Molecular basis for the early life sensitization of the brain to ultrafine carbonaceous particles: a study of the brain proteome, telomeres, and epigenetic modelling

Air pollution has been implicated in various adverse health effects, including neurodevelopmental and neurodegenerative impairments. However, the long-term impact of early-life ultrafine particle (UFP) exposure on the brain remains poorly understood. Using a sequential exposure mouse model, we investigated how early-life ultrafine carbonaceous particles (UFP^C) exposure programs neurobehavioural and molecular vulnerability upon adult re-exposure. Wild-type C57BL/6J mice were exposed to either HEPA-filtered air or UFP^C during the prenatal (gestational days 8-9 and 16-17) and/or postnatal periods (postnatal days 4-7 and 10-13), followed by a 4-day re-exposure in adulthood (postnatal days 142-145). Behavioural assessments revealed hippocampus-dependent spatial memory deficits and anxiolytic-like behaviour following cumulative exposure. Brain proteomic analysis identified reduced protein levels of key modulators of synaptic signalling and neurovascular homeostasis (Erbb4 and Ddah1), accompanied by gene-specific promoter methylation changes and shortened telomere length, indicating persistent epigenetic reprogramming and accelerated cellular aging. We validated the epigenetic sensitivity of ERBB4 to prenatal air pollution in human cord blood from the ENVIRONAGE birth cohort. The integrative design, encompassing behavioural phenotyping and molecular profiling, offers a comprehensive systems-level perspective on the neurobiological effects of UFP^C. Our findings suggest that developmental UFP^C exposure induces increased susceptibility to re-exposure on behavioural, epigenetic, and proteomic outcomes. This work provides evidence for UFP as a potentially critical environmental determinant of brain health throughout life.