The role of nuclear factor erythroid 2-related factor 2 (NRF2) in arsenic toxicity.

Arsenic, a naturally occurring toxic element, manifests in various chemical forms and is widespread in the environment. Exposure to arsenic is a well-established risk factor for an elevated incidence of various cancers and chronic diseases. The crux of arsenic-mediated toxicity lies in its ability to induce oxidative stress, characterized by an unsettling imbalance between oxidants and antioxidants, accompanied by the rampant generation of reactive oxygen species and free radicals. In response to this oxidative turmoil, cells deploy their defense mechanisms, prominently featuring the redox-sensitive transcription factor known as nuclear factor erythroid 2-related factor 2 (NRF2). NRF2 stands as a primary guardian against the oxidative harm wrought by arsenic. When oxidative stress activates NRF2, it orchestrates a symphony of downstream antioxidant genes, leading to the activation of pivotal antioxidant enzymes like glutathione-S-transferase, heme oxygenase-1, and NAD(P)H: quinone oxidoreductase 1. This comprehensive review embarks on the intricate and diverse ways by which various arsenicals influence the NRF2 antioxidant pathway and its downstream targets, shedding light on their roles in defending against arsenic exposure toxic effects. It offers valuable insights into targeting NRF2 as a strategy for safeguarding against or treating the harmful and carcinogenic consequences of arsenic exposure.

Roles of serum uric acid on the association between arsenic exposure and incident metabolic syndrome in an older Chinese population.

Growing evidences showed that heavy metals exposure may be associated with metabolic diseases. Nevertheless, the mechanism underlying arsenic (As) exposure and metabolic syndrome (MetS) risk has not been fully elucidated. So we aimed to prospectively investigate the role of serum uric acid (SUA) on the association between blood As exposure and incident MetS. A sample of 1045 older participants in a community in China was analyzed. We determined As at baseline and SUA concentration at follow-up in the Yiwu Elderly Cohort. MetS events were defined according to the criteria of the International Diabetes Federation (IDF). Generalized linear model with log-binominal regression model was applied to estimate the association of As with incident MetS. To investigate the role of SUA in the association between As and MetS, a mediation analysis was conducted. In the fully adjusted log-binominal model, per interquartile range increment of As, the risk of MetS increased 1.25-fold. Compared with the lowest quartile of As, the adjusted relative risk (RR) of MetS in the highest quartile was 1.42 (95% confidence interval, CI: 1.03, 2.00). Additionally, blood As was positively associated with SUA, while SUA had significant association with MetS risk. Further mediation analysis demonstrated that the association of As and MetS risk was mediated by SUA, with the proportion of 15.7%. Our study found higher As was remarkably associated with the elevated risk of MetS in the Chinese older adults population. Mediation analysis indicated that SUA might be a mediator in the association between As exposure and MetS.

Arsenic exposure and oxidative damage to lipid, DNA, and protein among general Chinese adults: A repeated-measures cross-sectional and longitudinal study.

Arsenic-related oxidative stress and resultant diseases have attracted global concern, while longitudinal studies are scarce. To assess the relationship between arsenic exposure and systemic oxidative damage, we performed two repeated measures among 5236 observations (4067 participants) in the Wuhan-Zhuhai cohort at the baseline and follow-up after 3 years. Urinary total arsenic, biomarkers of DNA oxidative damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)), lipid peroxidation (8-isoprostaglandin F2alpha (8-isoPGF2α)), and protein oxidative damage (protein carbonyls (PCO)) were detected for all observations. Here we used linear mixed models to estimate the cross-sectional and longitudinal associations between arsenic exposure and oxidative damage. Exposure-response curves were constructed by utilizing the generalized additive mixed models with thin plate regressions. After adjusting for potential confounders, arsenic level was significantly and positively related to the levels of global oxidative damage and their annual increased rates in dose-response manners. In cross-sectional analyses, each 1% increase in arsenic level was associated with a 0.406% (95% confidence interval (CI): 0.379% to 0.433%), 0.360% (0.301% to 0.420%), and 0.079% (0.055% to 0.103%) increase in 8-isoPGF2α, 8-OHdG, and PCO, respectively. More importantly, arsenic was further found to be associated with increased annual change rates of 8-isoPGF2α (ß: 0.147; 95% CI: 0.130 to 0.164), 8-OHdG (0.155; 0.118 to 0.192), and PCO (0.050; 0.035 to 0.064) in the longitudinal analyses. Our study suggested that arsenic exposure was not only positively related with global oxidative damage to lipid, DNA, and protein in cross-sectional analyses, but also associated with annual increased rates of these biomarkers in dose-dependent manners.

