R01ES036951

PFAS EXPOSURE IS DETRIMENTAL TO PLACENTAL FUNCTION AND FETAL DEVELOPMENT BY DISRUPTING MITOCHONDRIAL FUNCTION AND METABOLISM - PER- AND POLY-FLUOROALKYL SUBSTANCES (PFAS) EXPOSURE IS WIDESPREAD AND HAS SPARKED MAJOR CONCERNS ABOUT HEALTH IMPACTS IN HIGHLY CONTAMINATED COMMUNITIES. THE FENG LAB HAS MADE SIGNIFICANT CONTRIBUTIONS TO OUR UNDERSTANDING OF THE REPRODUCTIVE TOXICITY OF PFAS BY STUDYING PFAS MIXTURES THAT REPLICATE PFAS LEVELS IN HIGHLY CONTAMINATED DRINKING WATER, AS WELL AS EMERGING PFAS COMPOUNDS SUCH AS PERFLUOROBUTANE SULFONIC ACID (PFBS). WE HAVE REPORTED THAT MATERNAL EXPOSURE TO PFAS MIXTURES AND PFBS AT ENVIRONMENTALLY RELEVANT DOSES LEADS TO ADVERSE BIRTH OUTCOMES THROUGH DYSREGULATION OF PLACENTAL FUNCTION AND FETAL NEURODEVELOPMENT. RECENTLY, OUR PRELIMINARY DATA DEMONSTRATED THAT EXPOSURE TO A PFAS MIXTURE OR PFBS LEADS TO OXYGEN ACCUMULATION IN PLACENTAS AND EMBRYOS DURING PREGNANCY AND INDUCES MITOCHONDRIAL OXIDATIVE STRESS IN BOTH HUMAN PLACENTAL TROPHOBLAST STEM CELLS AND MURINE FETAL BRAINS. IN THIS PROPOSAL, WE WILL THOROUGHLY EXAMINE OUR HYPOTHESIS THAT PFAS EXPOSURE IS DETRIMENTAL TO PLACENTAL FUNCTION AND FETAL DEVELOPMENT VIA DISRUPTION OF MITOCHONDRIAL ACTIVITIES AND METABOLISM. OUR SPECIFIC AIMS ARE TO: 1) INVESTIGATE MITOCHONDRIAL PERTURBATIONS ASSOCIATED WITH PFBS EXPOSURES IN HUMAN PLACENTAL TROPHOBLAST CELLS; 2) DETERMINE WHICH SPECIFIC MITOCHONDRIA- RELEVANT SYNCYTIOTROPHOBLAST FUNCTIONS ARE ALTERED BY PFBS EXPOSURE; AND 3) ASSESS ALTERATIONS IN PLACENTAL HEMODYNAMICS, OXYGENATION, AND MITOCHONDRIA-RELEVANT METABOLISM BY PFBS AND PFAS MIXTURES IN MICE. NOVELTY: WE WILL ADDRESS THE HEALTH IMPACTS OF PFAS MIXTURES THAT MIMIC HIGHLY CONTAMINATED COMMUNITY DRINKING WATER AND SPECIFICALLY FOCUS ON AN EMERGING PFAS COMPOUND, WHEREAS MOST PREVIOUS STUDIES FOCUSED ON SINGLE LEGACY COMPOUNDS AND USED LESS CLINICALLY APPLICABLE EXPOSURE LEVELS. IN ADDITION, UNIQUE, OPTIMIZED, PHYSIOLOGICALLY RELEVANT HUMAN PLACENTAL TROPHOBLAST STEM CELL-DERIVED ORGANOID MODELS WILL BE USED TO MODEL THE HUMAN MATERNAL-FETAL INTERFACE IN VITRO. FINALLY, AN INNOVATIVE, IN VIVO PHOTOACOUSTIC IMAGING SYSTEM WILL BE USED TO STUDY PLACENTAL HEMODYNAMICS IN A MOUSE MODEL LONGITUDINALLY. THIS STUDY WILL UNCOVER POTENTIAL DRUGGABLE INTERVENTION TARGETS (MITOCHONDRIAL OXIDATIVE STRESS) THAT MIGHT MITIGATE THE ADVERSE EFFECTS OF PERINATAL PFAS EXPOSURE. FURTHERMORE, THIS STUDY WILL ADVANCE OUR UNDERSTANDING OF GENDER-SPECIFIC HEALTH EFFECTS OF PERINATAL PFAS EXPOSURE THAT WILL UNDOUBTEDLY HAVE IMPLICATIONS FOR PERSONALIZED DIAGNOSTICS AND THERAPEUTIC INTERVENTIONS. FEASIBILITY: COMBINING EXPERTISE AND PRELIMINARY STUDIES PROVIDES A STRONG FOUNDATION FOR THIS PROPOSAL. DR. FENG’S LAB HAS ESTABLISHED THE PERINATAL PFAS EXPOSURE IN VITRO AND IN VIVO MODELS; THIS PROPOSAL IS AN EXTENSION OF HER PREVIOUS PROJECTS. DR. SCHUST'S LAB HAS EXTENSIVE EXPERIENCE WORKING WITH PLACENTAL TROPHOBLAST-DERIVED ORGANOIDS AND DEVELOPED THE NOVEL PROPERLY POLARIZED SYSTEM USED HERE. DR. YAO’S LAB HAS FOCUSED ON DEVELOPING NOVEL PHOTOACOUSTIC TECHNOLOGIES FOR ASSESSING TISSUE HEMODYNAMIC PARAMETERS. DR. SANTOS IS AN ENVIRONMENTAL TOXICOLOGIST FOCUSING ON MITOCHONDRIAL TOXICANTS. OUR STUDY WILL SIGNIFICANTLY CONTRIBUTE TO OUR UNDERSTANDING OF THE HEALTH IMPACTS OF PFAS AND PROVIDE CLUES FOR INTERVENTION STRATEGIES.

