School of Food and Bioengineering, Hefei University of Technology, Hefei 230009, China.
Int J Environ Res Public Health. 2020 Jul 7;17(13):4878. doi: 10.3390/ijerph17134878.
Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.
环境铅（Pb）暴露与一系列神经疾病的发病机制密切相关，包括阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症（ALS）、注意缺陷/多动障碍（ADHD）等。表观遗传机制调节神经发育和活动，而表观遗传调节失常导致中枢神经系统（CNS）异常和疾病的多种形式。作为一种有效的表观遗传修饰物，铅被认为通过调节表观遗传机制导致神经疾病。具体而言，越来越多的证据将异常的 DNA 甲基化、组蛋白修饰以及非编码 RNA（ncRNA）与 AD 病例联系起来，其中 circRNA（环状 RNA）作为一个新的有前途的关联研究领域脱颖而出。在接受发育性铅处理的 23 岁灵长类动物中，Zawia 小组发现了与 AD 发病机制相关的多种表观遗传变化。这是直接证据表明，在整个寿命的铅诱导 AD 动物中，表观遗传基础与 AD 有关。此外，一些与 AD 病因相关的表观遗传分子也已知在类似的疾病模型中对慢性铅暴露有反应，表明在研究的神经毒性和病理事件方面存在潜在的相互交织的机制。值得注意的是，表观遗传分子通过全局或选择性地影响疾病相关基因的表达来发挥作用。与 AD 相比，铅暴露与其他神经疾病的关联主要得到了流行病学调查的支持，很少有研究将表观遗传调节剂与铅诱导的发病机制联系起来。一些药物，如组蛋白去乙酰化酶（HDAC）抑制剂和 DNA 甲基化抑制剂，通过针对表观遗传成分来开发治疗 CNS 疾病的药物。然而，对于表观遗传因素与神经疾病之间的因果关系，人们的理解还不够充分。因此，未来的研究应该提供明确的证据，以阐明新的表观遗传因素在铅诱导的神经疾病中的具体作用，并评估开发特定的表观遗传治疗方法的努力。
