The Disruption of Fetal Neurodevelopment as a Consequence of Gestational Exposure to Concentrated Ambient Fine and Ultrafine Particles in the Mouse

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Program in Toxicology, 2017.Increasing evidence indicates that gestation is a critical window of neurodevelopmental susceptibility to airborne pollutants. The particulate matter (PM) component of air pollution, specifically fine (≤2.5µm; PM2.5), and ultrafine (≤100nm; UFP) PM, has been shown to induce neuropathology in mice and has been epidemiologically linked to neurodevelopmental disorders such as autism spectrum disorders and schizophrenia. Previous studies in mice exposed postnatally to concentrated ambient UFPs using the University of Rochester HUCAPS system revealed white matter abnormalities and enlarged lateral ventricles (ventriculomegaly), which are poor prognostic indicators for neurodevelopment and are characteristic of some neurodevelopmental disorders. The current study sought to determine if the gestational period in mice is a critical window of neurodevelopmental susceptibility to concentrated ambient particles (CAPs), which include both PM2.5 and UFP. Pregnant mice were exposed to CAPs or filtered air control via whole-body inhalation for 6 hours daily from gestational days 0.5-16.5 using the VACES particle concentrator located in Sterling Forest, NY. Offspring brains were collected at postnatal days (PNDs) 11-15 and 57-61. Histological analyses revealed gestational CAPs exposure induced perinatal ventriculomegaly in both sexes at PNDs 11-15 that did not persist to PNDs 57-61. In contrast, CAPs exposure induced early and persistent white matter overgrowth of the corpus callosum (CC), indicated by increased myelin basic protein and compact myelin density with associated increase in CC area. Deposition of inorganic PM constituents was observed in the CC, suggesting translocation of particles across the placenta to the fetal brain. Examination of CC oligodendrocytes (OLs) revealed a premature maturational shift in CAPs-exposed offspring as well as disruption of the myelin sheath ultrastructure. These findings highlight the vulnerability of the brain and white matter during gestation to UFP/ PM2.5 exposures, and a corresponding potential for increased risk of NDs such as autism and schizophrenia. The parallel findings from two different CAPs-generating systems (HUCAPS and VACES) suggest the importance of common exposure elements as opposed to regionally-specific constituents of air pollution as the basis of such effects. Finally, this study underscores the need for UFP regulation as well as PM exposure limits for pregnant women