Fluoride-induced apoptosis in non-skeletal tissues of experimental animals: A systematic review and meta-analysis

Different studies have suggested that fluoride can induce apoptosis in non-skeletal tissues, however, evidence from these experimental studies is still controversial. This meta-analysis aims to clarify the mechanism of fluoride-induced apoptosis in non-skeletal tissues of experimental animals. Primary studies which measured apoptosis were identified through exhaustive database searching in PubMed, Embase, Web of Science Core Collection, Scopus, and references of included studies. A random effects model with standardized mean difference (SMD) was used for meta-analyses. The heterogeneity of the studies was evaluated using Higgin's I2 statistics. The risk of bias and publication bias were assessed using the SYRCLE's risk of bias tool and Egger's test, respectively. There was an increase in total apoptotic cells, and the expression of Bax, Bax/Bcl-2 ratio, caspase-3, caspase-8, caspase-9, Cyt c, and p53, and a decrease in the expression of Bcl-2 in the fluoride-treated groups as compared to the control groups. However, there was no evidence of a difference in the expression of APAF-1 in the two groups. The subgroup analysis highlighted the role of the intervention period in modification of the apoptotic effect of fluoride and that the susceptibility and tolerance of different animal species and tissues vary. Meta-regression analysis indicated that the studies' effect size for total apoptotic cells was influenced by animal species and that of Bax by the sample source. The results of this meta-analysis revealed that fluoride causes apoptosis by up-regulating caspase-3, -8, and -9, Cyt c, p53, Bax, and down-regulating Bcl-2 with a concomitant up-regulation of the Bax/Bcl-2 ratio.