Arsenic induces hepatotoxicity in chickens via PANoptosis pathway.

Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people's mining and smelting of arsenic compounds. In addition, the widespread use of arsenic compounds, such as the use and production of arsenic-containing pesticides, is also a source of arsenic contamination. Arsenic contamination leads to an increased risk of arsenic exposure, and the multi-organ toxicity induced by arsenic exposure is a global health problem. As a non-mammalian vertebrate with high nutrient levels, chickens readily absorb and accumulate arsenic from their food. Relevant studies have shown that arsenic exposure induces hepatotoxicity in chickens, and there has been a steady stream of research into the specific mechanisms involved. PANoptosis, a newly discovered and unique mode of programmed cell death (PCD) characterized by both apoptosis, cellular pyroptosis, and necroptosis. There are no studies to indicate whether chicken liver toxicity due to arsenic is associated with PANoptosis. Therefore, we established chicken animal models and chicken primary hepatocyte models exposed to different arsenic concentrations to dissect the role and mechanism of PANoptosis in arsenic exposure-induced hepatotoxicity in chickens. Our histopathological results showed that arsenic treatment caused dose-dependent damage to chicken liver structure. Meanwhile, different doses of arsenic treatment groups caused significant up-regulation of the protein level of ZBP1, a key factor of PANoptosis. And then consequently triggered the abnormal gene and protein expression levels of apoptosis-associated factors (Caspase-8, Caspase-7, Caspase-3), cellular pyroptosis-associated factors (NLRP3, ASC, GSDMD) and necroptosis-associated factors (RIPK1, RIPK3, MLKL). In conclusion, our study revealed that PANoptosis is involved in arsenic-induced chicken hepatotoxicity. Our findings provide a new perspective on the pathogenesis of arsenic exposure-induced hepatotoxicity in chickens.

Cultivating resilience in wheat: mitigating arsenic toxicity with seaweed extract and Azospirillum brasilense.

Arsenic (As) toxicity is a serious hazard to agricultural land due to growing industrialization, which has a negative effect on wheat crop yields. To address this issue, using seaweed extract and Azospirillum brasilense has emerged as an effective strategy for improving yield under stress conditions. However, the combined application of A. brasilense and seaweed extract in wheat crops under As toxicity has not been fully explored. The effectiveness of combining A. brasilense and seaweed extract in reducing As toxicity in wheat production was examined in this study through a 2-year pot experiment with nine treatments. These treatments included a control with no additives and two As concentrations (50 and 70 µM). At 50 and 70 µM, As was tested alone, with seaweed extract, with A. brasilense, and both. Significant results were achieved in reducing As toxicity in wheat crops. Arsenic at 70 µM proved more harmful than at 50 µM. The application of A. brasilense and seaweed extract was more effective in improving crop growth rates, chlorophyll levels, and stomatal conductance. The combined application notably decreased As concentration in wheat plants. It was concluded that applying A. brasilense and seaweed extract not only improves wheat growth but can also improve soil parameters under As toxicity conditions by increasing organic matter contents, boosting nutrient availability, and increasing the production of antioxidant enzymes.

Research progress on the regulatory mechanism of cell senescence in arsenic toxicity: a systematic review.

As an element with metalloid properties, arsenic is pervasively present in the environment and is recognized as a potent carcinogen. Consequently, the issue of human arsenic exposure has become a significant concern within the global public health sector. Numerous studies have indicated that arsenic induces cellular senescence through various mechanisms, including triggering epigenetic alterations, inducing the senescence-associated secretory phenotype (SASP), promoting telomere shortening, and causing mitochondrial dysfunction. This article collates and summarizes the latest research advancements on the involvement of cellular senescence in arsenic toxicity and explores the mechanisms of arsenic-induced toxicity. This study aims to provide new perspectives and directions for future research on arsenic toxicity and the development of prevention and treatment strategies.

Application of CuNPs and AMF alleviates arsenic stress by encompassing reduced arsenic uptake through metabolomics and ionomics alterations in Elymus sibiricus.