Parental arsenic exposure and tissue-specific DNA methylation in Bangladeshi infants with spina bifida.

An emerging hypothesis linking arsenic toxicity involves altered epigenetic mechanisms, such as DNA methylation. In this study, we examined the relationship between parents' arsenic exposure and DNA methylation in tissues obtained from 28 infants with spina bifida from Bangladesh. We analyzed arsenic in parents' toenails using inductively coupled plasma mass spectrometry (ICP-MS). DNA methylation was measured in infants' dural tissue, buccal swabs, and whole blood using the Illumina Infinium MethylationEPIC BeadChip. We performed epigenome-wide association analyses (EWAS) and tested differentially methylated regions (DMRs). In EWAS, DNA methylation at cg24039697 in dural tissue was positively associated (ß = 0.59, p = 7.6 × 10-9) with father's toenail arsenic concentrations, adjusting for covariates. We did not identify any CpG sites related to father's arsenic exposure in the other tissues, or any CpG sites related to mother's arsenic exposure. Gene ontology analysis identified many biological pathways of interest, including the Wnt signaling pathways. We identified several DMRs across the tissues related to arsenic exposure that included probes mapping to genes that have previously been identified in studies of neural tube defects. This study emphasizes the potential impact of arsenic exposure in fathers, often understudied in epidemiological studies, on DNA methylation in a unique neurological tissue specific to spina bifida.

New insights into zinc alleviating renal toxicity of arsenic-exposed carp (Cyprinus carpio) through YAP-TFR/ROS signaling pathway.

Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people mining and smelting arsenic compounds. In addition, arsenic compounds' widespread use and production of arsenic-containing pesticides, arsenic-rich water used to irrigate farms, or high arsenic levels in foods caused by coal burning are all sources of arsenic contamination. Arsenic contamination poses a significant threat to global public health. It is reported that exposure to arsenic can induce severe renal injury. However, the underlying mechanism needs to be clarified. In this study, the arsenic exposure model in vivo and in vitro was used to explore the mechanism of arsenic-induced renal injury, especially the role of ferroptosis and its regulatory mechanism, and then to evaluate its anti-pollution effect by supplementing zinc. The results showed that arsenic significantly induced ferroptosis, characterized by up-regulating the expression of YAP and TFR in kidney and CIK cells and then increasing the levels of Fe2+ and ROS, lipid peroxidation, and iron metabolism. Microscopic observation revealed the shrinkage of mitochondria and the increase in membrane density. In addition, molecular docking and inhibitor experiments further confirmed that arsenic is involved in the process of ferroptosis by activating YAP and TFR. These results clarify the harmful effects of arsenic on carp kidneys and its mechanism and highlight the critical interactions between the YAP-TFR pathway, ROS, and ferroptosis. Importantly, this study found that zinc can reduce ferroptosis caused by the arsenic-activated YAP-TFR pathway by inhibiting YAP activation and lipid peroxidation.

Taurine Reverses Arsenic-Induced Inhibition of Hippocampal Neurogenesis and Depression-Like Behavior in Mice.

