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The on‐going anthropogenic degradation of freshwater habitats has drastically altered the environmental supply of both nutrients and common pollutants. Most organisms living in these altered habitats experience interactive effects of various stressors that can initiate adjustments at multiple levels impacting their fitness. Hence, studies measuring response to a single environmental parameter fail to capture the complexities of the status quo. We tested both the individual and the interactive effect of arsenic (As) exposure, food quantity, and dietary phosphorus (P)‐supply on six life‐history traits (Juvenile Growth Rate; Adult Growth Rate; Age and Size at Maturity, Lifespan, and Fecundity) as surrogates for organismal fitness in the keystone aquatic grazer Daphnia pulex. We also tested the effect of food quantity and P‐supply on somatic As accumulation in Daphnia. Our results indicated an influence of P‐supply on neonatal growth and an influence of As and food quantity on growth and maintenance later in life. Maturation was strongly influenced by all three variables, with no reproduction observed in the presence of two or more environmental stressors. We found a strong interaction between As and dietary P, with increased P‐supply intensifing the toxicity effect of As. No such effects were seen between As and food quantity, indicating a differential role of quantity versus quality on As toxicity. We found a nominal effect of diet on somatic As accumulation. The results from the present study emphasize the importance of considering such interactions between co‐occurring environmental stressors and the dietary status of organisms, to better predict and manage impacts and risks associated with common environmental toxicants in highly vulnerable ecosystems. Environ Toxicol Chem 2024;43:1807–1819. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Lysine specific demethylase 1 (LSD1) is a histone demethylase that specifically catalyzes the demethylation of histone H3K4 (H3K4me1/2) and regulates gene expression. In addition, it can mediate the process of autophagy through its demethylase activity. Sestrin2 (SESN2) is a stress‐induced protein and a positive regulator of autophagy. In NaAsO2‐induced mouse fibrotic livers and activated hepatic stellate cells (HSCs), LSD1 expression is decreased, SESN2 expression is increased, and autophagy levels are also increased. Overexpression of LSD1 and silencing of SESN2 decreased the level of autophagy and attenuated the activation of HSCs induced by NaAsO2. LSD1 promoted SESN2 gene transcription by increasing H3K4me1/2 in the SESN2 promoter region. 3‐methyladenine (3‐MA) and chloroquine were used to inhibit autophagy of HSCs, and the degree of activation was also alleviated. Taken together, LSD1 positively regulates SESN2 by increasing H3K4me1/2 enrichment in the SESN2 promoter region, which in turn increases the level of autophagy and promotes the activation of HSCs. Our results may provide new evidence for the importance of LSD1 in the process of autophagy and activation of HSCs induced by arsenic poisoning. Increasing the expression and activity of LSD1 is expected to be an effective way to reverse the autophagy and activation of HSCs induced by arsenic poisoning. [ABSTRACT FROM AUTHOR]

In India, where millions of people use groundwater for drinking, arsenic pollution in groundwater is a major environmental and public health issue. The review begins by analyzing the sources and causes of groundwater arsenic pollution, including natural geological processes and anthropogenic activities like mining and industrial discharge. It emphasizes India's most arsenic‐contaminated regions and the health risks of long‐term exposure. The review's second section focuses on the use of biosensors to find arsenic in groundwater. A potential method is provided by biosensors because of their great sensitivity, selectivity, and quick response. The benefits and drawbacks of several types of biosensors, including optical, electrochemical, and microbiological biosensors, are discussed. The utilization of nanomaterials, biomolecular recognition components, and miniature devices are only a few of the most recent developments in biosensor technology for arsenic detection that are studied. The review's last section discusses methods for bio‐remediating aqueous systems that have been contaminated with arsenic. Various bioremediation techniques are covered in detail, including microbial degradation, phytoremediation, and biosorption. The promise for removing arsenic using native microbes and plant species is highlighted, along with the difficulties of widespread application and long‐term sustainability. Overall, focusing on the detection of arsenic using biosensors and investigating bioremediation techniques, this review offers a thorough grasp of the arsenic poisoning in groundwater in India. In order to combat arsenic contamination and protect the health and wellbeing of the impacted populations in India, it emphasizes the need for interdisciplinary research and collaboration among scientists, engineers, policymakers, and local communities. [ABSTRACT FROM AUTHOR]