Recent studies have exhibited a very promising role of copper nanoparticles (CuNPs) in mitigation of abiotic stresses in plants. Arbuscular mycorrhizae fungi (AMF) assisted plants to trigger their defense mechanism against abiotic stresses. Arsenic (As) is a non-essential and injurious heavy-metal contaminant. Current research work was designed to elucidate role of CuNPs (100, 200 and 300 mM) and a commercial inoculum of Glomus species (Clonex® Root Maximizer) either alone or in combination (CuNPs + Clonex) on physiology, growth, and stress alleviation mechanisms of E. sibiricus growing in As spiked soils (0, 50, and 100 mg Kg- 1 soil). Arsenic induced oxidative stress, enhanced biosynthesis of hydrogen peroxide, lipid peroxidation and methylglyoxal (MG) in E. sibiricus. Moreover, As-phytotoxicity reduced photosynthetic activities and growth of plants. Results showed that individual and combined treatments, CuNPs (100 mM) as well as soil inoculation of AMF significantly enhanced root growth and shoot growth by declining As content in root tissues and shoot tissues in As polluted soils. E. sibiricus plants treated with CuNPs (100 mM) and/or AMF alleviated As induced phytotoxicity through upregulating the activity of antioxidative enzymes such as catalase (CAT) and superoxide dismutase (SOD) besides the biosynthesis of non-enzymatic antioxidants including phytochelatin (PC) and glutathione (GSH). In brief, supplementation of CuNPs (100 mM) alone or in combination with AMF reduced As uptake and alleviated the As-phytotoxicity in E. sibiricus by inducing stress tolerance mechanism resulting in the improvement of the plant growth parameters.

Synchrotron tomography of magnetoprimed soybean plant root system architecture grown in arsenic-polluted soil.

The present study evaluated the repercussions of magnetopriming on the root system architecture of soybean plants subjected to arsenic toxicity using synchrotron radiation source based micro-computed tomography (SR-µCT). This will be used evey where as abbreviation for the technique for three-dimensional imaging. Seeds of soybean were exposed to the static magnetic field (SMF) of strength (200 mT) for 1h prior to sowing. Magnetoprimed and non-primed seeds were grown for 1 month in a soil-sand mixture containing four different levels of sodium arsenate (0, 5, 10, and 50 mg As kg-1 soil). The results showed that arsenic adversely affects the root growth in non-primed plants by reducing their root length, root biomass, root hair, size and number of root nodules, where the damaging effect of As was observed maximum at higher concentrations (10 and 50 mg As kg-1 soil). However, a significant improvement in root morphology was detected in magnetoprimed plants where SMF pretreatment enhanced the root length, root biomass, pore diameter of cortical cells, root hair formation, lateral roots branching, and size of root nodules and girth of primary roots. Qualitative analysis of x-ray micro-CT images showed that arsenic toxicity damaged the epidermal and cortical layers of the root as well as reduced the pore diameter of the cortical cells. However, the diameter of cortical cells pores in magnetoprimed plants was observed higher as compared to plants emerged from non-primed seeds at all level of As toxicity. Thus, the study suggested that magnetopriming has the potential to attenuate the toxic effect of As and could be employed as a pre-sowing treatment to reduce the phytotoxic effects of metal ions in plants by improving root architecture and root tolerance index. This study is the very first exploration of the potential benefits of magnetopriming in mitigating the toxicity of metals (As) in plant roots utilizing the micro-CT technique.

Arsenic Induced Oxidative Neural-Damages in Rat are Mitigated by Tea-Leave Extract via MMPs and AChE Inactivation, Shown by Molecular Docking and in Vitro Studies with Pure Theaflavin and AChE.

