Liver and Systemic Effects of Military Exposures in Veterans

About This Grant

This new application proposes the newly formed Liver MERP Consortium to investigate military exposures (MEs) in Veterans and the effects that these exposures have on liver health outcomes. The broad impact of the proposed work is to inform care and policy and improve the health of Veterans. The Consortium’s approach includes thorough exposure assessments at the individual subject level; and it conducts studies that contribute toward the understanding of the etiology, pathobiology, and biomarker indicators of ME-induced illness. The Liver MERP Consortium has eleven investigators from five collaborating Veterans Affairs Medical Centers (VAMCs) and four university affiliates/partners. The proposed work will test the hypothesis that per- and polyfluoroalkyl substances (PFAS), which are chemicals common to military use and burn pits, are associated with the development, severity, and progression of metabolic dysfunction associated steatotic liver disease (MASLD) and systemic metabolic disruption. MASLD is the most common liver disease and increasingly more prevalent in-service personnel and Veterans. PFAS were widely used in numerous military applications such as in aqueous film forming foam aqueous film forming foam (AFFF). There is little to no information regarding serum PFAS levels (i.e. exposure) or the relationship between PFAS exposures and MASLD for Veterans, US service members, or dependents. PFAS are metabolism disrupting chemicals which have been associated with blood and liver lipid disorders including MASLD in civilians. Innovation: This is the first study ever to evaluate toxic exposures and MASLD prevalence, severity, progression, and mode of action all within a single cohort; and the first evaluating PFAS and MASLD Veterans. The PFAS exposure assessments proposed are likely to be the most thorough ever performed in any clinical cohort. The specific aims are to i) test for associations of PFAS with MASLD in Veterans, ii) determine associations of PFAS with MASLD severity biomarkers and to elucidate underlying mechanisms, and iii) the impact of PFAS on liver fibrosis progression in Veterans with MASLD. We will recruit a new cohort of 1000 Veterans with (n=625) or without MASLD (n=375) from PFAS-diverse locations across the United States. Serum PFAS (n=54 individual PFAS) will be measured along with other biomarkers of MASLD severity, inflammation, and dyslipidemia. Serum metabolomic profiles will provide mechanistic insight into pathways and systemic alterations associated with PFAS exposure. Lastly, this will be the first study to examine the longitudinal effect of PFAS exposure on liver fibrosis. Overall, the proposed work will provide the most comprehensive evaluation of PFAS exposure and association with MASLD to date. Additionally, a unique biorepository that contains comprehensive liver outcome information will be generated. This repository can be mined in the future for other MEs and health outcomes.