Neuropathological Consequences of Gestational Exposure to Concentrated Ambient Fine and Ultrafine Particles in the Mouse

Abstract

Increasing evidence indicates that the central nervous system (CNS) is a target of air pollution. We previously reported that postnatal exposure of mice to concentrated ambient ultrafine particles (UFP; ≤100 nm) via the University of Rochester HUCAPS system during a critical developmental window of CNS development, equivalent to human 3rd trimester, produced male-predominant neuropathological and behavioral characteristics common to multiple neurodevelopmental disorders, including autism spectrum disorder (ASD), in humans. The current study sought to determine whether vulnerability to fine (≤2.5 μm) and UFP air pollution exposure extends to embryonic periods of brain development in mice, equivalent to human 1st and 2nd trimesters. Pregnant mice were exposed 6 h/day from gestational days (GDs) 0.5-16.5 using the New York University VACES system to concentrated ambient fine/ultrafine particles at an average concentration of 92.69 μg/m3 over the course of the exposure period. At postnatal days (PNDs) 11-15, neuropathological consequences were characterized. Gestational air pollution exposures produced ventriculomegaly, increased corpus callosum (CC) area and reduced hippocampal area in both sexes. Both sexes demonstrated CC hypermyelination and increased microglial activation and reduced total CC microglia number. Analyses of iron deposition as a critical component of myelination revealed increased iron deposition in the CC of exposed female offspring, but not in males. These findings demonstrate that vulnerability of the brain to air pollution extends to gestation and produces features of several neurodevelopmental disorders in both sexes. Further, they highlight the importance of the commonalities of components of particulate matter exposures as a source of neurotoxicity and common CNS alterations.

Pre‐natal brain development as a target for urban air pollution

“…33 The few published studies using neuroimaging suggest that pre-natal air pollution exposure affects myelinisation (ie smaller white matter volume, 29 white matter lesions 30 and decrease o pre-frontal cortical thickness 32 ). These results are consistent with the observed effects in mice exposed in utero 14,25 and in elderly human beings, [35][36][37] although cumulative exposure and the mechanisms of action could be different in later life. The studies in mice suggest that the effect of air pollution is principally mediated through chronic stimulation of microglial cells.…”

“…12 Among the various particle types, we found airborne copper to be associated with tissue modifications and functional connectivity in the caudate nucleus in children. 13 Other metals, such as iron, have been linked to structural changes in mice brain, 14 and environmental Fe nanoparticles were found in brain tissue. 15 Furthermore, two recent studies in rats exposed to NO 2 (an urban gas) reported clear evidence of brain damage, 16,17 suggesting a specific neurotoxicity of NO 2 .…”

“…The studies in mice suggest that the effect of air pollution is principally mediated through chronic stimulation of microglial cells. 14,25 Microglia support myelin protection and induce synapse formation. Accordingly, experiments in mice exposed to diesel particles pre-and neo-natally showed a reduction in the area of the corpus callosum (the largest white matter tract) and dilatation of the ventricles (indicating white matter damage).…”

“…We propose to focus research on pre-natal life ( Table 1) because, as elaborated above, it can be considered as a critical window of exposure and provide a great opportunity for prevention and there have been reports on transgenerational brain effects in mice. 14,[25][26][27] Disruptions in the embryological process during pre-natal period could impair or make more fragile the brain for the rest of the life. 19 Moreover, pregnancy offers the opportunity of a more feasible and valid assessment of the cumulative exposure.…”

Environment matters: microglia function and dysfunction in a changing world

“…Another recent study showed that exposure of pregnant dams to ultrafine particles (UFP), a component of air pollution, leads to increases in corpus callosum size, hypermyelination and microglial activation in offspring [64]. Similarly, administration of UFP to male and female mouse pups from P4-13 led to a persistent increase in microglia number in males only, as far out as P270 [65].…”