BACKGROUND: Chronic arsenic-exposure causes neuromuscular disorders and other health anomalies. Damage to DNA and cytoskeletal/extracellular matrix is brought on by reactive-oxygen-species (ROS)-induced intrinsic antioxidant depletion (thiols/urate). Therapeutic chelating-agents have multiple side-effects. OBJECTIVES: The protection of (Camellia sinensis) tea-extract and role of uric-acid (UA) or allopurinol (urate-depletor) on arsenic-toxicity were verified in rat model. METHODS: Camellia sinensis (CS dry-leaves), UA or allopurinol was supplemented to arsenic-intoxicated rats for 4-weeks. Purified theaflavins and their galloyl-ester were tested in-vitro on pure AChE (acetylcholinesterase) and their PDB/PubChem 3-D structures were utilized for in-silico binding studies. The primary chemical components were evaluated from CS-extracts. Biochemical analysis, PAGE-zymogram, DNA-stability comet analysis, HE-staining was performed in arsenic-exposed rat brain tissues. RESULTS: Animals exposed to arsenic showed symptoms of erratic locomotion, decreased intrinsic antioxidants (catalase/SOD1/uric acid), increased AChE, and malondialdehyde. Cerebellar and cerebrum tissue damages were shown with increased levels of matrix-metalloprotease (MMP2/9) and DNA damage (comets). Allopurinol- supplemented group demonstrated somewhat similar biochemical responses. In the CS-group brain tissues especially cerebellum is considerably protected which is evident from endogenous antioxidant and DNA and cytoskeleton protection with concomitant inactivation of MMPs and AChE. Present study indicates theaflavin-digallate (TFDG) demonstrated the highest inhibition of purified AChE (IC50 = 2.19 µg/ml with the lowest binding free-energy; -369.87 kcal/mol) followed by TFMG (IC50 = 3.86 µg/ml, -347.06 kcal/mol) suggesting their possible restoring effects of cholinergic response. CONCLUSIONS: Favorable responses in UA-group and adverse outcome in allo-group justify the neuro-protective effects of UA as an endogenous antioxidant. Role of flavon-gallate in neuro protection mechanism may be further studied.

Protective effects of baicalin against phenylarsine oxide-induced cytotoxicity in human skin keratinocytes.

Phenylarsine oxide (PAO) is a known environmental pollutant and skin keratinocytes are most seriously affected. Baicalin (BCN) was reported to have antioxidant and anti-inflammatory effects, but its protective effect against PAO toxicity is unknown. This study aimed at exploring whether baicalin can reverse the toxicity of human epidermal keratinocytes that are subjected to PAO exposure and underlying mechanisms. In silico analysis from a publicly accessible HaCaT cell transcriptome dataset exposed to chronic Arsenic showed significant differential expression of several genes, including the genes related to DNA replication. Later, we performed in vitro experiments, in which HaCaT cells were exposed to PAO (500 nM) in the existence of BCN (10-50 µM). Treatment of PAO alone induces the JNK, p38 and caspase-3 activation, which were engaged in the apoptosis induction, while the activity of AKT was significantly inhibited, which was engaged in the suppression of apoptosis. PAO suppressed SIRT3 expression and induced intracellular reactive oxygen species (ROS), causing a marked reduce in cell viability and apoptosis. However, BCN treatment restored the PAO-induced suppression of SIRT3 and AKT expression, reduced intracellular ROS generation, and markedly suppressed both caspase-3 activation and apoptosis induction. However, the protective effect of BCN was significantly attenuated after pretreatment with nicotinamide, an inhibitor of SIRT3. These findings indicate that BCN protects against cell death induced by PAO via inhibiting excessive intracellular ROS generation via restoring SIRT3 activity and reactivating downstream AKT pathway. In this study, we firstly shown that BCN is an efficient drug to prevent PAO-induced skin cytotoxicity, and these findings need to be confirmed by in vivo and clinical investigations.

From genes to ecosystems: Decoding plant tolerance mechanisms to arsenic stress.

Arsenic (As), a metalloid of considerable toxicity, has become increasingly bioavailable through anthropogenic activities, raising As contamination levels in groundwater and agricultural soils worldwide. This bioavailability has profound implications for plant biology and farming systems. As can detrimentally affect crop yield and pose risks of bioaccumulation and subsequent entry into the food chain. Upon exposure to As, plants initiate a multifaceted molecular response involving crucial signaling pathways, such as those mediated by calcium, mitogen-activated protein kinases, and various phytohormones (e.g., auxin, methyl jasmonate, cytokinin). These pathways, in turn, activate enzymes within the antioxidant system, which combat the reactive oxygen/nitrogen species (ROS and RNS) generated by As-induced stress. Plants exhibit a sophisticated genomic response to As, involving the upregulation of genes associated with uptake, chelation, and sequestration. Specific gene families, such as those coding for aquaglyceroporins and ABC transporters, are key in mediating As uptake and translocation within plant tissues. Moreover, we explore the gene regulatory networks that orchestrate the synthesis of phytochelatins and metallothioneins, which are crucial for As chelation and detoxification. Transcription factors, particularly those belonging to the MYB, NAC, and WRKY families, emerge as central regulators in activating As-responsive genes. On a post-translational level, we examine how ubiquitination pathways modulate the stability and function of proteins involved in As metabolism. By integrating omics findings, this review provides a comprehensive overview of the complex genomic landscape that defines plant responses to As. Knowledge gained from these genomic and epigenetic insights is pivotal for developing biotechnological strategies to enhance crop As tolerance.

