Chronic fluoride induces neurotoxicity in zebrafish through the gut-brain axis

Fluoride (F) is a common pollutant in aquatic environment. Chronic exposure to fluoride can cause toxicity to nervous system and behavior of fish. However, the underlying mechanism is still unclear. This study is designed to explore the effects and potential mechanisms of chronic fluoride exposure on zebrafish behavior. Zebrafish were exposed to CK, LF, MF, and HF for 90 days. The results showed that chronic fluoride exposure caused damage to the brain tissues of adult zebrafish and significantly reduced the total distance of free swimming per min. Fluoride significantly reduced dopamine content and dopamine pathway related gene expression in brain. In addition, fluoride disrupted the intestinal barrier function, reduced the expression of tight junction proteins and mucin related genes in intestinal tissues, increased intestinal permeability. Males in the HF group were more sensitive than the corresponding females. Fluoride significantly decreased the dopamine content in the intestine, disturbed the gene expression of dopamine pathway related genes. Fluoride significantly increased the relative abundance of g_uncultured_bacterium_c_Gammaprotebacteria in three F groups, while significantly reduced the relative abundance of g_lactobacilli and g_Lachnospiraceae NK4A136_group. At the same time, metabolic pathways including amino acid metabolism, nucleotide metabolism, and carbohydrate metabolism were also affected. These indicate that fluoride can result in neurotoxicity and behavioral changes by disrupting intestinal permeability and causing intestinal damage caused by imbalance of gut microbiota nucleotide metabolism, and the abnormal expression of dopamine related genes in the gut in zebrafish. Male zebrafish are more sensitive than female zebrafish.