The influence of prenatal maternal exposures on fetal sterol metabolomics

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Project abstract/summary Sterol metabolism includes the developmentally critical sex steroid hormones, bile acids, neurosteroids, and cholesterol metabolites of lipid membranes. Certain persistent organic pollutants, including polybrominated diphenyl ethers (PBDEs), as well as high volume production chemicals, including phenols such as triclosan (TCS), are thought to interfere with steroid metabolism and action. Meconium, the first bowel movements of a newborn, begins accumulation in approximately the 12th week of gestation, and contains high sterol content. Thus, meconium provides a window into the prenatal metabolic environment during neurodevelopmentally relevant periods. This proposal will quantify differences in sterol metabolites from meconium in children enrolled in a prospective cohort of early events in neurodevelopment by levels of maternal exposure to PBDEs and major phenols. To deal with the complexity of exposure quantification, we will use a novel variation on partial least squares (PLS) methods, incorporating assumptions of sparsity, non-negativity and biologically plausible structure. These additional modeling constraints will facilitate identification of the most likely biomarkers of exposure response within the already acquired dataset of sterol metabolites. To extend the relevance of the putatively identified sterols, the structures of the biomarkers will be partially or fully elucidated and targeted methods will be developed for future validation as potential biomarkers of exposure. We will conduct this research in three specific aims as follows; Aim 1: Identify unknown chromatographic features with differential abundance by maternal exposure to PBDEs and phenols. Aim 2: Elucidate structural characteristics of sterols identified as interesting in Aim 1. Aim 3: Examine the relationship of PBDE and phenol subtypes with sterols characterized in aim 2 using a Bayesian mixture model. This innovative work will generate testable hypotheses for future research in the field of prenatal neurodevelopment.