Molecular level toxicity effects of As(V) on Folsomia candida: Integrated transcriptomics and metabolomics analyses.

Arsenic (As) is a widespread metalloid with well-known toxicity. To date, numerous studies have focused on individual level toxicity (e.g., growth and reproduction) of As to typical invertebrate springtails in soils, however, the molecular level toxicity and mechanism was poorly understood. Here, an integrated transcriptomics and metabolomics approach was used to reveal responses of Folsomia candida exposed to As(V) of 10 and 60 mg kg-1 at which the individual level endpoints were influenced. Transcriptomics identified 5349 and 4020 differentially expressed genes (DEGs) in low and high concentration groups, respectively, and the most DEGs were down-regulated. Enrichment analysis showed that low and high concentrations of As(V) significantly inhibited chromatin/chromosome-related biological processes (chromatin/chromosome organization, nucleosome assembly and organization, etc.) in springtails. At high concentration treatment, structural constituent of cuticle, chitin metabolic process and peptidase activity (serine-type peptidase activity, endopeptidase activity, etc.) were inhibited or disturbed. Moreover, the apoptosis pathway was significantly induced. Metabolomics analysis identified 271 differential changed metabolites (DCMs) in springtails exposed to high concentration of As. Steroid hormone biosynthesis was the most significantly affected pathway. Several DCMs that related to chitin metabolism could further support above transcriptomic results. These findings further extended the knowledge of As toxic mechanisms to soil fauna and offer important information for the environmental risk assessment.

Arsenic in the Food Chain in Pakistan: Assessing Risks to Human Health and Ensuring Food Security Through Comprehensive Contamination Mitigation Strategies.

Arsenic is a natural element found in the earth's crust and is extensively present in various environmental components. Anthropogenic activities and a few natural events have generated contaminants that have led to massive environmental pollution, one form of which is arsenic contamination. Arsenic enters the human food chain via contaminated crops, water, seafood, and dairy products. In Pakistan, the increasing concentration of arsenic in the water is causing major health problems. Due to the serious health risks posed by arsenic, it is crucial to design and implement strategies for reducing and preventing the bioaccumulation of arsenic and its entry into the human food chain. There is a need for an institutional framework for arsenic mitigation, accountability, and systemic checks and balances. Targeted short- and long-term policies are required for effective and sustainable management.

Complexation and immobilization of arsenic in maize using green synthesized silicon nanoparticles (SiNPs).

Arsenic (As) is a heavy metal that is toxic to both plants and animals. Silicon nanoparticles (SiNPs) can alleviate the detrimental effects of heavy metals on plants, but the underlying mechanisms remain unclear. The study aims to synthesize SiNPs and reveal how they promote plant health in Arsenic-polluted soil. 0 and 100% v/v SiNPs were applied to soil, and Arsenic 0 and 3.2 g/ml were applied twice. Maize growth was monitored until maturity. Small, irregular, spherical, smooth, and non-agglomerated SiNPs with a peak absorbance of 400 nm were synthesized from Pycreus polystachyos. The SiNPs (100%) assisted in the development of a deep, prolific root structure that aided hydraulic conductance and gave mechanical support to the maize plant under As stress. Thus, there was a 40-50% increase in growth, tripled yield weights, and accelerated flowering, fruiting, and senescence. SiNPs caused immobilization (As(III)=SiNPs) of As in the soil and induced root exudates Phytochelatins (PCs) (desGly-PC2 and Oxidized Glutathione) which may lead to formation of SiNPs=As(III)-PCs complexes and sequestration of As in the plant biomass. Moreover, SiNPs may alleviate Arsenic stress by serving as co-enzymes that activate the antioxidant-defensive mechanisms of the shoot and root. Thus, above 70%, most reactive ROS (OH) were scavenged, which was evident in the reduced MDA content that strengthened the plasma membrane to support selective ion absorption of SiNPs in place of Arsenic. We conclude that SiNPs can alleviate As stress through sequestration with PCs, improve root hydraulic conductance, antioxidant activity, and membrane stability in maize plants, and could be a potential tool to promote heavy metal stress resilience in the field.

Nutrient and mycoremediation of a global menace 'arsenic': exploring the prospects of phosphorus and Serendipita indica-based mitigation strategies in rice and other crops.

