Project Grant F32AA032967

THE IMPACT AND MECHANISMS OF PFAS ON ALCOHOL-ASSOCIATED LIVER DISEASE - PROJECT SUMMARY: ALCOHOL-ASSOCIATED LIVER DISEASE (ALD) CONSISTS OF A COMPLEX RANGE OF DISORDERS WITH VARIABLE RATES OF PROGRESSION INFLUENCED BY GENETIC SUSCEPTIBILITY, ENVIRONMENTAL EXPOSURES, AND OTHER COMORBIDITIES. PER- AND POLYFLUOROALKYL SUBSTANCES (PFAS) ARE HIGHLY PERVASIVE SYNTHETIC COMPOUNDS WITH EMERGING EVIDENCE OF HEPATOTOXIC MECHANISMS WHICH PARALLEL THOSE IN ALD (E.G., OXIDATIVE STRESS, LIPID DYSREGULATION, IMMUNOMODULATION) AND MAY CONTRIBUTE TO CONTRIBUTE TO PATHOGENESIS. THESE RISKS ARE EXACERBATED BY DEMOGRAPHIC OVERLAP IN EXPOSURE-PRONE POPULATIONS, PARTICULARLY OCCUPATIONAL GROUPS WHICH EXPERIENCE ELEVATED PFAS EXPOSURE AND EXHIBIT HIGH RATES OF ALCOHOL CONSUMPTION. DESPITE SUCH RISKS, THE EFFECTS OF ALCOHOL AND PFAS CO-EXPOSURE REMAIN UNCLEAR. WE HYPOTHESIZE THAT PFOS AND ALCOHOL SYNERGISTICALLY WORSEN ALD PATHPHYSIOLOGY THROUGH ENHANCED DISRUPTION OF LIPID METABOLISM, OXIDATIVE STRESS, AND MITOCHONDRIAL DYSFUNCTION. TO TEST THIS HYPOTHESIS, WE PROPOSE TO PERFORM EXPERIMENTAL INVESTIGATIONS INTO THE SYNERGISTIC EFFECTS OF THE MOST PREVALENT PFAS COMPOUND, PERFLUOROOCTANESULFONIC ACID (PFOS), AND ALCOHOL IN A MOUSE MODEL. LIVER AND PLASMA SAMPLES WILL BE TAKEN ACROSS A RANGE OF PFOS CONCENTRATIONS, WITH THE ADDITION OF ALCOHOL OR ISOCALORIC CONTROL DIET, AND UNDERGO BIOCHEMICAL, HISTOPATHOLOGICAL, MULTI-OMIC, AND IMAGING MASS SPECTROMETRY (IMS) ANALYSIS. ADVANCED IMS TECHNIQUES WILL BE USED TO EVALUATE THE SPATIAL DISTRIBUTION OF COMPOUNDS (I.E., PFOS, METABOLITES, AND LIPIDS) AND COMPARE TO LIVER TISSUE ALTERATIONS. THESE STUDIES WILL BE CONDUCTED IN BOTH MALE AND FEMALE MICE TO IDENTIFY SEX-SPECIFIC RESPONSES. AIM 1 WILL DETERMINE THE EXTENT TO WHICH PFOS EXACERBATES ALCOHOL-INDUCED LIVER DAMAGE AND AIM 2 WILL ELUCIDATE THE MECHANISMS BY WHICH PFOS PROMOTES HEPATOTOXICITY IN THE CONTEXT OF ALD. THESE EXPERIMENTS WILL IMPROVE MECHANISTIC UNDERSTANDING OF THE HEPATIC EFFECTS OF PFAS AND ALCOHOL CO- EXPOSURE. IN DOING SO, THIS PROJECT WILL SUPPORT THE DEVELOPMENT OF TARGETED THERAPEUTIC INTERVENTIONS, REFINE DIAGNOSTIC TOOLS, AND INFORM PUBLIC HEALTH POLICY.