Department of Occupational Health, Army Medical University, 400038 Chongqing, People's Republic of China.
Department of Occupational Health, Army Medical University, 400038 Chongqing, People's Republic of China; Department of Medical Laboratory, General Hospital of the Central Theater Command of the Chinese People's Liberation Army, 430070 Wuhan, People's Republic of China.
Sci Total Environ. 2021 Aug 20;783:147014. doi: 10.1016/j.scitotenv.2021.147014. Epub 2021 Apr 10.
Nickel (Ni) is a heavy metal that is both an environmental pollutant and a threat to human health. However, the effects of Ni on the central nervous system in susceptible populations have not been well established. In the present study, the neurotoxicity of Ni and its underlying mechanism were investigated in vivo and in vitro. Ni exposure through drinking water (10 mg Ni/L, 12 weeks) caused learning and memory impairment in mice. Reduced dendrite complexity was observed in both Ni-exposed mouse hippocampi and Ni-treated (200 μM, 72 h) primary cultured hippocampal neurons. The levels of histone acetylation, especially at histone H3 lysine 9 (H3K9ac), were reduced in Ni-exposed mouse hippocampi and cultured neurons. RNA sequencing and chromatin immunoprecipitation (ChIP) sequencing analyses revealed that H3K9ac-modulated gene expression were downregulated. Treatment with sodium butyrate, a histone deacetylase inhibitor, attenuated Ni-induced H3K9 hypoacetylation, neural gene downregulation and dendrite complexity reduction in cultured neurons. Sodium butyrate also restored Ni-induced memory impairment in mice. These results indicate that Ni-induced H3K9 hypoacetylation may be a contributor to the neurotoxicity of Ni. The finding that Ni disturbs histone acetylation in the nervous system may provide new insight into the health risk of chronic Ni exposure.
镍（Ni）是一种重金属，既是环境污染物，也是对人类健康的威胁。然而，镍对易感人群的中枢神经系统的影响尚未得到充分证实。在本研究中，我们在体内和体外研究了镍的神经毒性及其潜在机制。通过饮用水（10 mg Ni/L，12 周）暴露镍会导致小鼠学习和记忆能力受损。在镍暴露的小鼠海马体和镍处理的（200 μM，72 h）原代培养海马神经元中，均观察到树突复杂性降低。在镍暴露的小鼠海马体和培养神经元中，组蛋白乙酰化水平降低，尤其是组蛋白 H3 赖氨酸 9（H3K9ac）。RNA 测序和染色质免疫沉淀（ChIP）测序分析表明，H3K9ac 调节的基因表达下调。用组蛋白去乙酰化酶抑制剂丁酸钠处理可减轻镍诱导的 H3K9 低乙酰化、神经基因下调和培养神经元树突复杂性降低。丁酸钠还可恢复镍诱导的小鼠记忆障碍。这些结果表明，镍诱导的 H3K9 低乙酰化可能是镍神经毒性的原因之一。该研究发现镍会干扰神经系统中的组蛋白乙酰化，这可能为慢性镍暴露的健康风险提供新的见解。
