Exposure to environmental contaminants is associated with sex-specific disturbances of hepatic lipid metabolism in non-alcoholic fatty liver disease

Background and aims: Liver has a vital role in metabolism, distribution, and excretion of exogenous chemicals. The endocrine disrupting chemicals (EDCs) may act as a‘second hit’in the progression of NAFLD, advancing the earlier stages of liver pathology such as steatosis to more severe stages. A specific class of ECDs that have been linked with NAFLD are perfluorinated alkyl substances (PFAS), a class of commonly used industrial chemicals that humans are widelyexposed to. Due to the their structural similarity with fatty acids, PFAS may disrupt hepatic lipid metabolism. Furthermore, functionally, PFAS share some features with bile acids, including similar enterohepatic circulation. Nevertheless, human data linking PFAS exposure and lipid metabolism in the liver are currently lacking. The principal aim of our study was to define the impact of PFAS exposure on hepatic metabolism, with specific focus on bile acid and lipid metabolism. Method: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the impact of PFAS exposure on liver metabolism in the individuals with NAFLD. Average BMI was 45.65 ± 5.99 kg/m2, with liver fat content varying between 0% and 80%. We comprehensively characterized both hepatic (liver biopsy) and serum metabolome using four analytical platforms, and measured PFAS in serum. We investigated the association between the NAFLD (liver fat %, NASH grade, fibrosis stage, insulin resistance), PFAS exposure, and metabolome. Results: PFAS exposurewas associated with NAFLD (Figure) as well as with changes in hepatic lipid and bile acid metabolism. Importantly, we observed sex-specific association between chemical exposure and NAFLD, linked with sex-specific changes in both hepatic and circulating metabolome. We noticed differences not only in the exposure profiles between the males and females, but, notably, also the impact of the exposure, as characterized both with the impact on metabolome but also on clinical parameters was cle