Introduction 介绍

Arsenic is a metalloid element present in the periodic table in 33rd position. It is widely distributed element in the environment. Environmental arsenic can exist in organic or inorganic form. Arsenic in organic states generally considered as nontoxic, whereas inorganic state is toxic. Organic forms are less toxic and poorly absorbed in the cells, whereas inorganic are highly reactive and affect the system through a series of reactions. Excess concentration of arsenic generates oxidative stress by reactive oxygen species (ROS) within subcellular compartments. ROS can directly damage proteins, amino acids, nucleic acid, and membrane lipids [1]. Enzymatic and nonenzymatic antioxidants in our body balance the homeostatic condition by quenching this reactive species and reduce oxidation-related stress. Exposure of arsenic in the environment occurs generally in the form of arsenite (As3+) or arsenate (As5+). Inorganic arsenic which is more toxic especially affects voltage-gated potassium channels and disrupts the electrolytic function of cell resulting in neurological disturbances, cardiovascular problem, nervous dysfunction, etc. [2]. Environmental exposure to heavy metals is suspected as a cause of neuropathology damage and cognitive impairment. Arsenic decreases neuronal migration and cellular maturation as well as it also inhibits the proliferation of neural progenitor cells. Arsenic exerts detrimental effects on general protein metabolism with high toxicity by reacting with sulfhydryl groups [3]. Due to this reason, arsenic toxicity decreases free thiol level in the system which is a potent antioxidant. When arsenic-related compounds enter in our body, they go through several metabolic pathways in the liver and convert in different forms of arsenic such as arsenite (As3+), arsenate (As5+), dimethylarsenite (DMA), and monomethylarsonate (MMA). By converting in these forms, arsenic circulates within the whole body through blood circulation. Researches show that trivalent arsenic compounds (AsIII, MMAIII, and DMA III) are the diabetes inducer by distorting glucose metabolism [4, 5]. Arsenic metabolism in humans occurs by the reduction of the trivalent arsenic (As3+) and oxidative methylation to the pentavalent state (As5+). The generation of trivalent arsenic by metabolism or by any other process generates greater toxicity to the cells and exhibits more carcinogenic properties [6]. Thus, exposure to arsenic and different stages of its metabolism may result various metabolic products of arsenic. The capabilities of arsenic to bind with reduced thiol in some protein generate targeted protein toxicity. And such interaction exhibits different metabolic dysregulations in specific tissues. On the other hand, these particular interactions are of great importance for the therapeutic interventions in arsenic toxicity.
砷是一种准金属元素，位于元素周期表中的第 33 位。它是环境中分布广泛的元素。环境砷可以有机或无机形式存在。有机态的砷通常被认为是无毒的，而无机态的砷则有毒。有机形式毒性较小，细胞吸收较差，而无机形式具有高反应性，并通过一系列反应影响系统。砷浓度过高会通过亚细胞室内的活性氧（ROS）产生氧化应激。 ROS可以直接损伤蛋白质、氨基酸、核酸和膜脂[ 1 ]。我们体内的酶和非酶抗氧化剂通过淬灭这种活性物质来平衡体内平衡状态并减少与氧化相关的应激。砷在环境中的暴露通常以亚砷酸盐（As3+）或砷酸盐（As5+）的形式存在。无机砷的毒性较大，尤其会影响电压门控钾通道，扰乱细胞的电解功能，导致神经系统紊乱、心血管问题、神经功能障碍等[ 2 ]。环境中的重金属暴露被怀疑是神经病理学损伤和认知障碍的原因。砷会减少神经元迁移和细胞成熟，并抑制神经祖细胞的增殖。砷通过与巯基反应，对一般蛋白质代谢产生有害影响，具有高毒性[ 3 ]。由于这个原因，砷的毒性会降低系统中游离硫醇的水平，而游离硫醇是一种有效的抗氧化剂。 当与砷相关的化合物进入我们的身体时，它们会通过肝脏中的多种代谢途径并转化为不同形式的砷，例如亚砷酸盐（As3+）、砷酸盐（As5+）、二甲基亚砷酸盐（DMA）和单甲基胂酸盐（MMA）。通过以这些形式转化，砷通过血液循环在全身内循环。研究表明，三价砷化合物（AsIII、MMAIII 和 DMA III）通过扭曲糖代谢而诱发糖尿病[ 4 , 5 ]。人体砷代谢是通过三价砷 (As3+) 的还原和氧化甲基化至五价态 (As5+) 进行的。通过代谢或任何其他过程产生的三价砷会对细胞产生更大的毒性，并表现出更多的致癌特性[ 6 ]。因此，接触砷及其代谢的不同阶段可能会产生不同的砷代谢产物。砷与某些蛋白质中还原的硫醇结合的能力产生有针对性的蛋白质毒性。这种相互作用在特定组织中表现出不同的代谢失调。另一方面，这些特殊的相互作用对于砷中毒的治疗干预非常重要。