Environmental arsenic exposure is a significant global public health concern. Previous studies have demonstrated the association between arsenic‐induced liver injury and oxidative stress as well as ferroptosis. However, the knowledge of the interactions among these mechanisms remains limited. Moreover, there is a lack of research on potential therapeutic interventions for liver injury resulting from arsenic exposure. To address these limitations, we established a rat model with liver injury caused by arsenic exposure and investigated the impact of the nuclear factor E2‐related factor 2 (Nrf2)/glutathione peroxidase 4 (GPx4) signaling pathway and ferroptosis on arsenic‐induced liver injury. Our findings revealed that arsenic increased Nrf2 expression and decreased GPx4 expression in the rat liver. This was accompanied by a substantial generation of reactive oxygen species and disruption of the antioxidant defense system, ultimately promoting liver injury through ferroptosis. Subsequently, we conducted intervention experiments using Rosa roxburghii Tratt (RRT) in rats exposed to arsenic. The results showed that the detrimental effects mentioned earlier were partially alleviated following RRT intervention. This study offers preliminary evidence that persistent activation of Nrf2 by arsenic triggers an adaptive antioxidant response, leading to liver injury through the promotion of ferroptosis. Additionally, we discovered that RRT inhibits Nrf2‐mediated adaptive antioxidant responses by reducing hepatic ferroptosis, thereby mitigating liver injury caused by arsenic exposure in rats. Our study contributes to a deeper understanding of the molecular mechanisms underlying liver injury resulting from arsenic exposure. Furthermore, our findings may facilitate the identification of a potential edible and medicinal plant extracts that could be utilized to develop a more effective adjunctive treatment approach. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Patients that are taking Ayurvedic supplements have an increased risk of heavy metal toxicity. Lead, arsenic, and mercury are frequently identified in these supplements and can cause clinically significant toxicity. Clinicians should screen patients routinely for use of non‐pharmaceutical medications and supplements. [ABSTRACT FROM AUTHOR]

Background: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. Methods: A cross‐sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case–control study was then conducted to determine the biomarker for pruritus. Arsenite‐treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double‐blind, placebo‐controlled trial was conducted to test the efficacy of naloxone in arsenic‐exposed patients with pruritus in Shimen. Results: Hair arsenic (μg/g) showed a dose–response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate‐to‐severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum β‐endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of β‐endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic‐exposed participants in 2 weeks (β = −0.98, p = 0.04). Conclusion: Arsenic exposure is associated with pruritus, and β‐endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis. [ABSTRACT FROM AUTHOR]

Soil phosphatase activity is identified as sensitive to arsenic (As) pollution and therefore, often used as an indicator to estimate As toxicity in soil. Nevertheless, the effect of As on soil phosphatase activity after its desorption by P is not adequately studied. This study employed sequential extraction procedure and ecological dose parameters to show As mobility and its toxicity to acid phosphatase (AcP). Results indicated that P application significantly increased As desorption ratio in the As ageing process. In S1 (As 2895 mg kg−1) soil, after P addition, the water‐soluble (FWS) fraction had the highest proportion of As, while for S2 (As 645 mg kg−1) and S3 (As 39 mg kg−1) it was residual (FRES) fraction. Additionally, P addition increased the As bioavailability in all soils. Generally, P addition significantly reduced soil AcP activity under all P concentrations and increased in the soil with minimum As content. The variation partitioning analysis indicated that for S1, P concentration was the major factor, for S2 and S3 soils, it was As desorption and ageing time, respectively, that influenced the AcP activity in soils. The calculated ecological dose (ED50) showed that in most cases, As toxicity increased at the end of ageing. Thus, it is essential to control the phosphorus fertilizer applications in silty soils with acid and neutral pH, since it can lead to increased As mobility and toxicity to soil AcP. Core Ideas: Increasing P concentration increased As mobility and bioavailabilityAcid phosphatase (AcP) activity decreased in high and medium As‐contaminated soilsP treatment, As desorption, and ageing greatly influenced AcP activity in soilsImportant to control P fertilizer application in managing As‐polluted soils [ABSTRACT FROM AUTHOR]

