45 Air pollution derived Fe-oxide inhalation produces persistent sex-specific behavioural and morphological deficits in mice

Abstract Iron-overload, a hallmark and potential contributor to neurodegeneration, comprises a significant portion of ultrafine particulate (UFP) matter of air pollution, with especially high concentrations in US subway systems. Previous research demonstrated that Fe-oxide nanoparticles can translocate along cranial nerves into brain, form deposits within the brain, and associate with degenerating myelin. We hypothesize that the essential role of Fe in myelination and the direct physical damage of particle transport along axons can contribute to the sex-specific white matter dysregulation observed in neurodegeneration. To assess the impact of Fe-oxide nanoparticle inhalation and age-related increases in brain Fe content on white matter, two cohorts of 10-week-old C57Bl/6 mice were randomly exposed to HEPA-filtered air or 1.5 ng/L iron-oxide UFPs for two hours daily for 20 d. An acute cohort was either acutely sacrificed followed by MRH or subjected to behaviour. The other cohort aged undisturbed until behaviour was examined at 12 and 18 mo. Acutely, Fe-exposure produced sex-specific diffusivity differences in olfactory bulbs. At 12 mo, only caudal regions on the olfactory circuit had significantly higher fractional anisotropy. Fe-exposed female mice had persistently lower novel recognition indices. Only at 18 mo, Fe-exposed male mice exhibited hypoactivity and motor deficits. Ultrastructural 18-mo corpus callosum myelin analyses demonstrated Fe-induced female-specific decreases in g-ratio and increases in axon area. Both sexes exhibited increases in fibre area, myelin area, and split myelin area. Fe-exposure produced a sex-specific effect on axon circularity indices in Fe-exposed animals potentially underlying sex differences in diffusivity.