Duke University

TO FOSTER UNDERSTANDING OF HUMAN HEALTH EFFECTS OF EXPOSURE TO ENVIRONMENTAL AGENTS IN THE HOPE THAT THESE STUDIES WILL LEAD TO: THE IDENTIFICATION OF AGENTS THAT POSE A HAZARD AND THREAT OF DISEASE, DISORDERS AND DEFECTS IN HUMANS, THE DEVELOPMENT OF EFFECTIVE PUBLIC HEALTH OR DISEASE PREVENTION STRATEGIES, THE OVERALL IMPROVEMENT OF HUMAN HEALTH EFFECTS DUE TO ENVIRONMENTAL AGENTS, THE DEVELOPMENT OF PRODUCTS AND TECHNOLOGIES DESIGNED TO BETTER STUDY OR AMELIORATE THE EFFECTS OF ENVIRONMENTAL AGENTS, AND THE SUCCESSFUL TRAINING OF RESEARCH SCIENTISTS IN ALL AREAS OF ENVIRONMENTAL HEALTH RESEARCH. SUPPORTED GRANT PROGRAMS FOCUS ON THE FOLLOWING AREAS: (1) UNDERSTANDING BIOLOGICAL RESPONSES TO ENVIRONMENTAL AGENTS BY DETERMINING HOW CHEMICAL AND PHYSICAL AGENTS CAUSE PATHOLOGICAL CHANGES IN MOLECULES, CELLS, TISSUES, AND ORGANS, AND BECOME MANIFESTED AS RESPIRATORY DISEASE, NEUROLOGICAL, BEHAVIORAL AND DEVELOPMENTAL ABNORMALITIES, CANCER, AND OTHER DISORDERS, (2) DETERMINING THE MECHANISMS OF TOXICITY OF UBIQUITOUS AGENTS LIKE METALS, NATURAL AND SYNTHETIC CHEMICALS, PESTICIDES, AND MATERIALS SUCH AS NANOPARTICLES, AND NATURAL TOXIC SUBSTANCES, AND THEIR EFFECTS OF ON VARIOUS HUMAN ORGAN SYSTEMS, ON METABOLISM, ON THE ENDOCRINE AND IMMUNE SYSTEMS, AND ON OTHER BIOLOGICAL FUNCTIONS, (3) DEVELOPING AND INTEGRATING SCIENTIFIC KNOWLEDGE ABOUT POTENTIALLY TOXIC AND HAZARDOUS CHEMICALS BY CONCENTRATING ON TOXICOLOGICAL RESEARCH, TESTING, TEST DEVELOPMENT, VALIDATION AND RISK ESTIMATION, (4) IDENTIFYING INTERACTIONS BETWEEN ENVIRONMENTAL STRESSORS AND GENETIC SUSCEPTIBILITY AND UNDERSTANDING BIOLOGIC MECHANISMS UNDERLYING THESE INTERACTIONS, INCLUDING THE STUDY OF ENVIRONMENTAL INFLUENCES ON EPIGENOMICS AND TRANSCRIPTIONAL REGULATION, (5) CONDUCTING ENVIRONMENTAL PUBLIC HEALTH RESEARCH, INCLUDING IN AREAS OF ENVIRONMENTAL JUSTICE AND HEALTH DISPARITIES, THAT REQUIRES COMMUNITIES AS ACTIVE PARTICIPANTS IN ALL STAGES OF RESEARCH, DISSEMINATION, AND EVALUATION TO ADVANCE BOTH THE SCIENCE AND THE DEVELOPMENT