Arsenic exposure results in damage to the neurological system. We previously demonstrated the arsenic-induced inhibition of hippocampal neurogenesis and its reversibility after exposure is terminated. The present study aimed to reveal whether arsenic-induced inhibition of hippocampal neurogenesis was ameliorated when taurine was co-administered, and we also investigated depression-like behavioral changes using the forced swim test. Mice were randomly divided into four groups. The first group received distilled water only for 4 months (control group), the second group received 4.0 mg/L As2O3 via drinking water for 4 months (arsenic group), the third group received 4.0 mg/L As2O3 and taurine (150 mg/kg body weight, by gavage, twice a week) for 4 months (arsenic + taurine group), and the fourth group received taurine only by gavage for 4 months (taurine group). The percentage of new mature neurons decreased in the arsenic group compared with the control group (64% ± 0.90% vs. 76% ± 1.9%, p < 0.01); however, this percentage was reversed to control levels in the arsenic + taurine group (76% ± 1.4%, p > 0.05). In the forced swim test, the immobility time during the last 4 min was significantly increased in the arsenic group, but restored to control levels in the arsenic + taurine group. The possible mechanisms of this taurine amelioration of hippocampal damage were further investigated, and included a reduction in oxidative stress as indicated by carbonyl content, inflammation, and aquaporin1, 4, and 8 expressions, as well as an increase in Wnt3a and brain-derived neurotrophic factor expression in western blot analyses.

Evaluation of arsenic induced genotoxicity and its impact on life processes of Daphnia magna.

Heavy metals like arsenic is ubiquitously present in the environment. Geologic and anthropogenic activities are the root cause behind high concentration of arsenic in natural water bodies demanding strict monitoring of water quality prior to human consumption and utilization. In the present study, we have employed Daphnia magna for studying the biological effects of environmentally relevant high concentration of arsenic in water. In acute toxicity study, the LC50 value for 24hr exposure was found to be 2.504 mg/L, which gradually decreased with increase in time period (24hr- 96hr) to 2.011 mg/ L at 96hr. Sub-chronic toxicity was evaluated over 12 days using sub-lethal concentrations (5 %, 10 %, 15 %, and 20 % of the 24-hr LC50). Survivability in Daphnia showed a decreasing trend from 96 % to 91 % with increase in arsenic concentrations from 5 % of LC50 24 hr value to 20 % of LC 50 24hr value respectively. Alongside decreased survivability, there was a significant reduction in body size, with organisms exposed to the highest concentration of arsenic measuring 0.87±0.01 mm compared to 1.51±0.10 mm in the control group. Reproductive potential declined concentration dependently with exposure, with the highest reduction observed at 20 % of LC50 24hr value, where offspring numbers decreased to 7±1 from 23±5 in the control. Heart rate decreased in concentration and time-dependent manners, with the lowest rates observed at the highest arsenic concentration (279±16 bpm after 24hr and 277±27 bpm after 48hr). Comet assay and micronucleus assay conducted after 48 hrs of exposure revealed concentration-dependent genotoxic effects in Daphnia magna. Our results indicate negative impact on physiology and reproduction of Daphnia magna at environmentally existent concentration of arsenic. Also Daphnia magna could serve as a sensitive test system for investigating arsenic contamination in water bodies.

Mitigation of heavy metal toxicity in pigeon pea by plant growth promoting Pseudomonas alcaliphila strain PAS1 isolated from contaminated environment.

The risk of arsenic contamination is rising globally, and it has negative impacts on the physiological processes and growth of plants. Metal removal from contaminated soils can be accomplished affordably and effectively with plant growth promoting rhizobacteria (PGPR)-based microbial management. From this angle, this research evaluated the mitigation of arsenic toxicity using the bacteria isolated from contaminated site, Mettur, Salem district, South India. The newly isolated bacterial strain was screened for plant growth promotion potential and arsenic tolerance such as (100 ppm, 250 ppm, 500 ppm, 800 ppm and 1200 ppm). The metal tolerant rhizobacteria was identified using 16S rRNA gene sequence analysis as Pseudomonas alcaliphila strain PAS1 (GenBank accession number: OQ804624). Pigeon pea (Cajanus cajan) plants were used in pot culture experiments with varying concentrations of arsenic, (5 ppm, 10 ppm and 25 ppm) both with and without bacterial culture, for a period of 45 days. At the concentration of 25 ppm after the application of PAS1 enhanced the plant growth, protein and carbohydrate by 35.69%, 18.31% respectively. Interestingly, P. alcaliphila strain PAS1 significantly reduced the stress-induced elevated levels of proline, flavonoid, phenol and antioxidant enzyme in pigeon pea plants was 40%, 31.11%, 27.80% and 20.12%, respectively. Consequently, PAS1 may significantly reduce the adverse effects that arsenic causes to plant development in acidic soils, improve plant uptake of nutrients, and increase plant production. The findings of this study reveal that P. alcaliphila PAS1 is intrinsic for phytoremediation by reducing arsenic accumulation in the root and shoot.

