Perinatal maternal lead exposure induces intergenerational neurotoxicity via mitochondrial dysfunction and mediation by perturbation of thyroid function.

Perinatal maternal lead (Pb) exposure, particularly from endogenous skeletal Pb, is a primary cause of early childhood Pb exposure and associated neurotoxicity. This study innovatively employed a model of male offspring rats experiencing maternal skeletal Pb mobilization, revealing offspring neurotoxicity characterized by astrocytic mitochondrial injury, and maternal-offspring thyroid dysfunction. Notably, mediation analysis indicated that maternal thyroid hormones (THs) played a crucial role in mediating Pb-induced intergenerational neurotoxicity. Additionally, Pb-related mitochondrial dysfunction was further validated in rat astrocytes. In a cohort of 298 mother-child pairs from Shanghai, cord blood Pb levels correlated with fine motor scores in 18-month-old girls and disrupted cord serum TH levels in infants, particularly total T4 (TT4) in boys. Furthermore, levels of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were negatively correlated with motor domains in infants, especially in boys. These findings highlight the "thyroid-astrocytic mitochondrial axis" as a critical pathway for intergenerational neurotoxicity resulting from perinatal maternal Pb exposure, particularly maternal endogenous Pb exposure, revealing significant sex-specific differences.