Abstract
Microglia are a resident population of phagocytic immune cells that reside within the central nervous system (CNS). During gestation, they are highly sensitive to their surrounding environment and can alter their physiology to respond to perceived neural insults, potentially leading to adverse influences on nearby neural progenitors. Given that bisphenol A (BPA) itself can impact developing brains, and that microglia express estrogen receptors to which BPA can bind, here we asked whether fetal microglia are responsive to gestational BPA exposure. Accordingly, we exposed pregnant dams to control or 50 mg of BPA per kg diet during gestation to investigate the impact of maternal BPA on embryonic hypothalamic microglia. Gestational BPA exposure from embryonic day 0.5 (E0.5) to E15.5 resulted in a significant increase in the number of microglia present in the hypothalamus of both male and female embryos. Staining for microglial activation using CD68 showed no change between control and prenatal BPA-exposed microglia, regardless of sex. Similarly, analysis of cultured embryonic brains demonstrated that gestational BPA exposure failed to change the secretion of cytokines or chemokines, regardless of embryo sex or the dose (50 μg of BPA per kg or 50 mg of BPA per kg maternal diet) of BPA treatment. In contrast, live-cell imaging of microglia dynamics in E15.5 control and gestationally-exposed BPA hypothalamic slices showed increased ramification of microglia exposed to BPA. Moreover, live-cell imaging also revealed a significant increase in the number of microglial phagocytic cups visible following exposure to gestational BPA. Together, these results suggest that gestational BPA exposure impacts embryonic hypothalamic microglia, perhaps leading them to alter their interactions with developing neural programs.
Highlights
Microglia are a resident population of macrophages and phagocytic immune cells within the central nervous system (CNS)
Staining for ionized calcium-binding adapter molecule-1 (IBA1) in the E15.5 hypothalamus of control (Figures 1E,E’) and bisphenol A (BPA) exposed (Figures 1F,F’) female embryos showed a significant increase in IBA1+ microglia numbers in gestationally exposed BPA females (Figure 1G; p = 0.0003)
Given that previously we identified a unique population of CCL3/CCL4-expressing microglia that reside adjacent to neural stem cells (NSCs) in the embryonic hypothalamus (Rosin et al, 2021c), and that BPA impacts hypothalamic neurogenesis (Kinch et al, 2015; Nesan et al, 2021), we quantified the number of CCL3+ and CCL4+ microglia in the embryonic hypothalamus in BPA exposed embryos
Summary
Microglia are a resident population of macrophages and phagocytic immune cells within the CNS. Microglia play unique roles in the development of specific brain regions, including neural progenitor maintenance in the cortex (Antony et al, 2011) and cortical progenitor engulfment as neurogenesis terminates (Cunningham et al, 2013) These important roles for microglia in neurodevelopment become evident in cases of maternal challenge, whereby gestational insults such as stress, infection, and air pollution alter microglial phenotypes (Frank et al, 2010; Levesque et al, 2011, 2013; Bolton et al, 2014; Rosin et al, 2021b,c). Maternal cold exposure—a paradigm for maternal stress—elicits a pro-inflammatory response and disrupts oxytocin neuron numbers in the paraventricular nucleus of the hypothalamus only in male embryos (Rosin et al, 2021c) These sexually dimorphic disruptions require microglia and continue into adulthood, with cold stress exposed male offspring showing aberrant social deficits (Rosin et al, 2021c). These types of analyses aimed at the long-term consequences of maternal challenge and gestational exposure to environmental stimuli suggest that immature microglia play an unappreciated role in sensing embryonic perturbations and translating these insults into neurodevelopmental disruptions
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