Arsenic-induced Neurotoxicity Research Articles

Changes in Energy Dynamics in Arsenic Exposure Based Neurotoxicity: A Comprehensive Review.

The by-product of naturally occurring rock, soil with different agricultural and industrial processes contaminated groundwater with a toxic metalloid- Arsenic (As3+), which results in different toxicities within the human body and in developing fetus. The present study emphasizes evaluating the presence of oxidative stress and excessive generation of reactive oxygen species (ROS) resulting in mitochondrial dysfunction and caspase activation followed by apoptosis due to arsenic-induced neurotoxicity along with epigenetic modifications at different molecular targets. Published articles available on PubMed and Scopus were studied and summarized. The precise mechanism causing arsenic-induced neurotoxicity at a critical stage of brain development is still unknown, while increased oxidative stress led to mitochondrial dysfunctions which are known to play a prominent role in this. AMPK acts as a metabolic checkpoint and restores ATP levels through a different anabolic pathway in energy starvation. At the same time, arsenic-induced AMPK activation leads to autophagy and neuronal cell death. This review summarized the molecular mechanisms involved in arsenic-induced neurotoxicity, which can help develop suitable future ameliorative and therapeutic strategies.

Arsenic impairs Drosophila neural stem cell mitotic progression and sleep behavior in a tauopathy model.

Despite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic-induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. In this study, we examine the effects of arsenic exposure on Drosophila larval neurodevelopment and adult neurologic function. Consistent with prior work, we identify significant developmental delays and heightened mortality in response to arsenic. Within the developing larval brain, we identify a dose-dependent increase in brain volume. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, we show arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex-specific and genetic vulnerabilities to sublethal exposure.

Epicatechin as a promising agent against arsenic-induced neurobehavioral toxicity in NMRI mice: behavioral and biochemical alterations.

Epicatechin (Epi) is one of the most abundant flavonoids present in different fruits and tea leaves. Emerging research illuminates the promising potential of catechins to serve as a shield against the damaging effects of arsenic (As) exposure in diverse organs.This study sought to discern whether Epi exhibits a therapeutic efficacy against arsenic-induced neurotoxicity in a murine model.The Naval Medical Research Institute (NMRI) mice were randomly partitioned into six distinct groups, which included a control group receiving normal saline, a group receiving a daily oral dose of arsenic (10mg/kg) for 5weeks, groups receiving As (10mg/kg/day) orally for 5weeks along with different doses of Epi (25-100mg/kg) orally for the last 2weeks, and a group receiving Epi (100mg/kg) orally for 2weeks. To assess the potential effects of Epi, neurobehavioral tests, various parameters of oxidative stress, and inflammation were evaluated.The findings of this investigation revealed that As-induced neurobehavioral toxicity was associated with a notable surge in lipid peroxidation and nitric oxide (NO) concentration, accompanied by a reduction in the levels of antioxidant markers. As heightened pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α) levels were observed alongside amplified nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. However, treatment with Epi reversed these effects.On the whole, these findings indicate that Epi may hold promise therapeutic efficacy on As-induced neurotoxicity by improving antioxidant status and mitigating oxidative stress and inflammation. Nevertheless, further research is imperative to comprehensively grasp the potential protective effects of Epi in this particular context.

Transgenerational Effects of Arsenic Exposure on Learning and Memory in Rats: Crosstalk between Arsenic Methylation, Hippocampal Metabolism, and Histone Modifications.

Arsenic (As) is widely present in the natural environment, and exposure to it can lead to learning and memory impairment. However, the underlying epigenetic mechanisms are still largely unclear. This study aimed to reveal the role of histone modifications in environmental levels of arsenic (sodium arsenite) exposure-induced learning and memory dysfunction in male rats, and the inter/transgenerational effects of paternal arsenic exposure were also investigated. It was found that arsenic exposure impaired the learning and memory ability of F0 rats and down-regulated the expression of cognition-related genes Bdnf, c-Fos, mGlur1, Nmdar1, and Gria2 in the hippocampus. We also observed that inorganic arsenite was methylated to DMA and histone modification-related metabolites were altered, contributing to the dysregulation of H3K4me1/2/3, H3K9me1/2/3, and H3K4ac in rat hippocampus after exposure. Therefore, it is suggested that arsenic methylation and hippocampal metabolism changes attenuated H3K4me1/2/3 and H3K4ac while enhancing H3K9me1/2/3, which repressed the key gene expressions, leading to cognitive impairment in rats exposed to arsenic. In addition, paternal arsenic exposure induced transgenerational effects of learning and memory disorder in F2 male rats through the regulation of H3K4me2 and H3K9me1/2/3, which inhibited c-Fos, mGlur1, and Nmdar1 expression. These results provide novel insights into the molecular mechanism of arsenic-induced neurotoxicity and highlight the risk of neurological deficits in offspring with paternal exposure to arsenic.

