Interleukin 17A deficiency alleviates fluoride-induced testicular injury by inhibiting the immune response and apoptosis.

The reproductive toxicity of fluoride (F) has been verified by various epidemiological and experimental studies. Our previous work suggested that the interleukin 17A (IL-17A) is involved in the testicular damage induced by excessive F exposure. In this study, we further investigated the role of IL-17A in F-induced testicular injury. Wild type (WT) and IL-17A knockout (IL-17A-/-) mice were exposed to 0, 25, 50, or 100 mg/L sodium fluoride (NaF) for 90 days. We found that exposure to excessive F levels caused testicular damage, decreased semen quality, negatively affected testicular morphology, and increased the inflammatory response. Specifically, excessive F intake increased the expression levels of IL-17A in the testis and increased the protein levels of Act1, NF-κB, IL-17R, C/EBP-α, and TRAF6 in the IL-17A signaling pathway. The increase in IL-17A expression corresponded to increases expression of IL-17R, IL-6, IL-23, IL-1β, TGF-β and TNF-α as assessed by RT-PCR and ELISA assays. Remarkably, IL-17A knockout in mice ameliorated the effects of F on testicular damage, semen quality, testicular morphology, and the immune response. Additionally, we found the in vitro exposure of Leydig cells to NaF and recombinant IL-17A led to abnormal apoptosis and a decrease in testosterone secretion. Our findings prove that IL-17A plays a key role in the exacerbation of testicular injuries in F-exposed mice, and that IL-17A deficiency can alleviate F-induced injury by inhibiting the immune response and apoptosis in the testis. These data suggest that targeting IL-17A may be a useful therapeutic strategy for treating F-mediated toxicity in the testis.