Postnatal particulate matter exposure alters developmental milestones and brain gene expression in apoE transgenic mice in a sex- and genotype-dependent manner.

Air pollution, with particulate matter (PM) as one of its most critical environmental contaminants, represents a major global health threat and a leading cause of premature mortality. PM can reach the central nervous system (CNS) and has been implicated in both neurodevelopmental and neurodegenerative disorders. Individual susceptibility to PM-induced neurotoxicity is shaped by genetic background. Apolipoprotein E (APOE), the major CNS apolipoprotein, plays a key role in brain homeostasis and neurodevelopment, and its isoforms may differentially modulate vulnerability to environmental insults. However, the interaction between APOE genotype and PM exposure during early development remains poorly understood. We aimed to investigate the developmental effects of early postnatal PM exposure in humanized apoE3 and apoE4 transgenic mice. From postnatal day (PND) 4-14, pups underwent daily whole-body inhalation exposure to Fine Atmospheric PM (SRM 2787, NIST), with a nominal theoretical chamber concentration of 3789 µg/m3. Physical milestones, neuromotor performance, and sexual maturation were monitored until PND42. Forebrain and cerebellum samples were analyzed for genes involved in neurotransmission, neurotrophic signaling, and neuroinflammation. Postnatal PM exposure reduced weight gain in females and impaired neuromotor performance. Furthermore, it accelerated eye and vaginal opening in apoE3 mice. The effects of PM exposure on gene expression were more pronounced in apoE4 mice, including alterations in GABAergic (Nkcc1), glutamatergic (Grin2b), serotonergic (5ht2c), and neurodevelopmental (Reln) markers. These findings indicate that early postnatal PM exposure disrupts neurodevelopment through sex- and genotype-specific mechanisms and support APOE genotype as a modifier of vulnerability to PM-induced developmental neurotoxicity.