Source of Arsenic Exposure
砷暴露来源

There are several sources for arsenic exposures throughout environment. Among these, arsenic poisoning through the drinking water is the most common way, worldwide [7]. It is also ingested through the food crops which are grown in arsenic-contaminated soil and/or are irrigated by using the arsenic-contaminated water. Ground water is an important and major source for arsenic contamination. Increasing level of arsenic metalloid in drinking water can manifest negative health effects in humans. According to the recommendations of World Health Organization (WHO), the maximum limit of arsenic concentration in drinking water is 10 μg/L [8]. The risk factor of arsenic poisoning in ground water is much higher than in surface water [9].
整个环境中砷的暴露有多种来源。其中，通过饮用水砷中毒是最常见的方式，在世界范围内[ 7 ]。它还通过在受砷污染的土壤中生长和/或使用受砷污染的水灌溉的粮食作物摄入。地下水是砷污染的重要和主要来源。饮用水中砷类金属含量的增加会对人类健康产生负面影响。根据世界卫生组织（WHO）的建议，饮用水中砷浓度最高限量为10μg/L[ 8 ]。地下水砷中毒的危险因素远高于地表水[ 9 ]。

In air, arsenic also exists by attaching to the particulate matter. Different studies suggest that methylated arsenic is a minor element mainly present in the air of urban, suburban, and industrial areas in the trivalent and pentavalent forms. Using of arsenic-related compounds in the industries for manufacturing antifungal wood preservatives leads to soil and water contamination. Arsenic is also used in the pharmaceuticals, microelectronics, optical, and glass industries. Widely, high amount of arsenic is observed in the pesticide which can contaminate soil as well as water.
在空气中，砷也以附着在颗粒物上的形式存在。不同的研究表明，甲基化砷是一种微量元素，主要以三价和五价形式存在于城市、郊区和工业区的空气中。在制造抗真菌木材防腐剂的行业中使用与砷相关的化合物会导致土壤和水污染。砷还用于制药、微电子、光学和玻璃工业。在农药中广泛观察到大量的砷，它会污染土壤和水。

Consuming food cultivated in arsenic-contaminated soil and/or using arsenic-contaminated water at the time of irrigation can be a way of entering arsenic in our body. Ingestion of such diet provides chronic arsenic exposure. In seafood, arsenic is present in high amount; this is organic in nature. Organic arsenic is less toxic than that of inorganic form [10].
食用在受砷污染的土壤中种植的食物和/或在灌溉时使用受砷污染的水可能是砷进入我们体内的一种方式。摄入此类饮食会导致慢性砷暴露。海鲜中的砷含量很高；这本质上是有机的。有机砷的毒性低于无机砷[ 10 ]。

Cosmetics are also considered as a source of direct arsenic exposure when arsenic present in more amount as impurity. Currently there is no international standard for heavy metals recommended in cosmetics. However, some countries have conducted experiment to decide the levels of heavy metals contents in cosmetics to provide a guideline for the limited use. The enormity and severity of arsenic toxicity is related to the duration of its exposure and how much of its concentration is exposed. Arsenic induces neurotoxicity in several ways.
当砷以杂质形式存在时，化妆品也被认为是直接砷暴露的来源。目前，化妆品中重金属尚无推荐的国际标准。不过，一些国家已经进行了试验，确定了化妆品中重金属的含量水平，为限量使用提供指导。砷毒性的严重程度与暴露时间和暴露浓度有关。砷以多种方式引起神经毒性。

