APOE genotype shapes persistent behavioral and molecular alterations following early postnatal particulate matter exposure in humanized apoE3 and apoE4 mice.

Early-life exposure to particulate matter (PM) can interfere with brain maturation and has been linked to persistent neurobehavioral alterations. However, individual susceptibility is likely influenced by both genetic background and biological sex. APOE is particularly relevant in this context because its ε4 allele is associated with altered neuroimmune, synaptic, metabolic, and stress-related responses that may modify vulnerability to environmental insults. Here, we investigated whether early postnatal PM exposure produces persistent behavioral and molecular alterations in young adult male and female humanized apoE3 and apoE4 targeted-replacement mice. Mice were exposed by whole-body inhalation to Fine Atmospheric PM (SRM 2787, NIST) or saline for 1 h/day from postnatal day (PND) 4 to PND14, using an exposure paradigm designed to achieve a nominal theoretical maximum chamber concentration of 3789 µg/m³. Nevertheless, the actual airborne concentration was not directly measured. Behavioral testing was performed from PND50 to PND96, followed by hippocampal and striatal gene-expression analyses. Early postnatal PM exposure produced selective rather than generalized neurotoxic effects. APOE genotype emerged as the main determinant of adult behavioral and transcriptional profiles, with apoE4 mice showing a more anxiety-like behavioral profile and hippocampal transcriptional reorganization involving synaptic, glutamatergic, glial, myelin-related, redox, and stress-response pathways. PM exposure produced subtle social-behavior effects and suggested potential sex- and region-dependent modulation of glutamatergic and stress-related molecular markers. Overall, APOE genotype strongly shaped adult behavioral and transcriptional profiles, whereas PM effects varied by genotype, sex, and brain region, supporting APOE-dependent neurodevelopmental trajectories as modulators of persistent brain responses to early-life air-pollution exposure.