Arsenic-induced neurotoxicity in patients with acute promyelocytic leukaemia.

Arsenic trioxide is an essential component of therapy for acute promyelocytic leukaemia (APL) and is currently dosed on actual body weight with no upper limit. Arsenic-induced neurotoxicity is a well-recognised complication; however, there is uncertainty about its relationship to arsenic dose and obesity. We conducted a large multicentre retrospective study of 487 patients with APL treated with arsenic-based therapy across 23 sites in Australia from 2008 to 2023. The primary outcome was incidence of neurotoxicity, and secondary outcomes included relationship of neurotoxicity to obesity and cumulative arsenic dose. Any-grade neurotoxicity occurred in 113 (23%) patients, predominantly peripheral neuropathy (91%). Most events were grade 1-2 severity (85%), with grade 3 events in 12% and grade 4-5 in 3%. The incidence of neurotoxicity increased with BMI (non-obese: 16%, obesity class I: 25%, obesity class II-III: 41%; p < 0.001). On univariable analysis, obesity class I (OR 1.81, p = 0.036), obesity class II-III (OR 3.93, p < 0.001), weight >100 kg (OR 2.72, p < 0.001), daily arsenic trioxide dose >15 mg (OR 5.05, p < 0.001) and cumulative induction dose >500 mg (OR 3.95, p < 0.001) were all significantly associated with neurotoxicity. Obesity class II-III and induction dose >500 mg remained significant on multivariable analysis. Our study highlights the strong association between BMI, arsenic trioxide dose and neurotoxicity. Pre-emptive dose reductions should be considered for obese patients receiving high doses of arsenic.

Arsenic induced neurotoxicity in the brain of ducks: The potential involvement of the gut-brain axis

BackgroundArsenic is a widely distributed ecotoxic pollutant that has been found to cause neurotoxicity in a variety of species. Gut-brain axis is a two-way information network between the gut microbiome and the brain, which is closely related to organismal health. However, the role of the gut-brain axis in arsenic-induced neurotoxicity remains largely unknown. MethodsIn order to explore whether there is a relationship between brain and gut microbiota of meat ducks, we performed molecular biological detection including RT-qPCR and Western blot, as well as morphological detection including, HE staining and immunohistochemistry. Meanwhile, intestinal contents were analyzed using 16 S ribosomal RNA gene sequencing and analysis ResultsIn this study, we investigated whether arsenic trioxide (ATO) can activate the gut microbiome-brain axis to induce intestinal and brain injury. The results showed that ATO-exposure disrupted the diversity balance of intestinal microbiota and integrity and injured the intestinal structure. ATO-exposure also reduced the number of glycogen and goblet cells in the duodenum. In addition, exposure to ATO caused intestinal inflammatory injury by activating NF-κB signaling pathway and promoting the expression of its target genes. Meanwhile, the tight junction-related proteins (ZO-1, occludin) of gut and brain were reduced by ATO exposure. Furthermore, results also revealed that ATO-exposure induced brain injury, including neuronal cell vacuolization and reduced numbers of neuronal cells in the cortex and hippocampus. Remarkably, ATO-exposure also disrupted neurotransmitter levels. Additionally, our further molecular mechanism study revealed that ATO-exposure increased the expression of autophagy and apoptosis related mRNA and proteins levels in the brain tissues. ConclusionAltogether, these findings provide a new insight into that ATO-exposure induced intestinal injury and aggravated neurotoxicity via the gut-brain axis.

Melatonin Attenuates Arsenic-Induced Neurotoxicity in Rats Through the Regulation of miR-34a/miR-144 in Sirt1/Nrf2 Pathway.

