R01ES037686

HEPATOTOXICITY OF LEGACY AND REPLACEMENT PFAS: ROLE OF BRUCE-MITOCHONDRIAL INTERACTIONS - EPIDEMIOLOGICAL STUDIES HAVE SHOWN A STRONG ASSOCIATION BETWEEN EXPOSURE TO PFAS (PER- AND POLY- FLUOROALKYL SUBSTANCES) AND LIVER TOXICITY. PARTICULARLY, LEGACY C8-PFAS MEMBERS, PFOS (PERFLUOROOCTANE SULFONATE) AND PFOA (PERFLUOROOCTANOIC ACID), ARE HIGHLY TOXIC, WITH PFOS ESTIMATED TO BE APPROXIMATELY 10 TIMES MORE TOXIC THAN PFOA IN ECOTOXICITY MODELS. CONSEQUENTLY, PFAS REPLACEMENTS SUCH AS GENX AND PFBS ARE MARKETED AS SAFE ALTERNATIVES, ALTHOUGH GROWING EVIDENCE INDICATES THAT THESE SUBSTITUTES ALSO EXHIBIT TOXIC EFFECTS. LAB ANIMAL MODEL STUDIES HAVE SHOWN HEPATOTOXIC EFFECTS OF BOTH LEGACY AND REPLACEMENT PFAS MEMBERS, CHARACTERIZED BY METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND ITS SEVERE FORM METABOLIC DYSFUNCTION- ASSOCIATED STEATOHEPATITIS (MASH), THE TWO CHRONIC LIVER DISEASES AFFECTING AN ESTIMATED 80-100 MILLION AMERICANS. THE BROADER OBJECTIVE OF THIS PROJECT IS TO UNDERSTAND THE UNDERLYING MECHANISMS OF PFAS HEPATOTOXICITY IN MASLD/MASH. IN THIS CONTEXT, OUR INITIAL STUDIES HAVE SHOWN THAT PFAS EXPOSURE OF MICE DOWNREGULATES HEPATIC BRUCE, AN AUTOPHAGY INHIBITOR, RESULTING IN DEVELOPMENT OF MASLD IN WT, AND MORE SEVERE MASLD AND EVEN PROGRESSION TO MASH IN BRUCE LIVER-KNOCKDOWN (BKO) MICE. USING PRIMARY HEPATOCYTES, WE FOUND PFAS-INDUCED BRUCE REDUCTION COMPROMISED MITOCHONDRIAL (MT) FUNCTIONS (RESPIRATION, FATTY ACID OXIDATION/FAO, AND ATP PRODUCTION) AND SUPPRESSED MITOPHAGY IN WT AND MORE SO IN BKO MICE. PHARMACOLOGICAL RESTORATION OF MT FUNCTION IN MICE PREVENTED PFAS-INDUCED MASLD/MASH. GUIDED BY THESE COMPELLING PRELIMINARY DATA AND SCIENTIFIC PREMISE, WE HYPOTHESIZE THAT PFAS DEGRADATION OF BRUCE IN HEPATOCYTES INDUCES EXCESSIVE AUTOPHAGY (RESULTING IN CYTOTOXICITY) AND INHIBITS MITOPHAGY (RESULTING IN ACCUMULATION OF DAMAGED MITOCHONDRIA), LEADING TO RELEASE OF MTDAMPS TO ACTIVATE INFLAMMATION/ FIBROSIS, THEREBY FACILITATING PROGRESSION FROM MASLD TO MASH. WE WILL TEST THIS BY THREE SPECIFIC AIMS. AIM 1 (EX VIVO) IS TO DETERMINE THE HUMAN-RELEVANT PFAS DOSES THAT MODULATE BRUCE LEVELS FOR HOMEOSTATIC VS CYTOTOXIC AUTOPHAGY AND HOW BRUCE IN TURN REGULATES AUTOPHAGY. AIM 2 (EX VIVO) WILL INVESTIGATE BRUCE-DRIVEN MITOPHAGY PATHWAY SPECIFIC TO PFAS EXPOSURE AT HUMAN-RELEVANT DOSES. AIM 3 (EX VIVO AND IN VIVO) WILL INVOLVE EX VIVO SIMULATION EXPERIMENTS TO CHARACTERIZE THE ROLE OF PFAS-INDUCED, BRUCE-DEPENDENT HEPATOCYTE- RELEASED MT DAMPS IN ACTIVATION OF IMMUNE AND FIBROGENIC CELLS USING CO-CULTURE ASSAYS. NEXT, WE WILL PERFORM IN VIVO INTERVENTION TO VALIDATE THE ROLE OF PFAS-DAMAGED MITOCHONDRIA IN DRIVING MASH PROGRESSION IN MOUSE MODELS. FURTHERMORE, HUMAN RELEVANCE OF THE DELINEATED MECHANISMS WILL BE ASCERTAINED AND VALIDATED USING IPSC-DERIVED HUMAN LIVER ORGANOID SYSTEM. IMPACT: THIS PROJECT WILL ADVANCE OUR UNDERSTANDING OF AUTOPHAGY/MITOPHAGY-CENTRIC MECHANISMS WITH THERAPEUTIC POTENTIAL IN THE CONTEXT OF PFAS-INDUCED LIVER DISEASE MASLD/MASH.

Cincinnati Univ Of

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.113 - Environmental Health

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

Cincinnati, Ohio 452066500 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)