Arsenic (As) poisoning has proven to be a major threat worldwide because of its toxic effects on the human body. As toxicity through drinking water is a global health concern. The toxicity of As is known to affect the liver, kidney, lungs, muscles, cardiovascular system, and nervous system and can even induce diabetes. Further As can cause skin lesions leading to notable diseases in the skin like Bowen's disease. Chronic exposure to As has caused many tragedies in Eastern, and several Southeast Asian and Latin American countries. Long‐term exposure to As makes it an immediate threat that should be dealt with as a priority, and one of the ways to handle it may be with the use of antioxidants. In this review, we have discussed the natural and anthropogenic sources of As, its metabolism, pathophysiology, and mechanism of toxicity. Besides, we have also discussed some of the synthetic chelators and the ameliorative role of antioxidants and natural compounds in reducing As toxicity. [ABSTRACT FROM AUTHOR]

Accumulation of random molecular damage such as oxidative DNA damage and inflammation is extremely found to be involved in the aging process. Due to extreme energy requirements and high lipid levels, the brain is more susceptible to oxidative damage during aging especially under exposure to toxic elements such as arsenic. Therefore, this study was aimed to evaluate the ameliorative effects of melatonin, as a neurohormone, on the arsenic‐induced behavioral abnormalities, and the underlying mechanisms. Forty‐eight rats, as young and old aged groups were exposed to 5.55 g/kg body weight arsenic for 4 weeks and then 10 mg/kg melatonin for 2 weeks. Our results showed that arsenic led to anxiety‐like behavioral abnormalities in rats. Increased oxidative stress‐induced damage to DNA, lipids and proteins, decreased potential of antioxidant defense system, induced apoptosis, elevated inflammation, and alteration in the histology of cortical region of brains are observed in the rats exposed to arsenic. These effects were more prominent in aged rats in comparison to young rats. Melatonin successfully attenuates arsenic induced adverse effects on the brain in both age groups. In conclusion, our study shows that melatonin has significant ameliorative impact on age‐dependent cytotoxicity of arsenic in rats' brains. [ABSTRACT FROM AUTHOR]

