Department of Environmental Health, School of Public Health, Zhengzhou University, Zhengzhou, Henan, 450001, China.
The First Affiliated Hospital of Henan University, Henan University, Kaifeng, Henan, 475000, China.
Environ Pollut. 2024 Sep 1;356:124371. doi: 10.1016/j.envpol.2024.124371. Epub 2024 Jun 14.
The negative regulation on neurogenesis has been implicated in fluoride neurotoxicity, while the evidence is limited. To explore whether fluoride interferes with neurogenesis via the Notch1 signaling and the potential alleviation effects of carvacrol (CAR), we conducted in vivo and in vitro experiments, as well as epidemiological analyses in this study. The results showed that urinary fluoride levels and circulating Notch1 levels were associated with IQ levels in boys. NaF-treated rats had fewer neurons, lower densities of dendritic spines, depressed neurogenesis, and impaired learning and memory abilities. In vitro experiments using undifferentiated PC12 cells mimicking neurogenesis revealed that NaF suppressed differentiation and neurite outgrowth. Besides, Notch1 signaling activation was detected in vivo and in vitro. The latter was confirmed using an in vitro model supplemented with DAPT, a potent Notch1 inhibitor. Furthermore, CAR supplementation negatively regulated NICD1 and Hes1 expressions and promoted hippocampal neurogenesis, thereby improving neurological functions in NaF-treated rats. These findings indicated that the inhibition of neurogenesis in hippocampi induced by fluoride via Notch1 signaling activation may be one of the underlying mechanisms of its neurotoxicity, and that CAR significantly alleviated the neurotoxicity of NaF via the Notch1 signaling.
神经发生的负调控与氟神经毒性有关，但其证据有限。为了探讨氟化物是否通过 Notch1 信号通路干扰神经发生，以及香芹酚（CAR）是否具有潜在的缓解作用，我们在本研究中进行了体内和体外实验以及流行病学分析。结果表明，男孩尿氟水平和循环 Notch1 水平与智商水平有关。NaF 处理的大鼠神经元数量减少，树突棘密度降低，神经发生受到抑制，学习和记忆能力受损。体外实验使用未分化的 PC12 细胞模拟神经发生，结果表明 NaF 抑制分化和神经突生长。此外，体内和体外实验均检测到 Notch1 信号通路的激活。后者在体外模型中得到了证实，该模型中添加了 DAPT，一种有效的 Notch1 抑制剂。此外，CAR 补充剂负调控 NICD1 和 Hes1 的表达，促进海马神经发生，从而改善 NaF 处理大鼠的神经功能。这些发现表明，氟化物通过 Notch1 信号通路激活抑制海马神经发生可能是其神经毒性的潜在机制之一，而 CAR 通过 Notch1 信号通路显著缓解了 NaF 的神经毒性。