Hybrid-genome sequence analysis of Enterobacter cloacae FACU and morphological characterization: insights into a highly arsenic-resistant strain.

Many organisms have adapted to survive in environments with high levels of arsenic (As), a naturally occurring metalloid with various oxidation states and a common element in human activities. These organisms employ diverse mechanisms to resist the harmful effects of arsenic compounds. Ten arsenic-resistant bacteria were isolated from contaminated wastewater in this study. The most efficient bacterial isolate able to resist 15,000 ppm Na2HAsO4·7H2O was identified using the 16S rRNA gene and whole genome analysis as Enterobacter cloacae FACU. The arsenic E. cloacae FACU biosorption capability was analyzed. To further unravel the genetic determinants of As stress resistance, the whole genome sequence of E. cloacae FACU was performed. The FACU complete genome sequence consists of one chromosome (5.7 Mb) and two plasmids, pENCL 1 and pENCL 2 (755,058 and 1155666 bp, respectively). 7152 CDSs were identified in the E. cloacae FACU genome. The genome consists of 130 genes for tRNA and 21 for rRNAs. The average G + C content was found to be 54%. Sequencing analysis annotated 58 genes related to resistance to many heavy metals, including 16 genes involved in arsenic efflux transporter and arsenic reduction (five arsRDABC genes) and 42 genes related to lead, zinc, mercury, nickel, silver, copper, cadmium and chromium in FACU. Scanning electron microscopy (SEM) confirmed the difference between the morphological responses of the As-treated FACU compared to the control strain. The study highlights the genes involved in the mechanism of As stress resistance, metabolic pathways, and potential activity of E. cloacae FACU at the genetic level.

Long-term arsenic exposure decreases mice body weight and liver lipid droplets.

Arsenic (As) is a widespread global pollutant, and there is significant controversy surrounding its complex relationship with obesity, primarily focused on short-term exposure. Recognizing the prolonged nature of dietary arsenic exposure, this study involved feeding mice with arsenic-contained food for 14 months. The results showed that mice exposed to arsenic developed a non-alcoholic fatty liver condition, characterized by a light-yellow hue on the liver surface and various pathological alterations in the liver cells, including enlarged nuclei, cellular necrosis, inflammatory infiltration, dysfunctional mitochondria, and endoplasmic reticulum disorganization. There were also disruptions in biochemistry indices, with a significant increase in total cholesterol (TC) level and a decrease in high-density lipoprotein (HDL) level. However, some contradictory observations occurred, such as a significant decrease in body weight, triglyceride (TG) level, and the numbers of lipid droplets. Several genes related to lipid metabolism were tested, and a model was used to explain these discrepancies. Besides, examinations of the colon revealed compromised intestinal barrier function and signs of inflammation. Fecal 16S rRNA sequencing and pseudo-targeted metabolomics revealed disruptions in internal homeostasis, such as modules, nodes, connections, and lipid-related KEGG pathways. Fecal targeted metabolomics analyses of short-chain fatty acids (SCFAs) and bile acids (BAs) demonstrated a significant upregulation in three primary bile acids (CA, CDCA, TCDCA), four secondary bile acids (TUDCA, DCA, LCA, GUDCA), and total SCFAs level. Oxidative stress and inflammation were also evident. Additionally, based on correlation analysis and mediation analysis, it was assumed that changes in the microbiota (e.g., Dubosiella) can impact the liver metabolites (e.g., TGs) through alterations in fecal metabolites (e.g., LPCs). These findings provide a theoretical reference for the long-term effect of arsenic exposure on liver lipid metabolism.