Arsenic Can Cross Blood-Brain Barrier
砷可以穿过血脑屏障

Blood-brain barrier (BBB) is composed of three main cellular components – endothelial cell, astrocyte end-feet, and pericytes (PCs). In between the cerebral endothelial cells, tight junctions (TJs) present as diffusion barrier where diffusion of water, some gases, and hydrophobic molecules takes entry passively, and elective transport for glucose and some amino acids is permissible for neural function. Impairment in TJs function can provide a background for many types of neurological complications and neuro-inflammatory disorders [11]. Increasing arsenic exposure with time can efficiently alter tight junctions (TJs) proteins (occluding, claudin, ZO-1, ZO-2) which further increase the blood-brain barrier (BBB) permeability. Arsenic can efficiently down-regulate TJs proteins and mTOR protein expression with a concomitant increase in Beclin 1, LC3 and Atg12 level [12, 13]. Due to more permeability, arsenic can easily cross through BBB and induce autophagy. Several studies show that arsenic can cross the blood-brain barriers (BBB) and can directly affect the CNS. Crossing capability through the blood-brain barrier and accumulating in different regions of brain tissue establish its importance in several neurological disorders (Fig. 1). Neurons are unable to divide, so the damage in the neurons leads to permanent functional aberration of the total nervous system. Damage in the nervous system impairs proper impulse propagation (Fig. 1).
血脑屏障 (BBB) 由三种主要细胞成分组成：内皮细胞、星形胶质细胞端脚和周细胞 (PC)。在脑内皮细胞之间，紧密连接（TJ）表现为扩散屏障，水、一些气体和疏水性分子的扩散被动地进入其中，并且允许葡萄糖和一些氨基酸的选择性转运以实现神经功能。 TJ 功能受损可为多种类型的神经系统并发症和神经炎症性疾病提供背景 [ 11 ]。随着时间的推移，砷暴露量的增加可以有效地改变紧密连接 (TJ) 蛋白（包括封闭蛋白、ZO-1、ZO-2），从而进一步增加血脑屏障 (BBB) 的通透性。砷可以有效下调 TJs 蛋白和 mTOR 蛋白表达，同时增加 Beclin 1、LC3 和 Atg12 水平 [ 12 , 13 ]。由于砷具有较强的渗透性，因此很容易穿过血脑屏障并诱导自噬。多项研究表明，砷可以穿过血脑屏障（BBB）并直接影响中枢神经系统。穿过血脑屏障并在脑组织不同区域积累的能力确立了其在多种神经系统疾病中的重要性（图1 ）。神经元无法分裂，因此神经元的损伤会导致整个神经系统的永久性功能失常。神经系统受损会损害正常的冲动传播（图1 ）。

Fig. 1 图1
figure 1

Arsenic can cross blood-brain barrier and induce autophagy
砷可以穿过血脑屏障并诱导自噬

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Neurotoxicity Effect by Oxidative Stress and Antioxidant Imbalance
氧化应激和抗氧化失衡的神经毒性作用

Toxic reactive oxygen species are generated spontaneously in small amount in our body during electron transport in mitochondria and endoplasmic reticulum. Electron leaking condition in this transport chain can induce the generation of superoxide radical (O2-). Lipid content is always high in brain tissue than the other parts of the body. About 30% of the weight of the brain contains lipid. Lipid molecule is very susceptible for damaging by reactive oxygen species. The oxidative degradation of lipid is known as lipid peroxidation. The end products of lipid peroxidation are malondialdehyde (MDA). In this process, free radicals take electron from the lipid and degrade it, so finally cell damage occurs. This process propagates through chain reaction. If slight lipid peroxidation (LPO) takes place, stress signaling generates in the cell followed by antioxidant induction, cell survive (Fig. 2). Stress signaling generated by moderate LPO induces death pathway and that leads to apoptotic death. High LPO production leads to necrotic death through membrane lyses. This suggests the biphasic pathway of LPO induced by arsenic and that end up in either necrotic or apoptotic pathway. There are several antioxidant enzymes present in our body which can fight against reactive oxygen species (ROS) and can reduce their level such as catalase, superoxide dismutase (SOD), glutathione peroxidase, etc. SOD converts superoxide radical to H2O2 with the addition of H+. This H2O2 is converted to H2O and O2 in the presence of catalase (Fig. 2).
在线粒体和内质网的电子传输过程中，我们体内会自发产生少量有毒活性氧。该传输链中的电子泄漏条件可以诱导超氧自由基(O 2 -)的产生。脑组织中的脂质含量始终高于身体其他部位。大脑重量的大约30%含有脂质。脂质分子非常容易受到活性氧的破坏。脂质的氧化降解称为脂质过氧化。脂质过氧化的最终产物是丙二醛（MDA）。在这个过程中，自由基从脂质中夺取电子并将其降解，最终导致细胞损伤。这个过程通过链式反应传播。如果发生轻微的脂质过氧化（LPO），细胞中会产生应激信号，然后诱导抗氧化剂，细胞就会存活（图2 ）。适度的 LPO 产生的应激信号会诱导死亡途径，从而导致细胞凋亡。高 LPO 产量会通过膜裂解导致坏死性死亡。这表明砷诱导 LPO 的双相途径，最终导致坏死或凋亡途径。我们体内存在多种抗氧化酶，可以对抗活性氧（ROS）并降低其水平，如过氧化氢酶、超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶等。SOD将超氧自由基转化为H 2 O 2添加H+。该H 2 O 2在过氧化氢酶的存在下转化为H 2 O和O 2 (图2 )。

