2,3,7,8-tetrachlorodibenzo-[p]-dioxin (TCDD) is a persistent global pollutant that exhibits a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. Epidemiological studies have associated AHR agonist exposure with multiple human neuropathologies. Consistent with the human data, research studies using laboratory models have linked pollutant-induced AHR activation to disruptions in learning and memory as well as motor impairments. Our understanding of endogenous AHR functions in brain development is limited and, correspondingly, scientists are still determining which cell types and brain regions are sensitive to AHR modulation. To identify novel phenotypes resulting from pollutant-induced AHR activation and ahr2 loss of function, we utilized the optically transparent zebrafish model. Early embryonic TCDD exposure impaired embryonic brain morphogenesis, resulted in ventriculomegaly, and disrupted neural connectivity in the optic tectum, habenula, cerebellum, and olfactory bulb. Altered neural network formation was accompanied by reduced expression of synaptic vesicle 2. Loss of ahr2 function also impaired nascent network development, but did not affect gross brain or ventricular morphology. To determine whether neural AHR activation was sufficient to disrupt connectivity, we used the Gal4/UAS system to express a constitutively active AHR specifically in differentiated neurons and observed disruptions only in the cerebellum; thus, suggesting that the phenotypes resulting from global AHR activation likely involve multiple cell types. Consistent with this hypothesis, we found that TCDD exposure reduced the number of oligodendrocyte precursor cells and their derivatives. Together, our findings indicate that proper modulation of AHR signaling is necessary for the growth and maturation of the embryonic zebrafish brain.

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Pollution is a driving force in climate change and an important modifier of human health. Humans are chronically exposed to complex chemical mixtures and, correspondingly, researchers are disentangling the contribution of different contaminants to human neuropathologies. Per- and polyfluoroalkyl substances (PFAS) are biopersistent pollutants and, due to their diverse applications, have become global contaminants. Perfluorooctane sulfonate (PFOS), a prevalent PFAS congener, impairs humoral immunity; however, its impact on innate immunity is unclear. Given the critical roles of innate immune cells, namely microglia, in brain development and homeostasis, we asked whether exposure adversely affects microglial function. Herein, we demonstrate developmental PFOS exposure produces microglial activation and upregulation of the microglia activation gene p2ry12. PFOS-induced microglial activation heightened microglial responses to brain injury, in the absence of increased cell death or inflammation. Use of the photoconvertible calcium indicator CaMPARI revealed PFOS exposure heightened neural activity, while optogenetic silencing of neurons was sufficient to normalize microglial responses to injury. Exposure to perfluorooctanoic acid, an immunotoxic PFAS, did not alter neuronal activity or microglial behavior, further supporting a role for neural activity as a critical modifier of microglial function. Together, this study reveals how contaminant-induced changes in brain activity can shape brain health.