KEY MESSAGE: Serendipita indica induced metabolic reprogramming in colonized plants complements phosphorus-management in improving their tolerance to arsenic stress on multifaceted biological fronts. Restoration of the anthropic damage done to our environment is inextricably linked to devising strategies that are not only economically sound but are self-renewing and ecologically conscious. The dilemma of heavy metal (HM) dietary ingestion, especially arsenic (As), faced by humans and animals alike, necessitates the exploitation of such technologies and the cultivation of healthy and abundant crops. The remarkable symbiotic alliance between plants and 'mycorrhizas' has evolved across eons, benefiting growth/yield aspects as well as imparting abiotic/biotic stress tolerance. The intricate interdependence of Serendipita indica (S. indica) and rice plant reportedly reduce As accumulation, accentuating the interest of microbiologists, agriculturists, and ecotoxicological scientists apropos of the remediation mechanisms of As in the soil-AMF-rice system. Nutrient management, particularly of phosphorus (P), is also praised for mitigating As phytotoxicity by deterring the uptake of As molecules due to the rhizospheric cationic competition. Taking into consideration the reasonable prospects of success in minimizing As acquisition by rice plants, this review focuses on the physiological, metabolic, and transcriptional alterations underlying S. indica symbiosis, recuperation of As stress together with nutritional management of P by gathering case studies and presenting successful paradigms. Weaving together a volume of literature, we assess the chemical forms of As and related transport pathways, discuss As-P-rice interaction and the significance of fungi in As toxicity mitigation, predominantly the role of mycorrhiza, as well as survey of the multifaceted impacts of S. indica on plants. A potential strategy for simultaneous S. indica + P administration in paddy fields is proposed, followed by future research orientation to expand theoretic comprehension and encourage field-based implementation.

Strigolactone and nitric oxide collaborate synergistically to boost tomato seedling resilience to arsenic toxicity via modulating physiology and antioxidant system.

Arsenic (As) poses a significant environmental threat as a metalloid toxin, adversely affecting the health of both plants and animals. Strigolactones (SL) and nitric oxide (NO) are known to play crucial roles in plant physiology. Therefore, the present experiment was designed to investigate the potential cumulative role of SL (GR24-0.20 µM) and NO (100 µM) in mitigating the adverse effect of AsV (53 µM) by modulating physiological mechanisms in two genotypes of tomato (Riogrand and Super Strain 8). A sample randomized design with four replicates was used to arrange the experimental pots in the growth chamber. 45-d old both tomato cultivars under AsV toxicity exhibited reduced morphological attributes (root and shoot length, root and shoot fresh weight, and root and shoot dry weight) and physiological and biochemical characteristics [chlorophyll (Chl) a and b content, activity of δ-aminolevulinic acid dehydratase activity (an enzyme responsible for Chl biosynthesis), and carbonic anhydrase activity (an enzyme responsible for photosynthesis), and enhanced Chl degradation, overproduction of reactive oxygen species (ROS) and lipid peroxidation due to enhanced malondialdehyde (MDA) content. However, the combined application of SL and NO was more effective in enhancing the tolerance of both varieties to AsV toxicity compared to individual application. The combined application of SL and NO improved growth parameters, biosynthesis of Chls, NO and proline. However, the combined application significantly suppressed cellular damage by inhibiting MDA and overproduction of ROS in leaves and roots, as confirmed by the fluorescent microscopy study and markedly upregulated the antioxidant enzymes (catalase, peroxidase, superoxide dismutase, ascorbate dismutase and glutathione reductase) activity. This study provides clear evidence that the combined application of SL and NO supplementation significantly improves the resilience of tomato seedlings against AsV toxicity. The synergistic effect of SL and NO was confirmed by the application of cPTIO (an NO scavenger) with SL and NO. However, further molecular studies could be imperative to conclusively validate the simultaneous role of SL and NO in enhancing plant tolerance to abiotic stress.

Hesperidin and chlorogenic acid mitigate arsenic-induced oxidative stress via redox regulation, photosystems-related gene expression, and antioxidant efficiency in the chloroplasts of Zea mays.

