Environmental exposure modulation of the ovarian lipidome

About This Grant

ABSTRACT Infertility affects over 50 million couples worldwide and it is associated with both, obesity and dyslipidemia. Lipids account for ~50% of all cell membranes, ~40% of cells, and play a key role in ovarian function. Despite its abundance, our understanding of the ovarian lipidome, including abundance, distribution, and function within specific ovarian regions, remains at its infancy. This hampers our ability to determine how ovarian dyslipidemia can result in infertility. Advancement in this field has been severely curtailed by: 1) loss of lipids when using common tissue preservation methods, 2) difficulty in lipid annotation, 3) lack of available human ovarian lipidome databases, and 4) difficulty to study lipids while retaining a spatial context. Using state-of-the- art Matrix-Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry Imaging (MALDI-TOF MSI) we are now capable of retaining the spatiality required to study the ovarian lipidome. This approach greatly enhances our ability to identify disruptions in the ovarian lipidome induced by chemical exposures, which is the goal of this proposal. Chemical exposures can induce dyslipidemia in adipose and non-adipose tissues, such as the ovary. One of such chemicals are organophosphate flame retardants (OPFRs), emerging chemicals that are increasingly prevalent human urine and plasma. We and others have demonstrated that OPFRs exposure leads to ovary and ovarian cells’ dyslipidemia, ovarian dysfunction, and poor reproductive outcomes. We hypothesize that OPFR-induced ovarian dyslipidemia is region- and lipid-specific. To address this, we will first develop a spatial ovarian lipidome map of the human and mouse ovary coupling untargeted lipidomics with mass spectrometry and MALDI-TOF MSI. We have demonstrated how this approach can robustly evaluate lipid distribution and abundance within ovarian regions (germ cells, follicles, cortex, and stroma) with superb specificity in both human and mouse ovaries. Capitalizing on this platform, we will next evaluate the impact of environmentally relevant OPFRs exposures on ovarian lipids at environmentally relevant exposures in a mouse model. Altogether, this will provide the first ovarian lipidome map of chemically-sensitive cellular ovarian regions for OPFRs. These results will help infer sensitive ovarian targets of OPFRs disruption. We expect that the results from these studies will provide a platform for discovering new predictors of ovarian dysfunction.