Exposure to methylparaben at environmentally realistic concentrations significantly impairs neuronal health in adult zebrafish

•Subchronic exposure to methylparaben shifted brain proteome in zebrafish.•A sex-specific mechanism of neurotoxicity was noted for methylparaben.•Methylparaben targeted the neurotransmission via synapse junctions.•A negative feedback regulation was initiated to reduce blood cortisol level.•Methylparaben increased endotoxin content and induced inflammation in male brain. Methylparaben (MeP) is an emerging aquatic pollutant that is found to impact neural functions. However, it still lacks a comprehensive understanding about its neurotoxicology. The present study exposed adult zebrafish to environmentally realistic concentrations (0, 1, 3, and 10 µg/L) of MeP for 28 days, with objectives to elucidate the neurotoxic effects and mechanisms. Proteomic profiling found that MeP pollutant induced distinct mechanism of neurotoxicity as a function of sex. MeP pollutant appeared to preferentially target the neurotransmission cascade via synapse junctions. In male brain, glutamatergic neural signaling was enhanced by 10 µg/L of MeP in characteristics of higher glutamate neurotransmitter content (by 61.9%) and up-regulated glutamate receptor expression by 2.6-fold relative to the control. In MeP-exposed female brain, biomarker proteins of synapse formation and regeneration had significantly lower abundance, accounting for the blockage of synaptic neurotransmission. Furthermore, under the stress of MeP pollutant, both male and female zebrafish initiated a negative feedback mechanism along stress neuroendocrine axis by down-regulating the transcriptions of corticotropin-releasing hormone and its binding protein, which subsequently decreased blood cortisol concentrations. MeP subchronic exposure also disturbed innate immune function. In particular, significant increases in lipopolysaccharide (LPS) content by 15.6% were caused by MeP exposure in male brain, thereby inducing the synthesis of pro-inflammatory cytokines. In contrast, female brain was able to adaptively up-regulate the protein expression of blood brain barrier to inhibit the infiltration of LPS endotoxin into brain. Overall, the present findings pinpoint the potent neurotoxicity of MeP pollutant even at environmentally realistic concentrations. [Display omitted]