Identification of potential mechanisms of cognitive dysfunction induced by environmentally relevant PFAS mixture in male rats

• Environmentally relevant PFAS mixture disrupts cognitive function and memory ability in rats • PFAS leads to morphological damage, apoptosis of hippocampal and disruption of colonic barrier. • Abnormal neurotransmission and inflammatory responses contribute to neurotoxicity. • Transcriptomics and metabolomics are promising tools to elucidate neurotoxicity of PFAS. • PFAS exposure causes disturbance of gut microbiota in rats. PFAS are emerging persistent organic pollutants, and their potential impacts and underlying mechanisms on cognitive function remain incompletely understood. This study utilized a male rat model to investigate the effects of an environmentally relevant PFAS mixture comprised of eight PFAS on spatial learning and memory, as well as the potential mechanisms through molecular biology assays and multi-omics analysis. Following the administration of PFAS via oral gavage at doses of 0, 0.001, 0.050, 0.250 and 7.000 mg/kg body weight for 28 days, resulting in a decrease in object location recognition ability, spatial learning and memory, as assessed by the new location recognition and Morris water maze tests at the exposure endpoint. These impairments may be closely related to the dysregulation of neurotransmitter secretion, enhanced inflammatory responses, neuronal damage and apoptosis, and impaired intestinal barrier function. Furthermore, exosomal transcriptomics and plasma metabolomics analyses revealed that 17 miRNAs and 7 metabolites were associated with PFAS-induced neurotoxicity. Meanwhile, PFAS exposure led to alterations in gut microbial diversity, with correlations observed between changes in metabolites and bacteria. These synergistic effects contributed to neurotoxicity associated with PFAS, which may be closely linked to the microbiota-gut-brain axis. These findings provide valuable insights for assessing the neurotoxicity of PFAS at environmentally relevant concentrations.