Gestational Exposure to Air Pollution Alters Cortical Volume, Microglial Morphology, and Microglia-Neuron Interactions in a Sex-Specific Manner

Abstract

Microglia are the resident immune cells of the brain, important for normal neural development in addition to host defense in response to inflammatory stimuli. Air pollution is one of the most pervasive and harmful environmental toxicants in the modern world, and several large scale epidemiological studies have recently linked prenatal air pollution exposure with an increased risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Diesel exhaust particles (DEP) are a primary toxic component of air pollution, and markedly activate microglia in vitro and in vivo in adult rodents. We have demonstrated that prenatal exposure to DEP in mice, i.e., to the pregnant dams throughout gestation, results in a persistent vulnerability to behavioral deficits in adult offspring, especially in males, which is intriguing given the greater incidence of ASD in males to females (∼4:1). Moreover, there is a striking upregulation of toll-like receptor (TLR) 4 gene expression within the brains of the same mice, and this expression is primarily in microglia. Here we explored the impact of gestational exposure to DEP or vehicle on microglial morphology in the developing brains of male and female mice. DEP exposure increased inflammatory cytokine protein and altered the morphology of microglia, consistent with activation or a delay in maturation, only within the embryonic brains of male mice; and these effects were dependent on TLR4. DEP exposure also increased cortical volume at embryonic day (E)18, which switched to decreased volume by post-natal day (P)30 in males, suggesting an impact on the developing neural stem cell niche. Consistent with this hypothesis, we found increased microglial-neuronal interactions in male offspring that received DEP compared to all other groups. Taken together, these data suggest a mechanism by which prenatal exposure to environmental toxins may affect microglial development and long-term function, and thereby contribute to the risk of neurodevelopmental disorders.

Environment matters: microglia function and dysfunction in a changing world

“…Because there is no evidence that DE particles cross the placenta, systemic inflammation in the mother is hypothesized to induce an inflammatory reaction within the uterine environment/placenta, and thereby the fetal brain, to alter development. Consistent with this hypothesis, we found a significant impact of maternal DEP on microglial morphology in fetal brains, consistent with activation and/or a delay in maturation in several brain regions, but notably only in males, along with striking changes in neural-glial interactions in males suggestive of a defect in phagocytosis [63]. …”

Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors

“…Due to their heightened responsiveness to local environmental signals across their developmental trajectory, microglia are particularly sensitive to the impact of extrinsic cues during the perinatal window. Prenatal high fat diet (Bilbo & Tsang, ), prenatal exposure to air pollution (Bolton et al, ; Bolton, Auten, & Bilbo, ), intrauterine inflammation (Makinson et al, ), early life experience or stress (Delpech et al, ; Diz‐Chaves, Astiz, Bellini, & Garcia‐Segura, ; Diz‐Chaves, Pernía, Carrero, & Garcia‐Segura, ; Gómez‐González & Escobar, ; Schwarz, Hutchinson, & Bilbo, ), and early life bacterial infection (Bland et al, ) all have lasting impact on offspring microglia, affecting activation or number, expression of inflammatory cytokines, and/or the interactions microglia have with other cell types in the brain. Several of these endpoints are sex‐specific; for example, the absence of a maternal microbiome disrupts the development of embryonic male microglia and induces lasting alterations in adult female microglia function (Thion et al, ).…”

“…Several of these endpoints are sex‐specific; for example, the absence of a maternal microbiome disrupts the development of embryonic male microglia and induces lasting alterations in adult female microglia function (Thion et al, ). Additionally, prenatal exposure to diesel exhaust particles alters microglia morphology and increases microglia–neuron interactions at postnatal Day 30 in males but not females (Bolton et al, ). This sex‐specific vulnerability to insult may be reflective of a difference in microglia maturation.…”

Maternal viral infection causes global alterations in porcine fetal microglia

“…As the persistent immune surveyors of the brain, microglia continuously shift through a spectrum of morphological states which closely align with the functions they are performing (44)(45)(46). More amoeboid cells (with retracted processes and enlarged cell bodies) often reflect more proinflammatory, reactive, and proliferative states and are the predominant morphology in the immature embryonic brain (1,47,48), whereas more mature cells take on a ramified phenotype (with elongated, branched processes and small cell bodies) and reflect a resolving and surveying state. Here microglia morphology was assessed by categorizing each cell into 1 of 4 phenotypes (depicted in Fig.…”