Arsenic induced cardiotoxicity: An approach for molecular markers, epigenetic predictors and targets.

Arsenic, a ubiquitous environmental toxicant, has been acknowledged as a significant issue for public health due to its widespread pollution of drinking water and food supplies. The present review aimed to study the toxicity associated with the cardiac system. Prolonged exposure to arsenic has been associated with several harmful health outcomes, especially cardiotoxicity. Arsenic-induced cardiotoxicity encompasses a range of cardiovascular abnormalities, including cardiac arrhythmias, ischemic heart disease, and cardiomyopathy. To tackle this toxicity, understanding the molecular markers, epigenetic predictors, and targets involved in arsenic-induced cardiotoxicity is essential for creating preventative and therapeutic approaches. For preventive measures against this heavy metal poisoning of groundwater, it is crucial to regularly monitor water quality, re-evaluate scientific findings, and educate the public about the possible risks. This review thoroughly summarised what is currently known in this field, highlighting the key molecular markers, epigenetic modifications, and potential therapeutic targets associated with arsenic-induced cardiotoxicity.

Occupational exposure to arsenic and leukopenia risk: Toxicological alert.

Arsenic and its inorganic compounds affect numerous organs and systemic functions, such as the nervous and hematopoietic systems, liver, kidneys, and skin. Despite a large number of studies on arsenic toxicity, rare reports have investigated the leukopenia incidence in workers exposed to arsenic. In workplaces, the main source of workers' exposure is the contaminated air by the inorganic arsenic in mines, arsenic or copper smelter industries, and chemical factories. Erythropoiesis inhibition is one of the arsenic effects and it is related to regulatory factor GATA-1. This factor is necessary for the normal differentiation of early erythroid progenitors. JAK-STAT is an important intracellular signal transduction pathway responsible for the mediating normal functions of several cytokines related to cell proliferation and hematopoietic systems development and regulation. Arsenic inactivates JAK-STAT by inhibiting JAK tyrosine kinase and using the IFNγ pathway. The intravascular hemolysis starts after the absorption phase when arsenic binds to the globin of hemoglobin in erythrocytes and is transported into the body, which increases the oxidation of sulfhydryl groups in hemoglobin. So, this article intends to highlight the potential leukopenia risk via inhalation for workers exposed to arsenic and suggests a possible mechanism for this leukopenia through the JAK-signal transducer and activator of transcription (STAT) pathway inhibition.

New insights into mechanism of ellagic acid alleviating arsenic-induced oxidative stress through MAPK/keap1-Nrf2 signaling pathway response, molecular docking and metabolomics analysis in HepG2 cells.

The increase of oxidative stress level is one of the vital mechanisms of liver toxicity induced by arsenic (As). Ellagic acid (EA) is widely known due to its excellent antioxidation. Nevertheless, whether EA could alleviate As-induced oxidative stress and the underlying mechanisms remain unknown. Herein, As (2 and 4 µM) and EA (25 and 50 µM) were selected for alone and combined exposure of HepG2 cells to investigate the effects of EA on As-induced oxidative stress. Results indicated that EA could alleviate the oxidative stress caused by As via decreasing intracellular ROS level and MDA content, as well as improving SOD, CAT and GSH-PX activities. qRT-PCR showed that EA might enhance the expression levels of antioxidant enzymes NQO1, CAT and GPX1 by activating MAPK (JNK, p38 and ERK)/keap1-Nrf2 signaling pathway. EA was found to promote dissociation from keap1 and nuclear translocation of Nrf2 by competing with Nrf2 at ARG-380 and ARG-415 sites on keap1 to exert antioxidation using molecular docking. Moreover, metabolomics revealed that EA might maintain the redox balance of HepG2 cells by modulating or reversing disorders of carbon, amino acid, lipid and other metabolisms caused by As. This study provides diversified new insights for the removal of liver toxicity of As and the application of EA.

Pseudochrobactrum asaccharolyticum mitigates arsenic induced oxidative stress of maize plant by enhancing water status and antioxidant defense system.

