A novel model of pre-pregnancy particulate matter exposure and house dust mite-induced maternal allergen-induced airway inflammation leading to altered maternal immune activation and increased neuroimmune responses in the offspring

Maternal immune activation (MIA) through infection, toxic exposure, or chronic inflammatory disease has been linked with an increased risk of neurodevelopmental disorders in offspring, such as autism spectrum disorder (ASD) or schizophrenia. Previously we have shown that inducing maternal allergic asthma with ovalbumin increased pro-inflammatory cytokines during pregnancy and altered behaviors in offspring. Other studies have separately shown that particulate matter (PM) can exacerbate the effects of allergic asthma. In this study, we used house dust mite (HDM) to induce maternal allergen-induced airway inflammation combined with a pre-pregnancy exposure to PM to assess the possible combinatorial effects on maternal inflammation and offspring brain cytokine levels. BALB/c mice were treated preconception with either PBS, HDM or PM, and subsequently challenged with HDM or PBS on gestational days (GD) 12.5 and 15.5 to create 4 groups; PBS, PM, HDM and HDM + PM. Maternal serum, placental tissue, and fetal brains were collected on GD15.5. Offspring brains were collected at postnatal day (p) 15 to analyze for differences in cytokine levels across treatments. HDM and HDM + PM treated dams were found to have elevated levels of pro-inflammatory and T-helper (T H ) type 2 cytokines in the serum and increased inflammation in the lungs, consistent with an allergic response. In the placenta, increased T H 2 cytokines IL-4 and IL-5 were found in the HDM + PM offspring, consistent with the maternal serum data. Fetal brains had a decrease in MIP-2, MCP-1, and G-CSF in HDM and HDM + PM treatment groups. In the p15 hippocampus, HDM and HDM + PM groups showed increases in several pro-inflammatory cytokines but decreased regulatory cytokine IL-10, representing a skewed inflammatory immune profile. We also saw decreased microglial density and soma size in the HDM + PM group in the hippocampus. Altered cytokine profiles were additionally noted in the cortex and cerebellum of p15 offspring. Overall, these data show an increased pro-inflammatory response in the brains of offspring in response to maternal immune activation with HDM and PM.