Fig. 2 图2
figure 2

Arsenic-induced oxidative damage and antioxidant impairment induce neuronal damages
砷诱导的氧化损伤和抗氧化损伤导致神经元损伤

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Arsenic-induced injury in GSH-depleted animals can be enhanced if methylation is impaired [14] because methylation makes arsenic less reactive with tissue and helps its elimination from the body [15]. Glutathione peroxidase acts in two ways [16, 17]: one is selenium depletion dependent and the other is independent. However, the selenium-independent activity is associated with a GSH transferase whether the selenium-dependent activity is related by the induction of arsenic because arsenic can disrupt selenium [18]. As a toxic metalloid, arsenic degenerates the ROS scavenging capability of these antioxidant enzymes. When the ROS generation starts due to arsenic toxicity, the antioxidant enzymes increase their level for boosting purpose. But when ROS level increases too much, it inactivates the antioxidant enzymes by inactivating the catalytic site. As a result, antioxidant enzymes level decreases and cell becomes toxic.
如果甲基化受损，砷对谷胱甘肽耗尽的动物造成的损伤可能会加剧[ 14 ]，因为甲基化使砷与组织的反应性降低，并有助于其从体内消除[ 15 ]。谷胱甘肽过氧化物酶以两种方式发挥作用 [ 16 , 17 ]：一种是硒消耗依赖性的，另一种是独立的。然而，硒独立活性与谷胱甘肽转移酶相关，无论硒依赖性活性是否与砷的诱导相关，因为砷会破坏硒[ 18 ]。作为一种有毒的非金属，砷会降低这些抗氧化酶的 ROS 清除能力。当由于砷毒性而开始产生ROS时，抗氧化酶会增加其水平以达到促进目的。但当ROS水平增加过多时，它会通过使催化位点失活而使抗氧化酶失活。结果，抗氧化酶水平下降，细胞变得有毒。

Neurotoxicity via Enzyme Disruption
酶破坏引起的神经毒性

When arsenic accumulates in the body greater its negligible and nontoxic level, it leads to a destruction of the cell slowly by inactivating important metabolic enzymes for cell survival like pyruvate dehydrogenase. At the end of glycolysis and before entering in TCA cycle, pyruvate is converted to acetyl co-A and CO2 by the help of pyruvate dehydrogenase complex. In this process, ATP is produced which is a demanding workable energy source for cell. Lipoic acid is an essential cofactor for the dehydrogenase enzymes. Lipoic acids having two sulfhydryl (-SH) groups act as an antioxidant and scavenge free radicals [19]. But in the presence of arsenic (arsenite), two hydrogen molecules are replaced and form a dihydrolipoyl arsenite chelate complex. For regaining the catalytic activity of this enzyme-mediated re-oxidation of dihydrolipoyl arsenite complex is needed. Due to the arsenic toxicity, the enzyme responsible for re-oxidation reaction of this complex is blocked. As a result, pyruvate production, a pivotal component of energy production, is reduced. When acetyl co-A level critically decreases, cell enters in death pathway. The impairment of energy metabolism in neuronal cells creates severe damages to these cells and as a whole neuronal control over the multiple organ and whole body diminished drastically. Arsenic also inhibits the production of succinyl co-A and hampers ATP production in cell and blocks the energy supply entirely as the succinyl co-A present in complex II of electron transport chain. So, the ATP synthesis is also prevented.
当砷在体内积累到可忽略且无毒的水平时，它会通过使细胞生存的重要代谢酶（如丙酮酸脱氢酶）失活而缓慢地破坏细胞。在糖酵解结束和进入 TCA 循环之前，丙酮酸在丙酮酸脱氢酶复合物的帮助下转化为乙酰辅酶 A 和 CO2。在此过程中，产生 ATP，这是细胞所需的可用能源。硫辛酸是脱氢酶的重要辅助因子。具有两个巯基（-SH）的硫辛酸可作为抗氧化剂并清除自由基[ 19 ]。但在砷（亚砷酸盐）存在下，两个氢分子被取代并形成二氢硫辛酰亚砷酸盐螯合物。为了恢复这种酶介导的二氢硫辛酰亚砷酸盐复合物的再氧化的催化活性是必要的。由于砷的毒性，负责该复合物再氧化反应的酶被阻断。结果，能源生产的关键组成部分丙酮酸的产量减少。当乙酰辅酶A水平严重降低时，细胞进入死亡途径。神经元细胞能量代谢的受损会对这些细胞造成严重损害，并且作为一个整体，神经元对多个器官和整个身体的控制急剧减弱。砷还抑制琥珀酰辅酶 A 的产生，阻碍细胞内 ATP 的产生，并完全阻断能量供应，因为琥珀酰辅酶 A 存在于电子传递链复合体 II 中。因此，ATP 合成也被阻止。