Background: Arsenic (As) may represent a risk for crop yield quality and human health since it may accumulate in the edible plant organs with the potential of leading to acute or chronic toxic effects in varied segments of the population. Management of soil fertility through compost has proven to be a valuable practice for increasing and maintaining soil organic matter, with nutritional benefits for crops. This work aimed to evaluate Swiss chard yield and the change in the bioavailability, bioaccumulation, and partitioning of As in the response of the use of compost or conventional mineral fertilization in an open‐field trial conducted in a volcanic area in central Italy characterized by the natural contamination of As in soil. Results: Compost treatment led to a short‐term increase trend in soil organic carbon, total nitrogen, and available phosphorus in a significant way. In the compost‐amended plots, the mitigation of the As uptake was detected in leaves, which are the edible part of Swiss chard. The As bioaccumulation factor in leaves of Swiss chard and the translocation factor for leaves/roots were also decreased using compost. Conclusion: Fertilization by compost can improve soil fertility, sustain Swiss chard production, and mitigate As accumulation in leaves of this crop grown in a naturally As‐contaminated soil. © 2022 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Ferroptosis is a novel form of iron‐dependent cell death that is involved in arsenic‐induced toxicity. Realgar is an arsenic‐containing Chinese medicine, which can result in nephrotoxicity because of long‐term exposure. However, it remains scientifically unknown whether Realgar is an inducer of ferroptosis in the kidney. This study investigated the role of ferroptosis in Realgar‐induced kidney toxicity in mice. ICR mice were exposed to Realgar for 28 days, and HK2 cells were exposed to Realgar in the presence or absence of treatment with ferrostatin‐1, a ferroptosis inhibitor. The ferroptosis‐related indicators were further evaluated. Realgar can cause nephrotoxicity in mice by continuous gavage for 28 days, accompanied by an increase in iron accumulation and reactive oxygen species (ROS). The reduced expression of Slc7A11 and Gpx4 further confirmed the ferroptosis mediated by Realgar. Meanwhile, Realgar disrupted the antioxidant system as evidenced by the formation of ROS leading to the inactivation of antioxidant enzymes. Realgar caused ferroptosis in a dose‐dependent manner, which was significantly reduced by ferrostatin‐1 in HK2 cells. This study revealed that Realgar‐induced ferroptosis triggered nephrotoxicity in mice and provided new clues to elucidate the mechanism of Realgar‐induced nephrotoxicity. This study investigated the mechanism of Realgar‐induced nephrotoxicity. To the best of our knowledge, this work was the first to prove Realgar caused ferroptosis in a dose‐dependent manner in vivo and in vitro, accompanied by a disruption of the antioxidant system, which provided new clues to elucidate the mechanism of Realgar‐induced nephrotoxicity. [ABSTRACT FROM AUTHOR]

Arsenic (As) contamination in water sources is a serious threat to safe drinking water afflicting many developed and developing nations. Among the different water treatment techniques, arsenic removal using metal‐loaded biochar has gained considerable interest as an efficient environmentally sustainable adsorbent. This review critically focuses on an in‐depth analysis of different adsorption mechanisms and various physicochemical properties such as pH, surface area and surface charge, porosity, and functional groups of the metal‐loaded biochar that are significant for As adsorption, which has not been previously described. It centers on addressing the overall effectiveness, governing mechanisms, and influential factors of metal‐loaded biochars for As removal from the aqueous medium. Special consideration on oxidation of arsenite to arsente and its removal was given. The oxidation processes are also effective in reducing arsenic toxicity by oxidation of arsenite to arsenate. A comprehensive insight into the utility of biochar for As removal for future field applications of biochar is delineated. [ABSTRACT FROM AUTHOR]

The accumulation of heavy metals like cadmium (Cd) and metalloids like arsenic (As) in plants can do harm to human health through the food chain, especially through the rice (Oryza sativa L.). To solve this problem, this study researched the application of magnesium slag (MS) and polyaspartic acid (PASP), which could accelerate rice growth and improve yield, increase soil pH and activate rice enzyme activity as well as reduce the bioavailability of Cd and As in the soil. After these two different treatments, rice yield increased by 17.0% and 18.9%, respectively. Meanwhile, the bioavailable As decreased by 49.1% and 42.5%, while the bioavailable Cd reduced by 72.6% and 44.3%. Besides, the Cd content in rice grains reduced by 77.7% and 17.3%, respectively, after two different treatments. In the MS treatment, the As content in rice grains was reduced by 21.8%, but showed no significant response to the other treatment. The contents of bioavailable Cd and As (determined by one‐step extraction) in soil were decreased by MS and PASP, which was favourable for the reduction of Cd and As accumulation in rice. The health risk assessment showed that the application of passivators can effectively reduce the risk of carcinogenesis, but it was still unacceptable. The application dose of MS and PASP still needs further exploration. [ABSTRACT FROM AUTHOR]

