Bisphenol F Impaired Zebrafish Cognitive Ability through Inducing Neural Cell Heterogeneous Responses

The central nervous system (CNS) is a sensitive target for endocrine-disrupting chemicals, such as bisphenol analogues. Bisphenol A (BPA) usage is associated with the occurrence of many neurological diseases. With the restricted use of BPA, bisphenol F (BPF) has been greatly introduced for industrial manufacture and brings new hazards to public CNS health. To understand how BPF affects the neural system, we performed a cognitive test for zebrafish that are continuously exposed to environmentally relevant concentrations (0.5 and 5.0 mu g/L) of BPF since embryonic stage and identified suppressed cognitive ability in adulthood. Single-cell RNA sequencing of neural cells revealed a cell composition shift in zebrafish brain post BPF exposure, including increase in microglia and decrease in neurons; these changes were further validated by immune staining. At the same time, a significant inflammatory response and increased phagocytic activity were detected in zebrafish brain post BPF exposure, which were consistent with the activation of microglia. Cell-specific transcriptomic profiles showed that abnormal phagocytosis, activated brain cell death, and apoptosis occurred in microglia post BPF exposure, which are responsible for the neuron loss. In addition, certain neurological diseases were affected by BPF in both excitatory and inhibitory neurons, such as the movement disorder and neural muscular disease, however, with distinctly involved genes. These findings indicate that BPF exposure could lead to an abnormal cognitive behavior of zebrafish through inducing heterogeneous changes of neural cells in brain and revealed the dominating role of microglia in mediating this effect.