The ubiquitous metalloid arsenic (As), which is not essential, can be found extensively in the soil and subterranean water of numerous nations, raising substantial apprehensions due to its impact on both agricultural productivity and sustainability. Plants exposed to As often display morphological, physiological, and growth-related abnormalities, collectively leading to reduced productivity. Polyphenols, operating as secondary messengers within the intricate signaling networks of plants, assume integral functions in the acquisition of resistance to diverse environmental stressors, including but not limited to drought, salinity, and exposure to heavy metals. The pivotal roles played by polyphenols in these adaptive processes underscore their profound significance in plant biology. This study aims to elucidate the impact of hesperidin (HP) and chlorogenic acid (CA), recognized as potent bioactive compounds, on maize plants exposed to As. To achieve this objective, the study examined the physiological and biochemical impacts, including growth parameters, photosynthesis, and chloroplastic antioxidants, of HP (100 µM) and CA (50 µM) on Zea mays plants exposed to arsenate stress (AsV, 100 µM - Na2HAsO4⋅7H2O). As toxicity led to reductions in fresh weight (FW) and dry weight (DW) by 33% and 26%, respectively. However, the application of As+HP and As + CA increased FW by 22% and 40% and DW by 14% and 17%, respectively, alleviating the effects of As stress. As toxicity resulted in the up-regulation of PSII genes (psbA and psbD) and PSI genes (psaA and psaB), indicating a potential response to the re-formation of degraded regions, likely driven by the heightened demand for photosynthesis. Exogenous HP or/and CA treatments effectively counteracted the adverse effects of As toxicity on the photochemical quantum efficiency of PSII (Fv/Fm). H2O2 content showed a 23% increase under As stress, and this increase was evident in guard cells when examining confocal microscopy images. In the presence of As toxicity, the chloroplastic antioxidant capacity can exhibit varying trends, with either a decrease or increase observed. After the application of CA and/or HP, a significant increase was observed in the activity of GR, APX, GST, and GPX enzymes, resulting in decreased levels of H2O2 and MDA. Additionally, the enhanced functions of MDHAR and DHAR have modulated the redox status of ascorbic acid (AsA) and glutathione (GSH). The HP or CA-mediated elevated levels of AsA and GSH content further contributed to the preservation of redox homeostasis in chloroplasts facing stress induced by As. In summary, the inclusion of HP and CA in the growth medium sustained plant performance in the presence of As toxicity by regulating physiological and biochemical characteristics, chloroplastic antioxidant enzymes, the AsA-GSH cycle and photosynthesis processes, thereby demonstrating their significant potential to confer resistance to maize through the mitigation of As-induced oxidative damage and the safeguarding of photosynthetic mechanisms.

Arsenic toxicity: sources, pathophysiology and mechanism.

Background: Arsenic is a naturally occurring element that poses a significant threat to human health due to its widespread presence in the environment, affecting millions worldwide. Sources of arsenic exposure are diverse, stemming from mining activities, manufacturing processes, and natural geological formations. Arsenic manifests in both organic and inorganic forms, with trivalent meta-arsenite (As3+) and pentavalent arsenate (As5+) being the most common inorganic forms. The trivalent state, in particular, holds toxicological significance due to its potent interactions with sulfur-containing proteins. Objective: The primary objective of this review is to consolidate current knowledge on arsenic toxicity, addressing its sources, chemical forms, and the diverse pathways through which it affects human health. It also focuses on the impact of arsenic toxicity on various organs and systems, as well as potential molecular and cellular mechanisms involved in arsenic-induced pathogenesis. Methods: A systematic literature review was conducted, encompassing studies from diverse fields such as environmental science, toxicology, and epidemiology. Key databases like PubMed, Scopus, Google Scholar, and Science Direct were searched using predetermined criteria to select relevant articles, with a focus on recent research and comprehensive reviews to unravel the toxicological manifestations of arsenic, employing various animal models to discern the underlying mechanisms of arsenic toxicity. Results: The review outlines the multifaceted aspects of arsenic toxicity, including its association with chronic diseases such as cancer, cardiovascular disorders, and neurotoxicity. The emphasis is placed on elucidating the role of oxidative stress, genotoxicity, and epigenetic modifications in arsenic-induced cellular damage. Additionally, the impact of arsenic on vulnerable populations and potential interventions are discussed. Conclusions: Arsenic toxicity represents a complex and pervasive public health issue with far-reaching implications. Understanding the diverse pathways through which arsenic exerts its toxic effects is crucial to developing effective mitigation strategies and interventions. Further research is needed to fill gaps in our understanding of arsenic toxicity and to inform public health policies aimed at minimising exposure.Arsenic toxicity is a crucial public health problem influencing millions of people around the world. The possible sources of arsenic toxicity includes mining, manufacturing processes and natural geological sources. Arsenic exists in organic as well as in inorganic forms. Trivalent meta-arsenite (As3+) and pentavalent arsenate (As5+) are two most common inorganic forms of arsenic. Trivalent oxidation state is toxicologically more potent due to its potential to interact with sulfur containing proteins. Humans are exposed to arsenic in many ways such as environment and consumption of arsenic containing foods. Drinking of arsenic-contaminated groundwater is an unavoidable source of poisoning, especially in India, Bangladesh, China, and some Central and South American countries. Plenty of research has been carried out on toxicological manifestation of arsenic in different animal models to identify the actual mechanism of aresenic toxicity. Therefore, we have made an effort to summarize the toxicology of arsenic, its pathophysiological impacts on various organs and its molecular mechanism of action.