Arsenic (As) exposure is known to cause several neurological disorders through various molecular mechanisms such as oxidative stress, apoptosis, and autophagy. In the current study, we assessed the effect of melatonin (Mel) on As-induced neurotoxicity. Thirty male Wistar rat were treated daily for 28 consecutive days. As (15 mg/kg, gavage) and Mel (10 and 20 mg/kg, i.p.) were administered to rats. Morris water maze test was done to evaluate learning and memory impairment in training days and probe trial. Oxidative stress markers including MDA and GSH levels, SOD activity, and HO-1 levels were measured. Besides, the levels of apoptosis (caspase 3, Bax/Bcl2 ratio) and autophagy markers (Sirt1, Beclin-1, and LC3 II/I ratio) as well as the expression of miR-144 and miR-34a in cortex tissue were determined. As exposure disturbed learning and memory in animals and Mel alleviated these effects. Also, Mel recovered cortex pathological damages and oxidative stress induced by As. Furthermore, As increased the levels of apoptosis and autophagy proteins in cortex, while Mel (20 mg/kg) decreased apoptosis and autophagy. Also, Mel increased the expression of miR-144 and miR-34a which inhibited by As. In conclusion, Mel administration attenuated As-induced neurotoxicity through anti-oxidative, anti-apoptotic, and anti-autophagy mechanisms, which may be recommended as a therapeutic target for neurological disorders.

Arsenic induced autophagy-dependent apoptosis in hippocampal neurons via AMPK/mTOR signaling pathway.

Arsenic contamination of groundwater remains a serious public health problem worldwide. Arsenic-induced neurotoxicity receives increasing attention, however, the mechanism remains unclear. Hippocampal neuronal death is regarded as the main event of arsenic-induced cognitive dysfunction. Mitochondria lesion is closely related to cell death, however, the effects of arsenic on PGAM5-regulated mitochondrial dynamics has not been documented. Crosstalk between autophagy and apoptosis is complicated and autophagy has a dual role in the apoptosis pathways in neuronal cells. In this study, arsenic exposure resulted in mitochondrial PGAM5 activation and subsequent activation of apoptosis and AMPK-mTOR dependent autophagy. Intervention by autophagy activator Rapamycin or inhibitor 3-MA, both targeting at mTOR, accordingly induced activation or inhibition of apoptosis. Intervention by MK-3903 or dorsomorphin, activator or inhibitor of AMPK, received similar results. Our findings suggested that arsenic-induced PGAM5 activation played a role in AMPK-mTOR dependent autophagy and arsenic induced autophagy-dependent apoptosis in hippocampal neurons via AMPK/mTOR signaling pathway.

The protective effect of natural or chemical compounds against arsenic-induced neurotoxicity: Cellular and molecular mechanisms.

Arsenic is a notorious metalloid that exists in the earth's crust and is considered toxic for humans and the environment. Both cancerous and non-cancerous complications are possible after arsenic exposure. Target organs include the liver, lungs, kidney, heart, and brain. Arsenic-induced neurotoxicity, the main focus of our study, can occur in central and peripheral nervous systems. Symptoms can develop in a few hours, weeks, or years depending on the quantity of arsenic and the duration of exposure. In this review, we aimed to gather all the compounds, natural and chemical, that have been studied as protective agents in cellular, animal, and human reports. Oxidative stress, apoptosis, and inflammation are frequently described as destructive mechanisms in heavy metal toxicity. Moreover, reduced activity of acetylcholinesterase, the altered release of monoamine neurotransmitters, down-regulation of N-methyl-D-aspartate receptors, and decreased brain-derived neurotrophic factor are important underlying mechanisms of arsenic-induced neurotoxicity. As for neuroprotection, though some compounds have yet limited data, there are others, such as curcumin, resveratrol, taurine, or melatonin which have been studied more deeply and might be closer to a reliable protective agent. We collected the available information on all protective agents and the mechanisms by which they fight against arsenic-induced neurotoxicity.

Neuroprotective Efficacy of Edaravone against Arsenic-Induced Behavioral and Neurochemical Deficits in Rats: Amelioration of Cholinergic and Mitochondrial Functions.

