Sex-specific neurotoxicity induced by long-term bisphenol A exposure: Single-cell sequencing reveals dual mechanisms involving hippocampal gliosis and neuronal apoptosis

Bisphenol A (BPA) is one of the most widely produced industrial chemicals globally. Exposure to BPA has been associated with neurobehavioral disorders and various other diseases. As an endocrine disruptor, BPA primarily binds to oestrogen receptors, thereby interfering with multiple neurological functions. Despite extensive research into its disruptive effects, the neurotoxicity of BPA remains incompletely understood. This study aimed to investigate the effects of long-term BPA exposure on behavioural memory and the neurological system in adult mice. Using a combination of behavioural and morphological analyses, along with single-cell sequencing technology, we examined the sex-specific effects of BPA and its underlying neurotoxic mechanisms. In female mice, prolonged BPA exposure disrupted oestrogen signalling, leading to glial hyperplasia in the hippocampus. This, in turn, resulted in depression-like behaviours and impairments in spatial learning and memory. In male mice, chronic BPA exposure induced apoptosis of granule neurons in the hippocampal dentate gyrus, contributing to a degree of brain atrophy. These changes led to depressive and anxiety-like behaviours, impaired spatial learning, and memory, and increased susceptibility to neurodegenerative conditions. This study elucidates the cellular and molecular mechanisms underlying the sex-specific neurotoxicity of BPA. The findings not only advance our understanding of the neurological risks posed by endocrine-disrupting chemicals but also provide critical scientific evidence to support precision medicine strategies and inform chemical policy development.