Moderate exercise relieves fluoride-induced liver and kidney inflammatory responses through the IKKß/NFκB pathway.

With the intensification of environmental pollution, the content of fluoride is increasing in human and animal living environments. Long-term fluoride exposure can cause damage to the liver and kidney, which are the main sites for fluoride metabolism, storage and removal. Moreover, exercise often accompanies the entire process of fluoride exposure in humans and animals. However, the mechanism of exercise on fluoride-induced liver and kidney injury remains unclear. Hence, we established a fluoride exposure and/or exercise mouse model to explore the influence of exercise on fluoride-induced liver and kidney inflammation and the potential mechanism. The results showed that fluoride caused obvious structural and functional damage and the notable recruitment of immunocytes in the liver and kidney. In addition, fluoride increased the levels of IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-21, TNF-α, and TGF-ß but decreased the ratio of IFN-γ/IL-4 and IL-2/IL-10, which indicated that fluoride disturbed the inflammatory balance and caused hepatonephritis. In addition, the expression levels of IKKß and NFκB were increased, and the expression of IκBα was decreased after fluoride exposure, indicating that fluoride activated the IKKß/NFκB pathway. In summary, long-term moderate treadmill exercise relieved fluoride-induced liver and kidney inflammatory responses through the IKKß/NFκB pathway, and exercise can be used to prevent fluoride-induced liver and kidney damage.

Exercise Ameliorates Fluoride-induced Anxiety- and Depression-like Behavior in Mice: Role of GABA.

Fluoride exposure caused anxiety- and depression-like behavior in mice. Meanwhile, exercise contributes to relieve anxiety and depression. However, the effects of exercise on anxiety- and depression-like behavior in fluorosis mice remain unclear. In the current study, thirty-six Institute of Cancer Research (ICR) female mice were randomly assigned to four groups: control group (C, gavage with distilled water); exercise group (E, gavage with distilled water and treadmill exercise (speed, 10 m/min; time, 30 min/day)); fluoride group (F, gavage with 24 mg/kg sodium fluoride (NaF)); and exercise plus fluoride group (EF, gavage with 24 mg/kg NaF and treadmill exercise). All treatments lasted for 8 weeks. A number of entries into and time spent in the open zone in the elevated zero maze (EZM), resting time in the tail suspension test (TST) and levels of serotonin (5-HT) and gamma-aminobutyric acid (GABA), were significantly altered in F when compared to C. Meanwhile, the anxiety-like behavior in the EZM and the depression-like behavior in the TST were significantly improved in EF when compared to group F. Exercise significantly enhanced fluoride-induced low GABA level, with less effect on the concentration of 5-HT. Moreover, the mRNA and protein expressions of GABA synthesis and transport-related proteins of glutamic acid decarboxylase (GAD) 65 and GAD67 and vesicular GABA transporter (VGAT) were all strikingly decreased in F, while those in EF were increased. In conclusion, exercise ameliorates anxiety- and depression-like behavior in fluorosis mice through increasing the expressions of GABA synthesis and transport-related proteins, rather than 5-HT system.

Exercise alleviated intestinal damage and microbial disturbances in mice exposed to fluoride.

Gastrointestinal reaction is an important symptom of fluorosis and is associated with intestinal morphological and functional impairment. Regular moderate exercise may reduce the incidence of infection and contribute to the maintenance of intestinal mucosal function and immune homeostasis. In this study, the mice were randomly divided to four groups: control group (C, distilled water), exercise group (E, distilled water and treadmill exercise), fluoride group (F, 100 mg/L NaF), and exercise plus fluoride group (EF, 100 mg/L NaF and treadmill exercise). The treadmill exercise was performed as 5 m/min, 5 min; 10 or 12 m/min, 20 min; 5 m/min, 5 min, with 5 consecutive days per week. After 6 months, exercise alleviated the intestinal morphological structure damage and restored the villus height (VH) and VH/crypt depth (VH/CD) in the duodenum of fluoride-exposed mice. Exercise decreased the mRNA expressions of IL-1ß, IL-6, TNF-α, TLR2 and NF-κB (p65) in fluoride-exposed mice, and restored the gene levels of Occludin and ZO-1 in the duodenum, as well as Occludin, ZO-1, and Claudin-1 in the colon. Although there were no significant differences in the Occludin and ZO-1 protein expressions between F and EF, two proteins in EF presented statistical homogeneousness when compared with the C. The 16S rDNA high-throughput sequencing found that exercise restored the variations in intestinal microbiota composition and the abundances of specific bacteria in fluoride-exposed mice, including increasing the abundances of Epsilonbacteraenta and Firmicutes, reducing the Bacteroidetes abundance at the phylum level, and restoring the abundances of 13 bacterial genera. In conclusion, exercise improved intestinal morphological structure damage in fluoride-exposed mice, inhibited the secretion of duodenal inflammatory factors, increased the expression of tight junctions, and alleviated the microbial disorder in mice caused by fluoride exposure for 6 months through actively regulating the composition of intestinal microorganisms and the abundance of specific bacteria.