PFOA and co-exposure with PFOS induce AMPK-dependent hypoglycemia in mice: integrated evidence from physiology, multi-omics, and molecular docking

Per- and polyfluoroalkyl substances, notably perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are persistent environmental contaminants with increasing evidence of metabolic toxicity. However, their effects on glucose homeostasis and the underlying mechanisms remain unclear. In this study, we investigated the metabolic consequences of PFOA, PFOS and co-exposure in male C57BL/6 mice for 28 days. Physiological indicators, including fasting blood glucose and hepatic glycogen, were evaluated, followed by transcriptomic, metabolomic, and molecular docking analyses. We found that PFOA and PFOS co-exposure significantly induced hypoglycemia and reduced hepatic glycogen content. Transcriptomic and metabolomic profiling revealed enriched pathways related to glucose metabolism, with the AMPK signaling pathway identified as a central mediator. Notably, PFOA and co-exposure upregulated glycolytic and fatty acid oxidation genes, while suppressing glycogen synthesis regulators. Molecular docking further indicated that both PFOA and PFOS could bind to adiponectin receptors (AdipoR1/2), potentially disrupting normal receptor-mediated AMPK activation. Together, these findings establish an AdipoR1/2-AMPK-mediated mechanism for PFAS-induced glucose metabolic disruption, particularly under PFOA or co-exposure. We provide the integrated physiological and mechanistic evidence linking PFAS exposure to AMPK-dependent hypoglycemia, highlighting the need for metabolic health risk assessments of PFAS mixtures in the environment.