BACKGROUND: Oxidative stress mediated by reactive oxygen species (ROS) is a common denominator in arsenic toxicity. Arsenic stress in soil affects the water absorption, decrease stomatal conductance, reduction in osmotic, and leaf water potential, which restrict water uptake and osmotic stress in plants. Arsenic-induced osmotic stress triggers the overproduction of ROS, which causes a number of germination, physiological, biochemical, and antioxidant alterations. Antioxidants with potential to reduce ROS levels ameliorate the arsenic-induced lesions. Plant growth promoting rhizobacteria (PGPR) increase the total soluble sugars and proline, which scavenging OH radicals thereby prevent the oxidative damages cause by ROS. The main objective of this study was to evaluate the potential role of Arsenic resistant PGPR in growth of maize by mitigating arsenic stress. METHODOLOGY: Arsenic tolerant PGPR strain MD3 (Pseudochrobactrum asaccharolyticum) was used to dismiss the 'As' induced oxidative stress in maize grown at concentrations of 50 and 100 mg/kg. Previously isolated arsenic tolerant bacterial strain MD3 "Pseudochrobactrum asaccharolyticum was used for this experiment. Further, growth promoting potential of MD3 was done by germination and physio-biochemical analysis of maize seeds. Experimental units were arranged in Completely Randomized Design (CRD). A total of 6 sets of treatments viz., control, arsenic treated (50 & 100 mg/kg), bacterial inoculated (MD3), and arsenic stress plus bacterial inoculated with three replicates were used for Petri plates and pot experiments. After treating with this MD3 strain, seeds of corn were grown in pots filled with or without 50 mg/kg and 100 mg/kg sodium arsenate. RESULTS: The plants under arsenic stress (100 mg/kg) decreased the osmotic potential (0.8 MPa) as compared to control indicated the osmotic stress, which caused the reduction in growth, physiological parameters, proline accumulation, alteration in antioxidant enzymes (Superoxide dismutase-SOD, catalase-CAT, peroxidase-POD), increased MDA content, and H2O2 in maize plants. As-tolerant Pseudochrobactrum asaccharolyticum improved the plant growth by reducing the oxidation stress and antioxidant enzymes by proline accumulation. PCA analysis revealed that all six treatments scattered differently across the PC1 and PC2, having 85.51% and 9.72% data variance, respectively. This indicating the efficiency of As-tolerant strains. The heatmap supported the As-tolerant strains were positively correlated with growth parameters and physiological activities of the maize plants. CONCLUSION: This study concluded that Pseudochrobactrum asaccharolyticum reduced the 'As' toxicity in maize plant through the augmentation of the antioxidant defense system. Thus, MD3 (Pseudochrobactrum asaccharolyticum) strain can be considered as bio-fertilizer.

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.

[NRF2 mediated redox stress in arsenic induced human keratinocytes malignant transformation].