OF PRACTICAL MATERIALS FOR USE IN COMMUNITIES, WITH A FOCUS ON TRANSLATING RESEARCH FINDINGS INTO TOOLS, MATERIALS, AND RESOURCES THAT CAN BE USED TO PREVENT, REDUCE, OR ELIMINATE ADVERSE HEALTH OUTCOMES CAUSED BY ENVIRONMENTAL EXPOSURES, (6) EXPANDING AND IMPROVING THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (7) EXPANDING AND IMPROVING THE STTR PROGRAM TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION, (8) PROVIDING SUPPORT FOR BROADLY BASED MULTI-DISCIPLINARY RESEARCH AND TRAINING PROGRAMS IN ENVIRONMENTAL HEALTH .THESE PROGRAMS INCLUDE THE ENVIRONMENTAL HEALTH SCIENCES CORE CENTERS , WHICH SERVE AS NATIONAL FOCAL POINTS AND RESOURCES FOR RESEARCH AND MANPOWER DEVELOPMENT. THROUGH THESE PROGRAMS, NIEHS EXPECTS TO ACHIEVE THE LONG-RANGE GOAL OF DEVELOPING NEW CLINICAL AND PUBLIC HEALTH APPLICATIONS TO IMPROVE DISEASE PREVENTION, DIAGNOSIS, AND THERAPY. ADDITIONAL CENTERS PROGRAMS DEVELOPED IN RECENT YEARS, INCLUDE THE CENTERS FOR OCEANS AND HUMAN HEALTH (CO-FUNDED WITH NSF), CHILDREN'S ENVIRONMENTAL HEALTH CENTERS (CO-FUNDED WITH US EPA) AND THE AUTISM CENTERS OF EXCELLENCE (CO-FUNDED WITH OTHER NIH INSTITUTES), AND THE HUMAN HEALTH EXPOSURE ANALYSIS RESOURCE (HHEAR) PROGRAM, (9) SUPPORTING RESEARCH TRAINING PROGRAMS WHICH SERVE TO INCREASE THE POOL OF TRAINED RESEARCH MANPOWER WITH NEEDED EXPERTISE IN THE ENVIRONMENTAL HEALTH SCIENCES THROUGH SUPPORT OF INDIVIDUAL AND INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS), (10) THE OUTSTANDING NEW ENVIRONMENTAL SCIENTIST PROGRAM WHICH PROVIDES FIRST TIME RESEARCH GRANT FUNDING TO OUTSTANDING JUNIOR SCIENTISTS IN THE FORMATIVE STAGES OF THEIR CAREER WHO ARE PROPOSING TO MAKE A LONG TERM COMMITMENT TO ENVIRONMENTAL HEALTH SCIENCES RESEARCH AND TO ADDRESS THE ADVERSE EFFECTS ON ENVIRONMENTAL EXPOSURES ON HUMAN BIOLOGY, HUMAN PATHOPHYSIOLOGY AND HUMAN DISEASE.

93.113 - Environmental Health

National Institute of Environmental Health Sciences (NIEHS) [HHS - NIH]

Durham, North Carolina 27710 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)