Developmental lead (pb) exposure induces anxiety and depression-like behaviors via inhibiting the AMPK/ACSS2 pathway.

Environmental lead (Pb) exposure is a risk factor for anxiety and depression. Our previous study showed Pb-induced neurotoxicity involves dysregulated epigenetic modifiers, yet the role of acyl-CoA synthetase short-chain family member 2 (ACSS2)-a key regulator of histone acetylation-in these behaviors remains unclear. Beginning at gestational day 0 (GD 0, plug day) and continuing through weaning (PND 21), C57BL/6 J dams received 100 ppm Pb in drinking water, exposing offspring indirectly via placenta and milk; after weaning, offspring received the same Pb solution directly from drinking water until PND 60. Behavioral tests revealed developmental Pb exposure induced anxiety and depression-like behaviors, accompanied by neuronal morphological damage in the medial prefrontal cortex (mPFC). Mechanistically, Pb inhibited AMP-activated protein kinase (AMPK) activity, suppressing ACSS2 expression and its nuclear translocation, which reduced nuclear acetyl-CoA and histone H3 lysine 9 acetylation (H3K9ac). The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) restored ACSS2 expression and phosphorylation, confirming AMPK as its upstream regulator. These epigenetic changes accompanied downregulated synaptic molecules (GluN2A, VGLUT1, PSD-95). ACSS2 restoration via D-mannose supplementation rescued synaptic protein loss, reversed neuronal structural impairments, and alleviated Pb-induced emotional deficits. Our findings identify the AMPK/ACSS2 pathway as a core regulator of Pb-induced affective disorders, whereby its inhibition epigenetically silences synaptic molecular expression, and nominates ACSS2 augmentation as a viable therapeutic strategy.