Prenatal PM2.5 exposure impairs hippocampal synaptic development in offspring via KDM5A-mediated epigenetic derepression of Pin1

Exposure to fine particulate matter (PM_2.5) has been increasingly associated with neurodevelopmental disorders, yet the underlying molecular mechanisms remain poorly defined. KDM5A, a histone lysine demethylase implicated in cognitive regulation, has not been thoroughly investigated in the context of PM_2.5-induced neurotoxicity. In this study, using an in vitro model of PM_2.5-exposed hippocampal neurons, we demonstrated that KDM5A overexpression significantly ameliorates synaptic damage. Transcriptomic analysis identified Pin1 as a key downstream effector of KDM5A. Mechanistically, PM_2.5 exposure led to KDM5A downregulation, resulting in increased H3K4me3 levels and upregulated Pin1 expression. Perturbing KDM5A or Pin1 expression altered synaptic protein levels, confirming their functional interplay in PM_2.5-induced synaptic damage. ChIP-qPCR revealed co-enrichment of KDM5A and H3K4me3 at the Pin1 promoter. Furthermore, dual-luciferase reporter assays and demethylase-inactive KDM5A mutants confirmed that KDM5A represses Pin1 transcription via its demethylase activity. It is noteworthy that KDM5A primarily regulates Pin1's transcription via its histone demethylase activity, rather than through direct protein-protein interaction influencing Pin1 protein activity. Site-directed mutagenesis identified critical regulatory elements within the Pin1 promoter responsible for KDM5A-mediated suppression. Collectively, our findings suggest that PM₂.₅ may impair synaptic plasticity via the KDM5A-Pin1 axis, offering fresh insights into the potential mechanisms underlying pollution-related neurodevelopmental disorders.