Chronic bisphenol A exposure impairs cognitive function in male mice associated with NLRP3 inflammasome-driven pyroptosis and gut microbiota dysbiosis along the microbiota-gut-brain axis

Abstract

The microbiota-gut-brain axis (MGBA) is a critical bidirectional communication system governing cognitive function and intestinal homeostasis. Despite growing evidence linking environmental chemicals to neurological disorders, the mechanisms underlying bisphenol A (BPA)-induced cognitive deficits remain poorly understood. Here, we demonstrate that chronic BPA exposure may induce cognitive impairment in male offspring through disruption of the MGBA, specifically via upregulation of the NLRP3 inflammasome/pyroptosis-related markers. Gravid Kunming mice received BPA (0, 2, 20, or 200 µg/kg body weight/day) in drinking water until weaning; their male offspring were then orally administered identical doses for nine weeks. Behavioral tests revealed significant deficits in short- and long-term memory following high-dose (200 µg/kg) BPA exposure. Mechanistically, high-dose BPA reduced hippocampal neuron density, compromised ileal barrier integrity, and induced dysbiosis characterized by decreased α-diversity (Chao1, ACE, Shannon; P < 0.05) and an elevated Firmicutes/Bacteroidota ratio. LEfSe analysis identified increased abundance of potentially pro-inflammatory genera at 200 µg/kg. Crucially, high-dose BPA upregulated the expression of NLRP3, ASC, Caspase-1, GSDMD, and IL-18 in both the hippocampus and ileum, alongside elevated serum TNF-α and IL-18, indicating systemic inflammation. Correlation analyses further linked specific microbial shifts to pyroptosis markers and cognitive decline. Collectively, our findings establish that chronic BPA exposure may triffer gut dysbiosis and barrier dysfunction, leading to NLRP3 inflammasome activation and pyroptotic cell death in both the gut and brain, ultimately impairing cognition. These results underscore the neurotoxic risk posed by BPA and provide a mechanistic rationale for stricter regulatory controls on its use in food-contact materials.