Neurobehavioral disorders induced by environmental zinc in female zebrafish (Danio rerio): Insights from brain and intestine transcriptional and metabolic signatures

Human activities can cause zinc (Zn) contamination of aquatic environments. Zn is an essential trace metal, but effects of environmentally relevant Zn exposure on the brain–intestine axis in fish are poorly understood. Here, six-month-old female zebrafish (Danio rerio) were exposed to environmentally relevant Zn concentrations for six weeks. Zn significantly accumulated in the brain and intestine, causing anxiety-like behaviors and altered social behaviors. Zn accumulation altered levels of neurotransmitters, including serotonin, glutamate, and γ-aminobutyric acid, in the brain and intestine, and these changes were directly associated with changes in behavior. Zn caused oxidative damage and mitochondrial dysfunction, and impaired NADH dehydrogenase, thereby dysregulating the energy supply in brain. Zn exposure resulted in nucleotide imbalance and dysregulation of DNA replication and the cell cycle, potentially impairing the self-renewal of intestinal cells. Zn also disturbed carbohydrate and peptide metabolism in the intestine. These results indicate that chronic exposure to Zn at environmentally relevant concentrations dysregulates the bidirectional interaction of the brain–intestine axis with respect to neurotransmitters, nutrients, and nucleotide metabolites, thereby causing neurological disorder-like behaviors. Our study highlights the necessity to evaluate the negative impacts of chronic environmentally relevant Zn exposure on the health of humans and aquatic animals.