Neurotoxicity via Hormonal and NEUROTRANMITTER Impairment
激素和神经递质损伤引起的神经毒性

Hypothalamus is located in the diencephalon part of the brain. The hormones secreted from hypothalamus directly and indirectly regulate the pituitary gland, also known as master gland. The hypothalamic-hypophyseal portal system is recruited for this communication. Arsenic consumption in brain can damage hypothalamus. As an outcome, the function of pituitary gland hampers and creates a hormonal imbalance throughout the whole body. Recent studies demonstrate that arsenic is a potent endocrine disrupter especially it alters steroid hormone receptor-mediated gene regulation at very low level. Glucocorticoid, androgen (AR), progesterone (PR), mineralocorticoid (MR), and estrogen receptor (ER) are the steroid receptors [20,21,22].
下丘脑位于大脑的间脑部分。下丘脑分泌的激素直接和间接调节垂体，也称为主腺。下丘脑-垂体门脉系统被用于这种沟通。大脑中砷的消耗会损害下丘脑。结果，脑下垂体的功能阻碍并造成全身荷尔蒙失衡。最近的研究表明，砷是一种有效的内分泌干扰物，特别是它会在非常低的水平上改变类固醇激素受体介导的基因调节。糖皮质激素、雄激素(AR)、黄体酮(PR)、盐皮质激素(MR)和雌激素受体(ER)是类固醇受体[20,21,22 ] 。

Endocrine disrupting element was thought to perform primarily in one of the two ways. One way is to bind in steroid receptor followed by mimicking the normal hormone, leading to improper activation of the receptor. Second one is to bind the receptor and inactivate the ability of normal hormone to activate the receptor. But arsenic does not follow both of the ways; rather it appears to act in a third way. The report revealed that in the presence of arsenic, the activated receptor is unable to stimulate the appropriate cascade of signals [23].
内分泌干​​扰素被认为主要以两种方式之一发挥作用。一种方法是结合类固醇受体，然后模仿正常激素，导致受体的不当激活。第二种是结合受体，使正常激素激活受体的能力失活。但砷并不遵循这两种方式；相反，它似乎以第三种方式起作用。该报告显示，在砷存在的情况下，激活的受体无法刺激适当的信号级联[ 23 ]。

Arsenic-induced neurotoxicity has impact on neurotransmitters which are responsible for communicating between cell to cell within the brain. Arsenic inversely regulates norepinephrine level and helps in inducing dopamine and serotonin level [24]. γ-aminobutyric acid (GABA), glutamate, and other biogenic amine levels can alter by arsenic effect [25] (Nagaraja et al.,1993). Arsenic can reduce synaptic vesicle in synapse [25]. Experimental research found that, inorganic arsenic consumption by rat decreases acetylcholinesterase (AChE) activity which helps in metabolism of another neurotransmitter, acetylcholine [26]. The result suggested that there is a certain decrease in the binding of muscarinic cholinergic receptors in frontal cortex (26%, 43%) and hippocampus (21%, 34%) associated with low acetylcholinesterase activity in arsenic-treated rats as compared against control group. Due to arsenic induction, partial learning and memory and muscle strength were reduced associated with cholinergic alterations. In this regard, neuronal cell death has been regarded as a determinant of cholinergic cell damage. Pro-apoptotic proteins expression in decreasing order as the oxidative stress is enhanced by arsenic in both frontal cortex and hippocampus [27].
砷引起的神经毒性会影响负责大脑内细胞与细胞之间通讯的神经递质。砷反向调节去甲肾上腺素水平并有助于诱导多巴胺和血清素水平[ 24 ]。 γ-氨基丁酸 (GABA)、谷氨酸和其他生物胺水平会因砷效应而改变 [ 25 ]（Nagaraja 等，1993）。砷可以减少突触中的突触小泡[ 25 ]。实验研究发现，大鼠摄入无机砷会降低乙酰胆碱酯酶（AChE）活性，从而有助于另一种神经递质乙酰胆碱的代谢[ 26 ]。结果表明，与对照组相比，砷处理的大鼠额叶皮层（26%、43%）和海马（21%、34%）毒蕈碱胆碱能受体的结合有一定程度的减少，这与乙酰胆碱酯酶活性降低有关。 。由于砷的诱导，部分学习和记忆以及肌肉力量因胆碱能改变而降低。在这方面，神经元细胞死亡被认为是胆碱能细胞损伤的决定因素。随着砷在额叶皮层和海马体中氧化应激的增强，促凋亡蛋白的表达呈递减顺序[ 27 ]。

