Sodium Fluoride Induces Inflammatory Responses Via Activating MAPK And NF-?B Signaling Pathway In The Mouse Liver

Fluoride is ubiquitous in the environment and is one of the essential trace elements in the body.However,many studies have found that excessive intake of fluorine can cause toxic effects on the body,including damage to bones,teeth,liver,kidney,brain,testis and other organs and tissues,and varying degrees of pathological changes.In this study,ICR 240 healthy four-week-old mice were randomly divided into four groups and given different concentrations of sodium fluoride(0,12,24 and 48 mg /kg)by intragastric administration for 42 days.On the 21 st and 42 nd days of the experiment,experimental pathology,quantitative real time polymerase chain reaction(qRT-PCR),western blot and other research methods were used to observe the pathological changes of the liver and detect the mRNA and protein expression levels of inflammatory cytokines and signaling molecules.The effects of different doses of sodium fluoride on the liver inflammatory response in mice were evaluated.The research results are as follows:1.Pathology of sodium fluoride-damaged liver: the liver volume is reduced.Hepatocytes showed granule degeneration,vacuolar degeneration,and even necrosis.And inflammatory cell infiltration was also observed.The liver structure was impaired.Histopathological damage presented a dose-and time-dependent effect.2.Effect of sodium fluoride on activation of MAPK signaling pathway in the liver.qRT-PCR and Western blotting showed that protein expression level of p-ASK1,pMEK1/2,p-Erk1/2,p-MEK3/6 and p-p38 were increased with the sodium fluoride 12 mg/kg and over when compared to the control group.At the same time,mRNA expression levels of ASK1,MEK1/2,Erk1/2,MEK4/7,JNK,MEK3/6 and p38 were also increased.3.Effect of sodium fluoride on activation of NF-?B signaling pathway in the liver.In comparison to the control group,the protein and mRNA expression levels of IKK-? and NF-?B were significantly increased when the dose of sodium fluoride exceeded 12 mg/kg,while I?B protein and mRNA expression levels were significantly decreased.4.Effect of sodium fluoride on the expression of COX-2 and pro-inflammatory cytokines in the liver.When compared to the control group,the protein expression levels of COX-2,IL-1?,IL-6,IL-8 and MCP-1 were significantly increased,and the mRNA expression levels of COX-2,IL-1? and MCP-1 were significantly increased and the mRNA expression levels of IL-6 and IL-8 were also significantly increased when sodium fluoride 12mg/kg and over.5.Effect of sodium fluoride on the expression of anti-inflammatory cytokines in the liver.The mRNA and protein expression of IL-4 and TGF-? were significantly reduced when the dose of sodium fluoride exceeded 12 mg/kg In comparison to the control group.In conclusion,sodium fluoride 12mg/kg over causes inflammation in the liver,which in turn results in hepatic pathological damage and impairs hepatic structure.Sodium fluoride increases the expression of COX-2 and pro-inflammatory cytokines by activation MAPK/NF-?B pathway and inhibits the expression of anti-inflammatory factors,which induce the development of hepatic inflammatory responses.Therefore,activation of MAPK/NF-?B signaling pathway and changes in the expression of proinflammatory and anti-inflammatory cytokines may be the molecular basis for the sodium fluoride-induced hepatic inflammatory response.