Early-life low-dose lead exposure impairs synaptic development via epigenetic repression of the PI3K/AKT/mTOR signaling pathway

BACKGROUND: High-dose lead (Pb) exposure is known to trigger neuroinflammation and glial activation; however, underlying the effects of chronic, low-level Pb exposure affects brain development remain poorly understood. METHODS: In this study, we investigated whether exposure to a sub-threshold concentration of Pb (50 ppm in drinking water), resulting in blood Pb levels (3.6 ± 1.6 ng/dL) well below current international safety standards, can impair neurodevelopment in mice using an integrative multi-omic and morphological approach. RESULTS: Chronic early-life exposure led to significant behavioral abnormalities, including reduced locomotor activity, altered repetitive behaviors, and deficits in working memory. Morphological analyses revealed region-specific dendritic atrophy in hippocampal CA1 neurons, characterized by shortened and less-branched basal dendrites, consistent with impaired hippocampal circuitry. Integrated transcriptomic and epigenomic profiling identified coordinated hypermethylation and downregulation of neurodevelopmental genes such as Rpl26, and Ube2r2. These epigenetic changes converged on suppression of the PI3K/AKT/mTOR signaling axis, as evidenced by the reduced phosphorylation of PI3K, AKT, mTOR, and GSK-3β, alongside reduced expression of essential synaptic proteins (Synapsin I, PSD95, and TrkB). In parallel, the downregulation of NF-κB and COX-2 indicated that these molecular and behavioral abnormalities arose through a non-inflammatory mechanism distinct from classical Pb-induced gliosis. CONCLUSION: Together, our findings demonstrate that even trace Pb exposure can disrupt neurodevelopment through epigenetic repression and signaling dysregulation, resulting in lasting synaptic and cognitive deficits. These results highlight the exceptional vulnerability of the developing brain to environmental Pb levels and underscore the urgent need to re-evaluate current global safety thresholds to ensure neurodevelopmental protection.