Arsenic Contamination of Groundwater Is Determined by Complex Interactions between Various Chemical and Biological Processes.

At a great many locations worldwide, the safety of drinking water is not assured due to pollution with arsenic. Arsenic toxicity is a matter of both systems chemistry and systems biology: it is determined by complex and intertwined networks of chemical reactions in the inanimate environment, in microbes in that environment, and in the human body. We here review what is known about these networks and their interconnections. We then discuss how consideration of the systems aspects of arsenic levels in groundwater may open up new avenues towards the realization of safer drinking water. Along such avenues, both geochemical and microbiological conditions can optimize groundwater microbial ecology vis-à-vis reduced arsenic toxicity.

Association Between Arsenic Toxicity, AS3MT Gene Polymorphism and Onset of Type 2 Diabetes.

Arsenic (As) exposure in drinking water has become a serious public health issue. AS3MT gene is involved in the metabolism of arsenic, so a single nucleotide polymorphism in this gene may lead to the development of type 2 diabetes in arsenic-exposed areas. This study aimed to evaluate the association of the AS3MT gene with the development of type 2 diabetes in highly arsenic-exposed areas of Punjab, Pakistan. Total 200 samples equal in number from high arsenic exposed-areas of Lahore (Nishtar) and Kasur (Mustafa Abad) were collected. rs11191439 was utilized as an influential variable to evaluate the association between arsenic metabolism and diabetes status to find a single nucleotide polymorphism in the AS3MT gene. We observed the arsenic level in drinking water of the arsenic-exposed selected areas 115.54 ± 1.23 µg/L and 96.88 ± 0.48 µg/L, respectively. The As level in the urine of diabetics (98.54 ± 2.63 µg/L and 56.38 ± 12.66 µg/L) was higher as compared to non-diabetics (77.58 ± 1.8 µg/L and 46.9 ± 8.95 µg/L) of both affected areas, respectively. Correspondingly, the As level in the blood of diabetics (6.48 ± 0.08 µg/L and 5.49 ± 1.43 µg/L) and non-diabetics (6.22 ± 0.12 µg/L and 5.26 ± 0.24 µg/L) in the affected areas. Genotyping showed significant differences in the frequencies of alleles among cases and controls. Nevertheless, notable disparities in genotype distribution were observed in SNPs rs11191439 (T/C) (P < 0.05) and when comparing T2D patients and non-diabetic control subjects. The AS3MT gene and clinical parameters show a significant association with the affected people with diabetes living in arsenic-exposed areas.

A Comprehensive Review on Molecular Mechanism Involved in Arsenic Trioxide Mediated Cerebral Neurodegenerative and Infectious Diseases.

Arsenic is an environmental toxicant and its toxicity is a global health problem affecting millions of people. Arsenic exposure occurs from natural geological sources leaching into aquifers, contaminating drinking water and may also occur from mining and other industrial processes. Both cancerous, noncancerous and immunological complications are possible after arsenic exposure. The many other target organs like lungs, thymus, spleen, liver, heart, kidney, and brain. Arsenic-mediated neuro, as well as immunotoxicity, is the main concern of this review. Long-term arsenic exposure can lead to various neurological dysfunctions, which may cause neurobehavioral defects and biochemical impairment in the brain, this might negatively affect one's quality of life in later stages. Arsenic also alters the levels of various neurotransmitters such as serotonin, dopamine and norepinephrine in the brain which produces neurotoxic effects and immunological deficiency. So, it is crucial to understand the neurotoxic mechanism of arsenic trioxide-mediated cerebro neurodegenerative and immunerelated alterations. One of the major mechanisms by which it exerts its toxic effect is through an impairment of cellular respiration by inhibition of various mitochondrial enzymes, and the uncoupling of oxidative phosphorylation. This review focuses on the various toxic mechanisms responsible for arsenic-mediated neurobehavioral and immune-related changes. Therefore, this review provides a critical analysis of mitochondrial dysfunctions, oxidative stress, glutamate excitatory, inflammatory and apoptosis-related mechanistic aspects in arsenic-mediated immunotoxicity, neurotoxicity, and neurodegenerative changes.