Mitochondrial Membrane Potential
线粒体膜电位

Mitochondria are the primary target in arsenic-induced genotoxicity (Fig. 3). Arsenic shows its mutagenic response through the mitochondrial damage. Mitochondrial membrane potential decreases along with arsenic toxicity by generating reactive oxygen species and DNA fragmentation. Overproduction of ROS is linked to the induction of apoptosis by As2O3. Accumulation of hydrogen peroxide (H2O2) leads to decreases in the mitochondrial membrane potential, resulting in cytochrome c release and activation of the caspase cascade [28]. Mitochondrial apoptotic markers such as bax, bak, bid, and bim and several inflammatory markers IL-6, TNF-α, IL-1β, and IFN-γ levels become altered (Fig. 3).
线粒体是砷引起的遗传毒性的主要靶标（图3 ）。砷通过线粒体损伤表现出其诱变反应。线粒体膜电位随着砷毒性的降低而降低，产生活性氧和 DNA 碎片。 ROS 的过量产生与 As 2 O 3诱导细胞凋亡有关。过氧化氢（H 2 O 2 ）的积累导致线粒体膜电位降低，导致细胞色素c释放和半胱天冬酶级联的激活[ 28 ]。线粒体凋亡标记物如bax、bak、bid和bim以及几种炎症标记物IL-6、TNF-α、IL-1β和IFN-γ水平发生改变（图3 ）。

Fig. 3 图3
figure 3

Arsenic toxicity induces apoptotic factors and suppresses anti-apoptotic factors in mitochondria
砷毒性诱导凋亡因子并抑制线粒体中的抗凋亡因子

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Due to mitochondrial damage, lots of superoxide anions generate which then react with nitric oxide and produce the highly reactive peroxynitrites. In vitro research has demonstrated that arsenic affects mitochondrial oxidations in the absence of inorganic phosphate [29, 30] and by stimulating the mitochondrial ATPase [31].
由于线粒体损伤，产生大量超氧阴离子，然后与一氧化氮反应并产生高反应性的过氧亚硝酸盐。体外研究表明，砷在缺乏无机磷酸盐的情况下影响线粒体氧化 [ 29 , 30 ]，并通过刺激线粒体 ATP 酶 [ 31 ]。

Neurotoxicity Manifestations
神经毒性表现

Physical Changes 身体变化

Arsenic induction in dose-dependent manner shows reduction of the brain and total body weight in several experiments [26, 32].
在几个实验中，以剂量依赖性方式进行的砷诱导显示出大脑和总体重的减少[ 26 , 32 ]。

Plasma histone protein concentration can be changed by the induction of arsenic metalloid. Arsenic alters the post translational modifications of histone protein in embryo’s brain with possible neural tube defects [33, 34]. Neural tube defects are birth defects that can take place when the developing neural plate fails to elevate and/or fuse in the first 3 to 4 weeks of gestation; this situation leads to permanent damage in the spinal cord or cause death [35]. Abnormality that grows in sensory nerve conduction is remarkable and moderate abnormalities in motor nerve conduction. Axonal degeneration is the possible outcome.
砷类金属的诱导可以改变血浆组蛋白浓度。砷改变胚胎大脑中组蛋白的翻译后修饰，可能导致神经管缺陷[ 33 , 34 ]。神经管缺陷是一种出生缺陷，当发育中的神经板在妊娠前 3 至 4 周内无法抬高和/或融合时，可能会发生；这种情况会导致脊髓永久性损伤或导致死亡[ 35 ]。感觉神经传导的异常是显着的，运动神经传导的异常是中度的。轴突变性是可能的结果。

