PFOS and GenX Induce Mitochondrial Toxicity and Differentially Alter Respiratory Complex Activities in Liver and Brain

Abstract

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants linked to adverse health effects, yet the mitochondrial consequences of exposure to individual PFAS and their mixtures remain incompletely understood. This study investigated the individual and combined effects of perfluorooctanesulfonic acid (PFOS) and hexafluoropropylene oxide dimer acid (GenX) on mitochondrial respiratory complex activities under acute, subchronic, and chronic exposure conditions. PFAS distribution in plasma, liver, and brain tissues, mitochondrial oxidative phosphorylation (OXPHOS) protein expression, and predicted interactions with mitochondrial Complexes III and IV were examined. Acute exposure inhibited Complex III and IV activities in isolated liver and brain mitochondria, with combined exposure generally producing greater inhibition than either compound alone. Following subchronic exposure (1 month), mitochondrial responses varied by dose and tissue type; liver enzymes showed significant inhibition of Complexes I to IV at 2 and 10 mg/kg BW, while brain mitochondria showed no alteration. After 5 months at 0.2 mg/kg BW, multiple liver complexes were inhibited, whereas the brain showed selective changes. PFOS and GenX were detected in plasma and brain tissues. In rats exposed to 2 mg/kg BW for 1 month, PFOS was higher than control in all three brain regions studied, with no difference between individual and combined exposure. OXPHOS protein expression varied across brain regions and exposure conditions. A comparison of internal levels in mice showed that co-exposure lowered GenX at 10 mg/kg BW, whereas at 0.2 mg/kg BW plasma PFOS and cortex GenX were higher with co-exposure. Plasma levels at 0.2 and 2 mg/kg BW were about ~ 2.5 and 4.5 times the highest serum levels reported in the general and occupationally exposed populations, respectively. Molecular docking indicated distinct predicted interaction patterns, with PFOS generally exhibiting more favorable scores at Complex III binding sites and GenX at selected Complex IV regions. Overall, these findings demonstrate exposure-dependent and tissue-specific mitochondrial responses to PFOS and GenX and highlight the importance of evaluating combined PFAS exposure across multiple exposure durations.

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