Per- and Polyfluoroalkyl Substances Suppress Macrophage Alternative Activation to Disrupt Hepatic Lipid Metabolism.

Per- and polyfluoroalkyl substances (PFAS) are pervasive environmental pollutants with diverse toxic effects (e.g., hepatotoxicity and metabolism disorder). Macrophages played a key role in metabolic response; however, the effect of macrophage on PFAS-induced toxicity and the underlying mechanisms remain poorly understood. In this study, we constructed a high-content cell model by utilizing the activation and differentiation of human THP-1 monocytes into alternative activation of macrophages, enabling rapid quantitative screening of numerous PFAS. We applied the cell model to screen 10 PFASs and identified that PFOA and PFUnDA significantly suppressed alternative activation of macrophages by disrupting the PPAR signaling pathway. Oral exposure to PFOA and PFUnDA in WT mice also significantly impaired alternative activation of macrophages in the liver and induced hepatocyte hypertrophy, liver dysfunction, and systemic lipid metabolism disorders. Moreover, macrophage-specific knockout of PPARγ exacerbated PFOA and PFUnDA-induced suppression of macrophage alternative activation and subsequent hepatotoxicity. Activation balance between PPARα and PPARγ may be a critical factor by PFOA and PFUnDA to affect the alternative activation of macrophage. These findings highlight the immunometabolism regulatory role of macrophage activation in PFAS-induced hepatotoxicity in humans.