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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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Zinc is an essential nutrient for life, but over-accumulation can result in toxicity. Anthropogenic activities can increase zinc concentrations in aquatic environments (e.g., to ∼0.46-1.00 mg/L), which are above the safe level of 0.1 mg/L. We investigated the behavior and physiology of zebrafish (Danio rerio) in response to environment-related exposure to zinc chloride at 0.0 (Ctrl), 1.0 (ZnCl 2 -low) and 1.5 (ZnCl 2 -high) mg/L for 6 weeks (the zinc conversion ratio of zinc chloride is ∼0.48 and the nominal (measured) values were: Ctrl, 0 (∼0.01); ZnCl 2 -low, 0.48 (∼0.51); ZnCl 2 -high, 0.72 (∼0.69) mg/L). Low-zinc exposure resulted in significantly increased locomotion and fast moving behaviors, while high-zinc exposure resulted in significantly increased aggression and freezing frequency. Single cell RNA-seq of neurons, astrocytes, and oligodendrocytes of the brain revealed expression of genes related to ion transport, neuron generation, and immunomodulation that were heterogeneously regulated by zinc exposure. Astrocyte-induced central nervous system inflammation potentially integrated neurotoxicity and behavior. Integrated analyses of brain and hepatic transcriptional signatures showed that genes (and pathways) dysregulated by zinc were associated with sensory functions, circadian rhythm, glucose and lipid metabolism, and amyloid β-protein clearance. Our results showed that environment-related zinc contamination can be heterogeneously toxic to brain cells and can disturb coordination of brain-liver physiology. This may disrupt neurobehavior and cause a neurodegeneration-like syndrome in adult zebrafish., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Anthropogenic activities discharge zinc into aquatic ecosystems, and the effects of long-term and low-concentration zinc exposure on fish behavior are unclear. We evaluated the behavior and physiology of male zebrafish (Danio rerio) after a 6-week exposure to 1.0 or 1.5 ppm (mg/L) zinc chloride. The exposure caused anxiety-like behaviors and altered the social preferences in both exposure groups. Analysis of transcriptional changes suggested that in the brain, zinc exerted heterogenetic effects on immune and neurotransmitter functions. Exposure to 1.0 ppm zinc chloride resulted in constitutive immune dyshomeostasis, while exposure to 1.5 ppm zinc chloride impaired the neurotransmitter glutamate. In the intestine, zinc dysregulated self-renewal of intestinal cells, a potential loss of defense function. Moreover, exposure to 1.5 ppm zinc chloride suppressed intestinal immune functions and dysregulated tyrosine metabolism. These behavioral alterations suggested that the underlying mechanisms were distinct and concentration-specific. Overall, environmental levels of zinc can alter male zebrafish behaviors by dysregulating neurotransmitter and immunomodulation signatures., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)