A substantial amount of evidence indicates that long-term arsenic exposure leads to various types of pathological complications, especially cognitive dysfunction. The present study was designed to assess the neuroprotective potential of edaravone (a potent free radical scavenger) against arsenic-induced neurotoxicity in Wistar rats. Adult male Wistar rats were randomly divided into five groups. Arsenic (20 mg/kg/day; p.o.) and Edaravone (5 and 10 mg/kg/day; i.p.) were administered in different experimental groups for 28 days. The results of various behavioral test paradigms revealed that arsenic caused significant learning and memory deficits, along with anxiety-like behavior. In biochemical analysis, we found marked elevations of oxidative-nitrosative stress (indicated by augmentation of lipid peroxidation and nitrite) and a reduction of glutathione levels in the hippocampus and frontal cortex region of arsenictreated rats. Moreover, arsenic administration caused mitochondrial complexes impairment and reduction of acetylcholinesterase level. On the other hand, chronic treatment with edaravone (10 mg/kg) significantly ameliorated the arsenic-induced behavioral deficits and neurochemical anomalies. This study suggests that edaravone confers neuroprotection against arsenic-induced memory impairment and anxiety-like behavior, which may be attributed to the inhibition of oxidativenitrosative stress and amelioration of cholinergic and mitochondrial functions.

Fenugreek seed powder protects mice against arsenic-induced neurobehavioral changes

The current study was designed to evaluate the protective effect of fenugreek seed powder against As-induced neurobehavioral and biochemical perturbations using a mouse model. Mice exposed to arsenic at 10 mg/kg body weight showed development of anxiety-like behavior and memory impairment compared to control mice in elevated plus maze and Morris water maze tests, respectively. A significantly decreased acetyl and butyrylcholinesterase, superoxide dismutase and glutathione reductase activities and brain-derived neurotrophic factor levels were found in the brain of arsenic-exposed mice compared to control mice. Interestingly, supplementation of fenugreek seed powder to arsenic-treated mice significantly restored the activity of cholinesterase and antioxidant enzymes (e.g. superoxide dismutase, glutathione reductase) as well as brain-derived neurotrophic factor levels in the brain tissue of arsenic-exposed mice. Consequently, reduced anxiety-like behavior, improved learning and memory were observed in fenugreek supplemented arsenic treated mice compared to only arsenic-exposed mice group. Thus, this study suggests that fenugreek seed powder reduces arsenic-induced neurotoxicity in mice.

Inorganic arsenic alters the development of dopaminergic neurons but not serotonergic neurons and induces motor neuron development via Sonic hedgehog pathway in zebrafish

The mechanism of inorganic arsenic-induced neurotoxicity at the cellular level is not known. In zebrafish, teratological effects of inorganic arsenic have been shown at various concentrations. Here, we used similar concentrations of inorganic arsenic to evaluate the effects on specific neuron types. Exposure of zebrafish embryos at 5 h post fertilization (hpf) to sodium arsenite induced developmental toxicity (reduced body length) in 72 hpf larvae, beginning at a concentration of 300 mg/L concentration. Mortality or overt morphological deformity was detected at 500 mg/L sodium arsenite. While 200 mg/L sodium arsenite induced development of tyrosine hydroxylase-positive (dopaminergic) neurons, there was no significant effect on the development of 5-hydroxytryptamine (serotonergic) neurons. Sodium arsenite reduced acetylcholinesterase activity. In the hb9-GFP transgenic larvae, both 200 and 400 mg/L sodium arsenite produced supernumerary motor neurons in the spinal cord. Inhibition of the Sonic hedgehog (Shh) pathway that is essential for motor neuron development, by Gant61, prevented sodium arsenite-induced supernumerary motor neuron development. Inductively coupled plasma mass spectrometry (ICP-MS) revealed that with 200 mg/L and 400 mg/L sodium arsenite treatment, each larva had an average of 387.8 pg and 847.5 pg arsenic, respectively. The data show for the first time that inorganic arsenic alters the development of dopaminergic and motor neurons in the zebrafish larvae and the latter occurs through the Shh pathway. These results may help understand why arsenic-exposed populations suffer from psychiatric disorders and motor neuron disease and Shh may, potentially, serve as a plasma biomarker of arsenic toxicity.

A review of mechanisms underlying the protective effects of natural compounds against arsenic-induced neurotoxicity.

