LONG-TERM EFFECTS OF POSTNATAL PM<SUB>10</SUB> INHALATION ON NEUROBEHAVIOR AND BRAIN MOLECULAR PROFILES IN APOE3 AND APOE4 HUMANIZED MICE

Air pollution is a major global health concern, and particulate matter (PM) stands out among its constituents due to its well-documented health impact. PM exposure has been consistently associated with neurodevelopmental and behavioral alterations, and it has also been linked to biological changes commonly observed in neurodegenerative diseases, suggesting a potential contribution to neurodegenerative vulnerability. Apolipoprotein E (APOE) is a polymorphic gene in humans, with APOE3 as the most common allele, whereas APOE4 is the strongest genetic risk factor for Alzheimer’s disease—particularly in females—and may confer increased susceptibility to environmental toxicants. Accordingly, this study aimed to investigate whether early postnatal PM₁₀ inhalation produces persistent neurobehavioral and molecular alterations relevant to brain aging in ApoE3 and ApoE4 humanized mice. From postnatal day 4 to 14, male and female mice were exposed to inhaled PM₁₀ (SRM 2787; NIST) in whole-body exposure chambers. At 9 months of age, locomotor activity and anxiety-like behavior were assessed using the Open Field test (OFT), and spatial learning and memory were evaluated using the Morris Water Maze (MWM). Following behavioral testing, brains were collected for multiplex RNAscope HiPlex v2 analyses in the frontal cortex and hippocampus, targeting oligodendrocyte/myelination markers and inflammatory-related genes. Overall, ApoE3 mice showed increased activity and poorer MWM performance compared with ApoE4 mice. PM₁₀ exposure induced an anxiolytic-like phenotype in the OFT and impaired short-term memory in PM₁₀-exposed ApoE4 mice. Taken together, these findings support APOE-dependent susceptibility to early-life PM₁₀ exposure and highlight gene–environment interactions shaping long-term neurobiological trajectories.