CD200 is a neural surface glycoprotein expressed in neurons and can give protection by binding to the microglial CD200 receptor (CD200R) (Fig. 4). CD200 transmits receptor-mediated signals for regulating pro-inflammatory activity of microglial cells [36]. Production of the reactive oxygen species in microglial and its neighboring tissues initiates both pro- and anti-inflammatory cytokine actions in microglia. Notwithstanding, the cytokine activation has been shown to be regulated by the ROS-activated nuclear factor Nrf-2 and NF-κβ [37]. The pro-inflammatory responses initiated by arsenic trioxide in the cultured microglial cells generate apoptotic signaling via IL-1β. This signaling may be inhibited by STAT, p38/MAPK blocker suggesting that the responses are mediated by STAT- and MAPK-dependent manner [38]. In relation to the therapeutic study, it may be explained that the ellagic acid (EA) which is a strong antioxidant can significantly diminish arsenic-induced microglial and other neuronal toxicities. This therapeutic action is basically accomplished by the nullification of arsenic-induced free radicals and apoptotic markers, BAX and Bcl2, as well as inflammatory markers, IL-1β, TNFα, and INFγ. In summary, it is indicative that arsenic-induced inflammation and apoptotic events are the eventuality of the ROS-mediated mitochondrial dysfunctions [39].
CD200是在神经元中表达的神经表面糖蛋白，可以通过与小胶质细胞CD200受体（CD200R）结合来提供保护（图4 ）。 CD200 传递受体介导的信号来调节小胶质细胞的促炎活性[ 36 ]。小胶质细胞及其邻近组织中活性氧的产生启动了小胶质细胞中的促炎和抗炎细胞因子作用。尽管如此，细胞因子的激活已被证明受到ROS激活的核因子Nrf-2和NF-κβ的调节[ 37 ]。在培养的小胶质细胞中，三氧化二砷引发的促炎症反应通过 IL-1β 产生凋亡信号。该信号传导可能被 STAT、p38/MAPK 阻断剂抑制，表明该反应是由 STAT 和 MAPK 依赖性方式介导的 [ 38 ]。就治疗研究而言，可以解释的是，鞣花酸（EA）是一种强抗氧化剂，可以显着减少砷诱导的小胶质细胞和其他神经元毒性。这种治疗作用基本上是通过消除砷诱导的自由基和细胞凋亡标记物 BAX 和 Bcl2，以及炎症标记物 IL-1β、TNFα 和 INFγ 来实现的。总之，这表明砷诱导的炎症和细胞凋亡事件是ROS介导的线粒体功能障碍的必然结果[ 39 ]。

Fig. 4 图4
figure 4

Arsenic-mediated activation of microgial cells and induction of inflammatory mediators and signaling molecules
砷介导的小胶质细胞激活以及炎症介质和信号分子的诱导

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Cognitive Disorders and Behavioral Changes
认知障碍和行为改变

Arsenic (As) exposure affects the central nervous system and shows negative effect on memory and learning. In the brain, organic chemicals or hormone of catecholamine family does not act as neurotransmitter such as nor do epinephrine (NE), dopamine (DA), and serotonin (5-HT). These neurotransmitters have a crucial role in learning and memory. The dopaminergic system is a target of arsenic induction. Functional alteration at the time of DA synthesis and signaling which create abnormality in DA levels in a gender-specific manner which creates changes in mRNA level associated with dopaminergic and antioxidant system [40, 41]. In experimental mice, NE, DA, and 5-HT were assessed in the cerebrum and cerebellum part by HPLC method. The mRNA expressions of dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) as NE, DA, and 5-HT enzymes were assessed and analyzed by real-time PCR (RT-PCR). Mice exposed to arsenic gives decreasing concentrations of NE, DA, and 5-HT and the expressions of TH, TPH, and DBH genes in the brains than other groups [42].
砷 (As) 暴露会影响中枢神经系统，并对记忆和学习产生负面影响。在大脑中，儿茶酚胺家族的有机化学物质或激素不像肾上腺素 (NE)、多巴胺 (DA) 和血清素 (5-HT) 那样充当神经递质。这些神经递质在学习和记忆中起着至关重要的作用。多巴胺能系统是砷诱导的目标。 DA 合成和信号传导时的功能改变会以性别特异性方式产生 DA 水平异常，从而导致与多巴胺能和抗氧化系统相关的 mRNA 水平发生变化 [ 40 , 41 ]。采用HPLC法测定实验小鼠大脑和小脑部分的NE、DA和5-HT。通过实时 PCR (RT-PCR) 评估和分析多巴胺β羟化酶 (DBH)、酪氨酸羟化酶 (TH) 和色氨酸羟化酶 (TPH) 作为 NE、DA 和 5-HT 酶的 mRNA 表达。与其他组相比，暴露于砷的小鼠大脑中NE、DA和5-HT的浓度以及TH、TPH和DBH基因的表达降低[ 42 ]。

