Environmental air pollution is one risk factor associated with the onset and progression of multiple sclerosis (MS). In this project, we investigated the effects of ubiquitous traffic-generated pollutants, namely a mixture of gasoline and diesel vehicle exhaust (MVE), on signaling pathways associated with the pathophysiology of MS in the central nervous system (CNS) of either ovary intact (ov+) or ovariectomized (ov-) female Apolipoprotein (Apo) E-/-. Specifically, we investigated whether a subchronic inhalation exposure to MVE (200 PM μg/m3; 6 hr/d, 7d/wk, 30d) vs. filtered air (FA) controls altered myelination, T cell infiltration, blood-brain barrier (BBB) integrity, or production of reactive oxygen species (ROS) and expression of neuroinflammation markers in the CNS ov+ and ov- Apo E-/- mice. Our results revealed that inhalation exposure to MVE resulted in increased demyelination and CD4+ and CD8+ T cell infiltration, associated with alterations in BBB integrity. Disruption of the BBB was evidenced by decreased tight junction (TJ) protein expression, increased matrix metalloproteinase (MMPs) activity, and increased permeability of immunoglobin (Ig) G, which were more pronounced in the MVE ov- group. Moreover, MVE-exposure also promoted ROS and neuroinflammatory signaling in the CNS of ov+ and ov- mice, compared to FA groups. To analyze mechanisms that may contribute to MVE-exposure mediated inflammatory signaling in the CNS, we examined the NF-κB signaling pathway components, namely IKK subunits, IKKα, and IKKβ, as well as RelA. MVE -exposure did not alter the expression of either IKKα and IKKβ or RelA. However, increased expression of IKKα and IKKβ mRNA was observed in both FA ov- and MVE ov- groups, indicating female sex steroid hormone signaling involvement. Investigation of hormone receptors expression revealed a reduction in cerebral ERα mRNA expression, compared to ov+ mice; however, MVE-exposure resulted in an even further decrease in expression of ERα mRNA, while ERβ and PRO A/B transcript expressions were unchanged across groups. Collectively, these study findings revealed that subchronic inhalation exposure to MVE mediates alterations in ER expression in the CNS of ApoE-/- female mice, associated with altered cerebrovascular integrity and increased ROS production and inflammatory signaling. These detrimental outcomes in the CNS, resulting from MVE-exposure, are further associated with increased CD4+/CD8+ infiltration and local demyelination in the CNS of female ApoE-/-mice, which are hallmarks of MS. Such findings suggest that exposure to ubiquitous traffic-generated air pollutants may contribute to pathologies that exacerbate demyelinating diseases in the CNS of females.
