midlife women. To address these urgent clinical and public health needs, we will use single cell RNAseq to identify novel pathways of EDC-induced toxicity at the single cell level in the ovary as well as other female reproductive organs, spatial transcriptomics to map EDC-induced changes in gene activity while preserving spatial context, advanced 3-D ovarian follicle culture techniques to uncover the direct effects of EDCs on the ovary in a controlled environment, pioneering in vitro and in vivo experiments that include environmentally relevant individual EDCs and mixtures of EDCs, state-of-the-art LC-MS techniques to detect the concentrations of EDCs that reach the female reproductive organs and determine the ability of the ovary to detoxify or bioactive EDCs, high resolution LC-MS/MS techniques to conduct quantitative global and targeted proteomics, whole genome methylome analysis or reduced-representation bisulfite sequencing (RRBS) to identify the effects of EDCs on cell-type specific DNA methylation patterns in the ovary, spatial epigenome- transcriptome co-profiling to localize EDC-induced changes in specific cell types in the ovary and determine the interaction between EDC-induced methylation and gene expression changes, CRISPR-Cas 9 technology to correct EDC-induced DNA methylation errors in cells, LC-MS techniques at the forefront of the field to measure selected EDCs and biomarkers of reproductive function and aging in a prospective cohort of midlife women, and leading edge statistical models to assess associations between EDC mixtures and selected biomarkers/outcomes. The applicant is uniquely qualified to successfully lead the RIVER program. The applicant served as PI on 24 NIH-funded awards and her research produced over 325 peer-reviewed publications. The applicant has demonstrated a broad vision, conducted ground-breaking research, and made seminal contributions to the understanding of the impacts of EDCs on the ovary and female reproduction. The flexible and sustained RIVER support will help the applicant to continue pioneering and impactful research, mentoring, and leadership in environmental health sciences.
