Evaluation of neural regulation and microglial responses to brain injury in larval zebrafish exposed to perfluorooctane sulfonate

Abstract

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.

Perfluorooctane Sulfonate (PFOS) Negatively Impacts Prey Capture Capabilities in Larval Zebrafish

“…Zebrafish from all PFOS treatment groups survived throughout early larvae development, agreeing with data of similar treatment periods and concentrations from recent work (Paquette et al, 2022). While different studies can normalize treatment conditions, understanding PFOS uptake kinematics in varying concentrations is critical to interpretation of any results, especially between treatment groups.…”

“…The complex behaviors necessary for survival require precise communication between neurons that receive sensory input and those that initiate and coordinate (Paquette et al, 2022) fundamental motor outputs. Several lines of experimental evidence suggest that PFOS disrupts neurotransmission.…”

“…As such, they provide an excellent experimental framework to study the impacts of PFAS on nervous system function and on complex behaviors. Zebrafish embryos and larvae have been used to assess the impacts of PFAS, including PFOS, on development, immune response, and locomotor behaviors (Gaballah et al, 2020;Han et al, 2021;Kalyn et al, 2023;Paquette et al, 2022;Rericha et al, 2021;Tal & Vogs, 2021;Ulhaq et al, 2013). At early stages, zebrafish skin is highly permeable, and PFAS are readily absorbed (Tal & Vogs, 2021).…”

Investigation of Peroxisome Proliferator-Activated Receptor Genes as Requirements for Visual Startle Response Hyperactivity in Larval Zebrafish Exposed to Structurally Similar Per- and Polyfluoroalkyl Substances (PFAS)

“…In larval zebrafish, dark-phase hyperactivity has been reported following exposure to receptor antagonists 76 – 78 and exposure to PFOS has been shown to directly perturb neural activity in vivo . 79 In addition, loss-of-function mutations in the subunit in zebrafish was reported to induce behavioral hyperactivity. 80 Taken together, these data indicate a relationship between receptor function and dark-phase locomotion in the light–dark transition test.…”