Arsenic (As) is a toxic metalloid that is widely distributed in the earth's crust. People are continuously exposed to this toxicant in their food and drinking water. Inorganic arsenic occurs in two oxidation states, arsenite 3+ (iAs3+) and arsenate 5+ (iAs5+). The most toxic form is its trivalent form which interferes with the electron transfer cycle and induces overproduction of reactive oxygen species, leading to depletion of the antioxidant defense system, as well as altering fatty acid levels and mitochondrial action. Since arsenic crosses the blood-brain barrier, it can damage cells in different regions of the brain, causing neurological disorders through the induction of oxidative stress, inflammation, DNA damage, and cell death. Hydroxytyrosol, taurine, alpha-lipoic acid, ellagic acid, and thymoquinone have been shown to effectively alleviate arsenic-induced neurotoxicity. The protective effects are the result of the anti-oxidative and anti-inflammatory properties of the phytochemicals and in particular their anti-apoptotic function via the Nrf2 and PI3/Akt/SIRT1 signaling pathways.

Arsenic Induces GSK3β-Dependent p-Tau, Neuronal Apoptosis, and Cognitive Impairment via an Interdependent Hippocampal ERα and IL-1/IL-1R1 Mechanism in Female Rats.

Arsenic is an environmental contaminant with potential neurotoxicity. We previously reported that arsenic promoted hippocampal neuronal apoptosis, inducing cognitive loss. Here, we correlated it with tau pathology. We observed that environmentally relevant arsenic exposure increased tau phosphorylation and the principal tau kinase, glycogen synthase kinase-3 beta (GSK3β), in the female rat hippocampal neurons. We detected the same in primary hippocampal neurons. Because a regulated estrogen receptor (ER) level and inflammation contributed to normal hippocampal functions, we examined their levels following arsenic exposure. Our ER screening data revealed that arsenic down-regulated hippocampal neuronal ERα. We also detected an up-regulated hippocampal interleukin-1 (IL-1) and its receptor, IL-1R1. Further, co-treating arsenic with the ERα agonist, 4,4',4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), or IL-1R antagonist (IL-1Ra) resulted in reduced GSK3β and p-tau, indicating involvement of decreased ERα and increased IL-1/IL-1R1 in tau hyperphosphorylation. We then checked whether ERα and IL-1/IL-1R1 had linkage, and detected that although PPT reduced IL-1 and IL-1R1, the IL-1Ra restored ERα, suggesting their arsenic-induced interdependence. We finally correlated this pathway with apoptosis and cognition. We observed that PPT, IL-1Ra and the GSK3β inhibitor, LiCl, reduced hippocampal neuronal cleaved caspase-3 and TUNEL+ve apoptotic count, and decreased the number of errors during learning and increased the saving memory for Y-Maze test and retention performance for Passive avoidance test in arsenic-treated rats. Thus, our study reveals a novel mechanism of arsenic-induced GSK3β-dependent tau pathology via interdependent ERα and IL-1/IL-1R1 signaling. It also envisages the protective role of ERα agonist and IL-1 inhibitor against arsenic-induced neurotoxicity.

Minocycline as a Neuroprotective Agent in Arsenic-Induced Neurotoxicity in PC12 Cells.

Arsenic is a naturally occurring metalloid that exists in water, soil, food, and air. Humans can be exposed to arsenic through occupational, medical, or nutritional routes. Both acute and chronic forms of toxicity with severe outcomes are likely following arsenic exposure. Neurotoxicity is one of the serious manifestations of arsenic toxicity. In our study, the effect of minocycline, a widely used antimicrobial agent with antioxidant aspects and the ability to cross the blood-brain barrier, was evaluated against arsenic-induced neurotoxicity. PC12 cell line was used as the cellular model of this study. Cells were pre-treated with minocycline (50nM-1µM) for 2h, and then incubated for 24h after adding sodium arsenite (10µM). The MTT assay and fluorimetry were performed to study cytotoxicity and reactive oxygen species generation, respectively. Finally, Western blotting was done to determine the levels of caspase-8, Bax, Bcl-2, and caspase-3. Once exposed to arsenic, the cell viability was significantly reduced, the intracellular oxidative balance was significantly disrupted, and the levels of proteins caspase-8, Bax/Bcl-2, and caspase-3 were significantly increased. Minocycline not only attenuated arsenic-induced cytotoxicity and reduced oxidative stress, but also led to lower levels of caspase-8, Bax/Bcl-2, and caspase-3 proteins compared with the arsenic-treated cells. Minocycline can significantly protect cells against arsenic-induced neurotoxicity by antioxidant and anti-apoptosis properties via both intrinsic and extrinsic caspase-dependent apoptotic pathways; therefore, at this point, it's worth considering it as a promising agent for the treatment of arsenic toxicity.