Targeting the 'DNA methylation mark': Analysis of early epigenetic-alterations in children chronically exposed to arsenic.

Chronic exposure to arsenic causes adverse health effects in children. Aberrant epigenetic modifications including altered DNA methylation pattern are one of the major steps towards malignant transformation of cells. Our group has previously identified significant alteration in DNA methylation mark in arsenic exposed adults, affecting major biological pathways. Till date, no information is available exploring the altered DNA methylation mark in telomere regulation and altered mitochondrial functionality in association with DNA damage in arsenic-exposed children. Our study aims in identifying signature epigenetic pattern associated with telomere lengthening, mitochondrial functionality and DNA damage repair in children with special emphasis on DNA methylation. Biological samples (blood and urine) and drinking water were collected from the children aged between 5 and 16 years of arsenic exposed areas (N = 52) of Murshidabad district and unexposed areas (N = 50) of East Midnapur districts, West Bengal, India. Methylation-specific PCR was performed to analyse subtelomeric methylation status and promoter methylation status of target genes. Results revealed altered DNA methylation profile in the exposed children compared to unexposed. Promoter hypermethylation was observed in MLH1 and MSH2 (p < 0.05 and p < 0.001) indicating inefficiency in DNA damage repair. Hypomethylation in mitochondrial D-loop (p < 0.05) and TFAM promoter region (p < 0.05) along with increased mitochondrial DNA copy number among exposed children was also observed. Significant increase in telomere length and region specific subtelomeric hypermethylation (XpYp, p < 0.05) was found. Analysis of S-Adenosyl Methionine (SAM) and 8-oxoDG level revealed significant depletion of SAM (p < 0.001) and elevated oxidative DNA damage (p < 0.001) respectively in arsenic toxicity. Our study identified key methylation patterns in arsenic-exposed children which may act as an early predictive biomarker in the near future. Further in-depth studies involving large sample size and transcriptomic analysis are required for understanding the mechanistic details.

The Influence of Arsenic Co-Exposure in a Model of Alcohol-Induced Neurodegeneration in C57BL/6J Mice.

Both excessive alcohol consumption and exposure to high levels of arsenic can lead to neurodegeneration, especially in the hippocampus. Co-exposure to arsenic and alcohol can occur because an individual with an Alcohol Use Disorder (AUD) is exposed to arsenic in their drinking water or food or because of arsenic found directly in alcoholic beverages. This study aims to determine if co-exposure to alcohol and arsenic leads to worse outcomes in neurodegeneration and associated mechanisms that could lead to cell death. To study this, mice were exposed to a 10-day gavage model of alcohol-induced neurodegeneration with varying doses of arsenic (0, 0.005, 2.5, or 10 mg/kg). The following were examined after the last dose of ethanol: (1) microglia activation assessed via immunohistochemical detection of Iba-1, (2) reactive oxygen and nitrogen species (ROS/RNS) using a colorimetric assay, (3) neurodegeneration using Fluoro-Jade® C staining (FJC), and 4) arsenic absorption using ICP-MS. After exposure, there was an additive effect of the highest dose of arsenic (10 mg/kg) in the dentate gyrus of alcohol-induced FJC+ cells. This additional cell loss may have been due to the observed increase in microglial reactivity or increased arsenic absorption following co-exposure to ethanol and arsenic. The data also showed that arsenic caused an increase in CYP2E1 expression and ROS/RNS production in the hippocampus which could have independently contributed to increased neurodegeneration. Altogether, these findings suggest a potential cyclical impact of co-exposure to arsenic and ethanol as ethanol increases arsenic absorption but arsenic also enhances alcohol's deleterious effects in the CNS.