OBJECTIVE: To explore the role of nuclear transcription factor E2-related factor 2(NRF2)-mediated reductive stress in arsenite induced malignant transformation in human keratinocytes. METHODS: HaCaT cells and fluorescent labeled mitochondrial glutathione HaCaT cells(Mito-Grx1-roGFP2 HaCaT) were cultured to 35 passages in medium containing 0.0 and 1.0 µmol/L NaAsO_2 to establish a model of malignant transformation of cells. Cellular and mitochondrial reduced glutathione/oxidized glutathione(GSH/GSSG) and reduced coenzyme II/oxidized coenzyme II(NADPH/NADP~+) ratios were measured in HaCaT cells. Cell doubling time, cell migration ability, soft agar clone formation ability and GSH/GSSG at different times in the 0 passage, the early stage(1st, 7th and 14th passages) and later stage(21st, 28th and 35th passages) were measured in Mito-Grx1-roGFP2 HaCaT cells. NaAsO_2 induced malignant transformation cells were transfected with NRF2 siRNA, and detected the expression level of NRF2 and the redox-related indexes and malignant transformation indexes. RESULTS: Compared with the control group, the GSH/GSSG ratio in 1.0 µmol/L NaAsO_2 treated HaCaT cells significantly decreased in the 1st and 7th generations, but significantly increased after the 21st generation, and the NADPH/NADP~+ ratio significantly increased in the 1st, 14th, 21st, 28th and 35th generations; The levels of GSH/GSSG in mitochondria significantly increased from 1st to 35th generation, and the levels of NADPH/NADP~+ in mitochondria significantly increased at 1st, 7th, 21st, 28th and 35th generation. After continuous treatment of Mito-Grx1-roGFP2 HaCaT cells with 0.0 or 1.0 µmol/L NaAsO_2 to 35 passages, the doubling time of cells treated with 1.0 µmol/L NaAsO_2 was significantly shortened, the cell migration rate was increased greatly, and more clones with larger volumes than the control cells formed. The GSH/GSSG ratio in mitochondria of Mito-Grx1-roGFP2 HaCaT cells showed a significant decrease in the 1st generation and increased from the 7th generation onwards(all P<0.05). After transfection of NaAsO_2 treated cells with NRF2 siRNA, the levels of hydrogen peroxide and superoxide increased compared with the siRNA controls. The levels of cell and mitochondrial NADPH/NADP~+ and GSH/GSSG decreased and the level of mitochondrial GSH/GSSG in Mito-Grx1-roGFP2 HaCaT cells decreased. Cell doubling time increased, cell migration rate and soft agar clone formation ability decreased(all P<0.05). The malignant phenotype was reversed. CONCLUSION: In the early stage(1st, 7th and 14th passages) of NaAsO_2 treated HaCaT cells, oxidative stress occurred with continuous high NRF2 expression. Later(21st, 28th and 35th passages), NRF2 induced reductive stress, leading to malignant transformation.

Prevalence of perturbed gut microbiota in pathophysiology of arsenic-induced anxiety- and depression-like behaviour in mice.

Severe toxic effects of arsenic on human physiology have been of immense concern worldwide. Arsenic causes irrevocable structural and functional disruption of tissues, leading to major diseases in chronically exposed individuals. However, it is yet to be resolved whether the effects result from direct deposition and persistence of arsenic in tissues, or via activation of indirect signaling components. Emerging evidences suggest that gut inhabitants play an active role in orchestrating various aspects of brain physiology, as the gut-brain axis maintains cognitive health, emotions, learning and memory skills. Arsenic-induced dysbiosis may consequentially evoke neurotoxicity, eventually leading to anxiety and depression. To delineate the mechanism of action, mice were exposed to different concentrations of arsenic. Enrichment of Gram-negative bacteria and compromised barrier integrity of the gut enhanced lipopolysaccharide (LPS) level in the bloodstream, which in turn elicited systemic inflammation. Subsequent alterations in neurotransmitter levels, microglial activation and histoarchitectural disruption in brain triggered onset of anxiety- and depression-like behaviour in a dose-dependent manner. Finally, to confirm whether the neurotoxic effects are specifically a consequence of modulation of gut microbiota (GM) by arsenic and not arsenic accumulation in the brain, fecal microbiota transplantations (FMT) were performed from arsenic-exposed mice to healthy recipients. 16S rRNA gene sequencing indicated major alterations in GM population in FMT mice, leading to severe structural, functional and behavioural alterations. Moreover, suppression of Toll-like receptor 4 (TLR4) using vivo-morpholino oligomers (VMO) indicated restoration of the altered parameters towards normalcy in FMT mice, confirming direct involvement of the GM in inducing neurotoxicity through the arsenic-gut-brain axis. This study accentuates the potential role of the gut microbiota in promoting neurotoxicity in arsenic-exposed mice, and has immense relevance in predicting neurotoxicity under altered conditions of the gut for designing therapeutic interventions that will target gut dysbiosis to attenuate arsenic-mediated neurotoxicity.

Drying-rewetting alters arsenic ecotoxicity: From the perspective of enzyme-based functional diversity.

