Pamphlett Roger, Bishop David P
Department of Pathology, Brain and Mind Centre, School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia.
Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Front Neurol. 2023 Jun 23;14:1173779. doi: 10.3389/fneur.2023.1173779. eCollection 2023.
Multiple sclerosis and the major sporadic neurogenerative disorders, amyotrophic lateral sclerosis, Parkinson disease, and Alzheimer disease are considered to have both genetic and environmental components. Advances have been made in finding genetic predispositions to these disorders, but it has been difficult to pin down environmental agents that trigger them. Environmental toxic metals have been implicated in neurological disorders, since human exposure to toxic metals is common from anthropogenic and natural sources, and toxic metals have damaging properties that are suspected to underlie many of these disorders. Questions remain, however, as to how toxic metals enter the nervous system, if one or combinations of metals are sufficient to precipitate disease, and how toxic metal exposure results in different patterns of neuronal and white matter loss. The hypothesis presented here is that damage to selective locus ceruleus neurons from toxic metals causes dysfunction of the blood-brain barrier. This allows circulating toxicants to enter astrocytes, from where they are transferred to, and damage, oligodendrocytes, and neurons. The type of neurological disorder that arises depends on (i) which locus ceruleus neurons are damaged, (ii) genetic variants that give rise to susceptibility to toxic metal uptake, cytotoxicity, or clearance, (iii) the age, frequency, and duration of toxicant exposure, and (iv) the uptake of various mixtures of toxic metals. Evidence supporting this hypothesis is presented, concentrating on studies that have examined the distribution of toxic metals in the human nervous system. Clinicopathological features shared between neurological disorders are listed that can be linked to toxic metals. Details are provided on how the hypothesis applies to multiple sclerosis and the major neurodegenerative disorders. Further avenues to explore the toxic metal hypothesis for neurological disorders are suggested. In conclusion, environmental toxic metals may play a part in several common neurological disorders. While further evidence to support this hypothesis is needed, to protect the nervous system it would be prudent to take steps to reduce environmental toxic metal pollution from industrial, mining, and manufacturing sources, and from the burning of fossil fuels.
多发性硬化症以及主要的散发性神经退行性疾病，如肌萎缩侧索硬化症、帕金森病和阿尔茨海默病，被认为具有遗传和环境因素。在寻找这些疾病的遗传易感性方面已经取得了进展，但要确定引发它们的环境因素却很困难。环境有毒金属与神经疾病有关，因为人类通过人为和自然来源普遍接触有毒金属，并且有毒金属具有破坏特性，人们怀疑这些特性是许多此类疾病的潜在原因。然而，关于有毒金属如何进入神经系统、一种或多种金属组合是否足以引发疾病，以及有毒金属暴露如何导致神经元和白质损失的不同模式等问题仍然存在。这里提出的假说是，有毒金属对蓝斑核选择性神经元的损伤会导致血脑屏障功能障碍。这使得循环中的毒物能够进入星形胶质细胞，从那里它们被转移到少突胶质细胞并对其造成损伤，进而损伤神经元。所出现的神经疾病类型取决于：（i）哪些蓝斑核神经元受损；（ii）导致对有毒金属摄取、细胞毒性或清除易感性的基因变异；（iii）毒物暴露的年龄、频率和持续时间；以及（iv）各种有毒金属混合物的摄取情况。本文提供了支持这一假说的证据，重点是研究人类神经系统中有毒金属分布的研究。列出了神经疾病之间共有的临床病理特征，这些特征可能与有毒金属有关。详细说明了该假说如何适用于多发性硬化症和主要的神经退行性疾病。还提出了进一步探索神经疾病有毒金属假说的途径。总之，环境有毒金属可能在几种常见的神经疾病中起作用。虽然需要进一步的证据来支持这一假说，但为了保护神经系统，谨慎的做法是采取措施减少来自工业、采矿和制造业以及化石燃料燃烧的环境有毒金属污染。
