EDC MIXTURES, BIRTH OUTCOMES, AND THE FETAL METABOLOME: AN EPIDEMIOLOGIC AND EXPERIMENTAL STUDY. - PROJECT SUMMARY EXPOSURE TO KNOWN ENDOCRINE DISRUPTING CHEMICALS (EDCS) PHTHALATES, PARABENS, AND PHENOLS IS UBIQUITOUS IN THE UNITED STATES (US). THE US ALSO PERSISTENTLY HAS ONE OF THE HIGHEST RATES OF ADVERSE BIRTH OUTCOMES COMPARED TO OTHER DEVELOPED NATIONS. THUS, THERE IS AN URGENT NEED TO IDENTIFY IF MODIFIABLE ENVIRONMENTAL EXPOSURES CONTRIBUTE TO THESE ADVERSE OBSTETRIC OUTCOMES. EPIDEMIOLOGIC STUDIES HAVE INVESTIGATED PRENATAL EXPOSURE TO INDIVIDUAL EDCS AND ADVERSE BIRTH OUTCOMES AND HAVE FOUND MIXED RESULTS. ALTHOUGH HUMAN EXPOSURE LIKELY ENTAILS CO-OCCURRING MIXTURES OF EDCS, THERE REMAINS A CRITICAL GAP IN OUR UNDERSTANDING OF THE RELATIONSHIP BETWEEN MULTI-EDC EXPOSURE AND BIRTH OUTCOMES. THE AMERICAN COLLEGE OF OBSTETRICS AND GYNECOLOGY HAS ALSO RECOMMENDED THAT PROVIDERS START INCLUDING QUESTIONS ABOUT PATIENTS' ENVIRONMENTAL EXPOSURES DURING PRENATAL VISITS, HIGHLIGHTING A GROWING CONCERN SURROUNDING ENVIRONMENTAL CONTAMINANTS AND A NEED FOR EVIDENCE-BASED RESEARCH TO INFORM ANTENATAL CARE GUIDELINES. THERE IS ALSO LITTLE KNOWN REGARDING THE BIOLOGICAL MECHANISMS OF EDC EXPOSURE, WHICH IS USEFUL IN IDENTIFYING THERAPEUTIC TARGETS TO REDUCE ADVERSE BIRTH OUTCOMES. MEASURING THE METABOLIC PROFILES OF FETAL TISSUES, SUCH AS THE PLACENTA AND UMBILICAL CORD BLOOD, COULD GIVE INSIGHT INTO THE MOLECULAR PATHWAYS ASSOCIATED WITH EXPOSURE TO EDC MIXTURES. UNTARGETED METABOLIC PROFILES OFFER A COMPREHENSIVE PROFILE OF ENDOGENOUS AND EXOGENOUS METABOLITES IN A BIOSPECIMEN, INCREASING THE POTENTIAL TO DISCOVER BIOMARKERS OF ALTERED PHENOTYPES. YET, NO STUDY TO DATE HAS INVESTIGATED THE IMPACT OF EDC MIXTURES ON METABOLOMIC PROFILES OF FETAL TISSUES DESPITE THEIR CRITICAL ROLES IN FETAL DEVELOPMENTAL PROCESSES. HENCE, WE PROPOSE TO LEVERAGE A LONGITUDINAL EPIDEMIOLOGIC BIRTH COHORT STUDY AT THE COLUMBIA CENTER FOR CHILDREN'S ENVIRONMENTAL HEALTH (CCCEH) ALONG WITH A WELL-CHARACTERIZED IN VITRO SYSTEM TO INVESTIGATE THE IMPACT OF PRENATAL EXPOSURE TO EDC MIXTURES ON BIRTH OUTCOMES AND THE FETAL METABOLOME. OUR OBJECTIVES ARE TO EVALUATE THE ASSOCIATION OF PRENATAL EDC MIXTURE EXPOSURE WITH AIM 1) ADVERSE BIRTH OUTCOMES AMONG 700 BIRTHS AND AIM 2) PLACENTAL (N=54) AND UMBILICAL CORD BLOOD (N=293) METABOLOMIC PROFILES FROM THE CCCEH COHORT. WE WILL LEVERAGE MATERNAL URINARY BIOMARKERS OF EDC EXPOSURE TO ASSIGN BIRTHS AND BIOSPECIMENS AN EDC-MIXTURE EXPOSURE PROFILE. IN AIM 3) WE WILL EXPOSE A THIRD-TRIMESTER PLACENTAL CELL LINE TO A HUMAN-RELEVANT MIXTURE OF PARABEN, PHENOL, AND PHTHALATE METABOLITES RECENTLY MEASURED IN THE CCCEH COHORT AND MEASURE THE EFFECT ON THE METABOLOME AND CELLULAR PHENOTYPES. THIS WORK WILL INCREASE OUR UNDERSTANDING OF HOW EDC MIXTURES MAY IMPACT BIRTH OUTCOMES VIA ALTERATIONS TO THE PLACENTAL AND UMBILICAL CORD BLOOD METABOLOMES AND CAN INFORM GUIDELINES TO REDUCE EXPOSURE TO EDCS DURING PREGNANCY.