Drying-rewetting (DW) cycles can significantly influence soil properties and microbial community composition, leading to direct or indirect changes in arsenic (As) toxicity, which inturn affects soil ecological functions. Despite this, there has been insufficient focus on accurately evaluating As ecotoxicity and its impact on soil ecological function under DW conditions. This study seeks to address this gap by examining the effects of DW on As toxicity and the characteristics of soil ecological function, specifically from the perspective of enzyme-based functional diversity. Our results reveal that compared to constant moisture conditions, DW treatment significantly increased the toxicity of As on alkaline phosphatase and ß-glucosidase, with maximum inhibition rates observed at 46.29% and 21.54%, respectively. Conversely, for other tested enzymes including invertase, fluorescein diacetate hydrolase, and dehydrogenase, DW treatment decreased As toxicity, possibly be due to the different stability of these enzymes under varying soil moisture conditions. From an enzyme functional diversity perspective, DW treatment reduced the As toxicity, as evidenced by the reduced inhibition rates and a lower coefficient of variation. In conclusion, DW appears to enhance soil functional resilience against arsenic pollution. These findings contribute to a better understanding of changes in ecological functions in heavy metal-contaminated soils under dynamic environmental conditions, offering insights for improved monitoring and mitigation strategies for metalloids toxicity in natural environments.

High arsenic contamination in the breast milk of mothers inhabiting the Gangetic plains of Bihar: a major health risk to infants.

Groundwater arsenic poisoning has posed serious health hazards in the exposed population. The objective of the study is to evaluate the arsenic ingestion from breastmilk among pediatric population in Bihar. In the present study, the total women selected were n = 513. Out of which n = 378 women after consent provided their breastmilk for the study, n = 58 subjects were non-lactating but had some type of disease in them and n = 77 subjects denied for the breastmilk sample. Hence, they were selected for the women health study. In addition, urine samples from n = 184 infants' urine were collected for human arsenic exposure study. The study reveals that the arsenic content in the exposed women (in 55%) was significantly high in the breast milk against the WHO permissible limit 0.64 µg/L followed by their urine and blood samples as biological marker. Moreover, the child's urine also had arsenic content greater than the permissible limit (< 50 µg/L) in 67% of the studied children from the arsenic exposed regions. Concerningly, the rate at which arsenic is eliminated from an infant's body via urine in real time was only 50%. This arsenic exposure to young infants has caused potential risks and future health implications. Moreover, the arsenic content was also very high in the analyzed staple food samples such as rice, wheat and potato which is the major cause for arsenic contamination in breastmilk. The study advocates for prompt action to address the issue and implement stringent legislative measures in order to mitigate and eradicate this pressing problem that has implications for future generations.

Environmental arsenic exposure and reproductive system toxicity in male and female and mitigatory strategies: a review.

Environmental Arsenic (As) exposure is one of the main health challenges in different area of the world. As is a significant factor responsible to the reproductive system toxicity in both male and female. In this study, the most important effects mechanisms and biomarkers related to environmental exposure to As and the reproductive system toxicity, and infertility risk are reviewed in male and female. The results showed that the most important As-induced reproductive system toxicity in the male were alteration in the quantity and quality of semen, testicular toxicity, oxidative stress, testosterone reduction, and sperm apoptosis. For female were oxidative stress, spontaneous miscarriage, reproductive cycle disruption, decrease in the estradiol, progesterone, and testosterone levels and impair fecundity. The main mechanisms of reproductive system toxicity caused by As exposure in male were, genotoxic effects, reduction of glutathione, disruption of sex hormones, sperm flagellum formation impairment, inhibition of spermatogenesis, disruption of cell signaling pathways, and metabolites disruption. For female were abnormal signaling in gene expression, hormonal homeostasis, As-accumulation in placental tissue and creation of reactive oxygen, disruption in the neurotransmitters balance, and sex hormones disruption. The suitable biomarkers for As-induced reproductive toxicity in male were changes in testosterone, one-carbon and lipid metabolism, noncoding RNAs, and steroid hormone homeostasis, and for female was human chorionic gonadotropin (hCG) changes. Finaly, taking selenium, zinc, silymarin, vitamins (C and E) and phytonutrients can be effective in reducing the As-induced reproductive system toxicity and infertility risk.