Therapeutics 疗法

Recently phototherapy has gained its popularity against arsenic toxicity. Flavonoids are using as therapeutics for their pharmacological function due to presence of phenolic group. Neurotransmitter level disruption caused by arsenic toxicity can be reversed by taurine [42] treatment and curcumin [43]. Taurine is a sulfonic acid derivative of cysteine which defends against mitochondrial superoxide generation and protects from damage [44]. Chelators are mostly used for escaping from chronic arsenic-related toxicity. Among them thiol chelators are also present. Arsenic forms insoluble complexes with thiol chelators like monoisoamyl meso 2–3-dimercaptosuccnic acid (MiADMSA), a strong thiol chelator. This thiol chelator reduces the deficient antioxidant environment and helps to reduce oxidative damage [45]. Use of arsenic chelators like selenium and zinc can reverse the situation caused by arsenic consumption. Selenium (Se) has an antioxidant property as well as an anticarcinogenic property. Selenium treatment can reduce arsenic toxicity via the formation of conjugates with arsenic and excretes from the body [46]. That is why arsenic-exposed tissue gives a decrease concentration of selenium. Zinc (Zn) metal can attenuate the lacking generated by arsenic. When arsenic and zinc are present in drinking water in a proper ratio, it can give the protective effect. Research has revealed that zinc is capable of preventing the apoptosis in neuronal cells which is outcome of arsenic toxicity.
最近，针对砷中毒的光疗法越来越受欢迎。由于酚基团的存在，类黄酮因其药理功能而被用作治疗剂。砷中毒引起的神经递质水平破坏可以通过牛磺酸[ 42 ]治疗和姜黄素[ 43 ]来逆转。牛磺酸是半胱氨酸的磺酸衍生物，可防止线粒体超氧化物的产生并免受损伤[ 44 ]。螯合剂主要用于逃避慢性砷相关毒性。其中还存在硫醇螯合剂。砷与硫醇螯合剂形成不溶性络合物，例如单异戊基内消旋 2-3-二巯基琥珀酸 (MiADMSA)（一种强硫醇螯合剂）。这种硫醇螯合剂可以减少抗氧化环境的不足，有助于减少氧化损伤[ 45 ]。使用硒、锌等砷螯合剂可以扭转砷消耗造成的情况。硒 (Se) 具有抗氧化特性和抗癌特性。硒治疗可以通过与砷形成结合物并从体内排出来降低砷的毒性[ 46 ]。这就是为什么暴露于砷的组织中硒浓度降低的原因。锌（Zn）金属可以减弱砷所产生的缺乏。当砷和锌以适当的比例存在于饮用水中时，可以起到保护作用。研究表明，锌能够防止神经元细胞凋亡，这是砷中毒的结果。

Conclusions 结论

Arsenic may directly attack the central nervous system. Due to the alteration in blood-brain barrier (BBB), it takes entry and activates several toxicity generating pathways. Arsenic can disrupt cell-cell communication via neurotransmitter alteration. Sometimes arsenic induction in neurons may increase the level of inhibitory neurotransmitters and decrease the level of excitatory neurotransmitter. As a result, total integrated system of body is affected. Arsenic can induce cellular and organ toxicity in multiple ways that finally change the metabolic regulations and develop life-threatening diseases manifestations. The current review on the mechanistic layout will help in therapeutic interventions in arsenic-induced neurotoxicity.
砷可能直接攻击中枢神经系统。由于血脑屏障（BBB）的改变，它进入并激活多种毒性产生途径。砷可以通过改变神经递质来破坏细胞间的通讯。有时，神经元中的砷诱导可能会增加抑制性神经递质的水平并降低兴奋性神经递质的水平。结果，身体的整个综合系统受到影响。砷可以多种方式诱导细胞和器官毒性，最终改变代谢调节并发展出危及生命的疾病表现。目前对机制布局的综述将有助于砷引起的神经毒性的治疗干预。