Evaluation of the neuroprotective activity of P. amarus in attenuating arsenic-induced neurotoxicity - an in vivo study

BackgroundArsenic is viewed as a bizarre and frightful element in human history. Recent studies showed that even low levels of arsenic can cause neurological damage. Phyllanthus amarus is an important medicinal herb proved to have neuro protective effect in experimental animals. This pre-clinical study used an animal model of arsenic toxicity and screened the different neuroprotective mechanisms of Phyllanthus amarus ethanolic extract. PurposeTo assess the effect of Phyllanthus amarus ethanolic extract on various biochemical parameter's in the brain of arsenic administered Wistar albino rats. MethodologyThe neuroprotective activity of P. amarus against arsenic induced toxicity was studied in Wistar albino rats. The experimental animals (n=24) were divided into four groups of 6 rats each. Rats in group I received distilled water, whereas rats in groups II, III, and IV received arsenic as sodium arsenite salt (40 mg/kg b.w) in drinking water daily for 28 days. In addition, rats from groups III, and IV also received P. amarus ethanolic extract 100 and 200 mg/kg b.w, by intragastric route, once daily for a period of 28 days. At the end of the experiment rats were subjected to various neurobehavioral tests such as Elevated plus maze, Light dark arena, Forced swim test and Tail suspension test. After 24 h of the last treatment, the animals were euthanized and brain tissue was assayed for various biochemical parameters. ResultsANOVA and Post hoc testing of behavioral and biochemical data (Dunnett's t-test and Student unpaired T test) showed co-administration of P. amarus ethanolic extract significantly reversed anxiety and depression-like behaviors in experimental animals. P. amarus ethanolic extract effectively reduced acetyl cholinesterase activity in the brain, and it also increased the levels of dopamine and serotonin in the brains of arsenic-treated animals as compared to only arsenic treated group. P. amarus ethanolic extract significantly decreased lipid peroxidase and increased brain catalase and super oxidase dismutase activities. ConclusionBased on the pharmacological, and biochemical analysis the plant extracts of P. amarus have shown protective effects against arsenic induced neurotoxicity.

TNF-α derived from arsenite-induced microglia activation mediated neuronal necroptosis

Arsenic, an identified environmental toxicant, poses threats to the health of human beings through contaminated water and food. Recently, increasing reports focused on arsenic-induced nerve damage, however, the underlying mechanism remains elusive. Microglia are important immune cells in the nervous system, which produce a large number of inflammatory factors including TNF-α when activated. Recent reports indicated that TNF-α is involved in the process of necroptosis, a new type of programmed cell death discovered recently. Although there were evidences suggested that arsenic could induce both microglia activation and TNF-α production in the nervous system, the mechanism of arsenic-induced neurotoxicity due to microglia activation is rarely studied. In addition, the role of microglia-derived TNF-α in response to arsenic exposure in necroptosis has not been documented before. In this study, we found that arsenite induced microglial activation through p38 MAPK signaling pathway, leading to the production of TNF-α. Microglia-derived TNF-α further induced necroptosis in the neuronal cells. Our findings suggested that necroptosis induced by microglia-derived TNF-α upon arsenite exposure partially played a role in arsenic-induced cell death which underlie the fundamental event of arsenic-related neurotoxicity.

Arsenic Induces Differential Neurotoxicity in Male, Female, and E2-Deficient Females: Comparative Effects on Hippocampal Neurons and Cognition in Adult Rats.

We earlier reported that arsenic induced hippocampal neuronal loss, causing cognitive dysfunctions in male rats. This neuronal damage mechanism involved an altered bone morphogenetic protein (BMP2)/Smad and brain-derived neurotrophic factor (BDNF)/TrkB signaling. Susceptibility to toxicants is often sex-dependent, and hence we studied the comparative effects of arsenic in adult male and female rats. We observed that a lower dose of arsenic reduced learning-memory ability, examined through passive avoidance and Y-maze tests, in male but not female rats. Again, male rats exhibited greater learning-memory loss at a higher dose of arsenic. Supporting this, arsenic-treated male rats demonstrated larger reduction in the hippocampal NeuN and %-surviving neurons, together with increased apoptosis and altered BMP2/Smad and BDNF/TrkB pathways compared to their female counterparts. Since the primary female hormone, estrogen (E2), regulates normal brain functions, we next probed whether endogenous E2 levels in females offered resistance against arsenic-induced neurotoxicity. We used ovariectomized (OVX) rat as the model for E2 deficiency. We primarily identified that OVX itself induced hippocampal neuronal damage and cognitive decline, involving an increased BMP2/Smad and reduced BDNF/TrkB. Further, these effects appeared greater in arsenic + OVX compared to arsenic + sham (ovary intact) or OVX rats alone. The OVX-induced adverse effects were significantly reduced by E2 treatment. Overall, our study suggests that adult males could be more susceptible than females to arsenic-induced neurotoxicity. It also indicates that endogenous E2 regulates hippocampal BMP and BDNF signaling and restrains arsenic-induced neuronal dysfunctions in females, which may be inhibited in E2-deficient conditions, such as menopause or ovarian failure.

Polyphenolics with Strong Antioxidant Activity from Acacia nilotica Ameliorate Some Biochemical Signs of Arsenic-Induced Neurotoxicity and Oxidative Stress in Mice.

Neurotoxicity is a serious health problem of patients chronically exposed to arsenic. There is no specific treatment of this problem. Oxidative stress has been implicated in the pathological process of neurotoxicity. Polyphenolics have proven antioxidant activity, thereby offering protection against oxidative stress. In this study, we have isolated the polyphenolics from Acacia nilotica and investigated its effect against arsenic-induced neurotoxicity and oxidative stress in mice. Acacia nilotica polyphenolics prepared from column chromatography of the crude methanol extract using diaion resin contained a phenolic content of 452.185 ± 7.879 mg gallic acid equivalent/gm of sample and flavonoid content of 200.075 ± 0.755 mg catechin equivalent/gm of sample. The polyphenolics exhibited potent antioxidant activity with respect to free radical scavenging ability, total antioxidant activity and inhibition of lipid peroxidation. Administration of arsenic in mice showed a reduction of acetylcholinesterase activity in the brain which was counteracted by Acacia nilotica polyphenolics. Similarly, elevation of lipid peroxidation and depletion of glutathione in the brain of mice was effectively restored to normal level by Acacia nilotica polyphenolics. Gallic acid methyl ester, catechin and catechin-7-gallate were identified in the polyphenolics as the major active compounds. These results suggest that Acacia nilotica polyphenolics due to its strong antioxidant potential might be effective in the management of arsenic induced neurotoxicity.

Cortex metabolome and proteome analysis reveals chronic arsenic exposure via drinking water induces developmental neurotoxicity through hnRNP L mediated mitochondrial dysfunction in male rats

Lots of people are at the risk of arsenic-contaminated drinking water. Arsenic exposure was confirmed to be closely linked to neurocognitive deficits, particularly during childhood. The multi-omics approaches are known be well suitable for toxicological research. Thus, this study aimed to explore the molecular mechanisms of arsenic-induced learning and memory function impairments through the integrative proteome and metabolome analysis of cortex in rats. The weaned rats were exposed to arsenic-contaminated drinking water for six months to mimic the developmental exposure. 220 differential proteins and 19 differential metabolites were identified in the cortex, and nine potential biomarkers were found to be related to impaired Morris water maze (MWM) indicators. Chronic arsenic exposure affected the cognitive function by inducing the overproduction of amyloid-β (Aβ) peptides and the redox imbalance in the mitochondria. Glycolysis and tricarboxylic acid (TCA) cycle enhancement driven by the increased heterogeneous nuclear ribonucleoprotein L (hnRNP L) is a low-dose protective mechanism against arsenic-induced ATP deficiency and oxidative stress. Moreover, apoptosis is another important pathway of arsenic-induced neurotoxicity. This study provides new evidence about the alterations of proteins and metabolites in the cortex of the exposed rats under arsenic toxicity. These findings suggest hnRNP L could be a potential target for the treatment of arsenic-induced neurotoxicity.