Chronic exposure to high‐dose inorganic arsenic through groundwater, air, or food remains a major environmental public health issue worldwide. Apoptosis, a method of cell death, has recently become a hot topic of research in biology and medicine. Previous studies have demonstrated that extracellular signal‐regulated kinase (ERK) is related to arsenic‐induced apoptosis. However, the reports are contradictory, and the knowledge of the above‐mentioned mechanisms and their mutual regulation remains limited. In this study, the associations between the TGF‐β1/ERK signaling pathway and arsenic‐induced cell apoptosis were confirmed using the HaCaT cell model. The relative expressions of the indicators of the TGF‐β1/ERK signaling pathway, apoptosis‐related genes (cytochrome C, caspase‐3, caspase‐9, cleaved caspase‐3, cleaved caspase‐9, and Bax), the mitochondrial membrane potential, and the total apoptosis rate were significantly increased (P <.05), while the expression of the antiapoptosis gene Bcl‐2 was significantly decreased (P <.05) in cells of the group exposed to arsenic. Moreover, the results demonstrated that the ERK inhibitor (PD98059) and TGF‐β1 inhibitor (LY364947) could inhibit the activation of the ERK signaling pathway, thereby reducing the mitochondrial membrane potential, the total apoptosis rate, and the expression of pro‐apoptosis‐related genes in the cells, while the expression of the antiapoptosis gene Bcl‐2 was significantly increased (P <.05). By contrast, the recombinant human TGF‐β1 could promote apoptosis of the HaCaT cells by increasing the activation of the ERK signaling pathway (P <.05). These results indicate that inorganic arsenic promotes the apoptosis of human immortal keratinocytes through the TGF‐β1/ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Arsenic is a heavy metal ubiquitous in soil, rocks and water. Both acute and chronic toxicity are reported in various species of animal, including humans, although publications specifically related to pigs are uncommon. This article describes a case of chronic arsenic poisoning in a pig finishing unit associated with the use of contaminated water being used to produce liquid meals and as source of water. Food safety was also considered. Mortality linked to clinical signs (lack of coordination, flaccid limb paralysis, collapse) was 2.8%. Resolution of the clinical case was reached by replacing 50% of the water used for producing the meals with dairy whey, thereby lowering the exposure dose. In conclusion, the presence of inorganic arsenic at the dose of 300 μg/L in drinking water administered for more than 6 weeks in pigs weighing 30–60 kg might determine a chronic intoxication. [ABSTRACT FROM AUTHOR]

Summary: Pteris vittata is an arsenic (As) hyperaccumulator that can accumulate several thousand mg As kg−1 DW in aboveground biomass. A key factor for its hyperaccumulation ability is its highly efficient As long‐distance translocation system. However, the underlying molecular mechanisms remain unknown.We isolated PvAsE1 through the full‐length cDNA over‐expression library of P. vittata and characterized it through a yeast system, RNAi gametophytes and sporophytes, subcellular‐location and in situ hybridization. Phylogenomic analysis was conducted to estimate the appearance time of PvAsE1.PvAsE1 was a plasma membrane‐oriented arsenite (AsIII) effluxer. The silencing of PvAsE1 reduced AsIII long‐distance translocation in P. vittata sporophytes. PvAsE1 was structurally similar to solute carrier (SLC)13 proteins. Its transcripts could be observed in parenchyma cells surrounding the xylem of roots. The appearance time was estimated at c. 52.7 Ma.PvAsE1 was a previously uncharacterized SLC13‐like AsIII effluxer, which may contribute to AsIII long‐distance translocation via xylem loading. PvAsE1 appeared late in fern evolution and might be an adaptive subject to the selection pressure at the Cretaceaou–Paleogene boundary. The identification of PvAsE1 provides clues for revealing the special As hyperaccumulation characteristics of P. vittata. [ABSTRACT FROM AUTHOR]

Well‐switching programs in Bangladesh have successfully lowered arsenic exposure. In these programs, households switch from wells that are labeled "unsafe" to nearby wells labeled "safe," but these designations are usually based on inherently inaccurate field kit measurements. Here, we (a) compare the efficacy of field‐kit measurements to accurate laboratory measurements for well switching, (b) investigate the potential impact on well switching of the chosen "safe" threshold, and (c) consider the possible benefits of providing more detailed concentration information than just "safe" and "unsafe." We explore different hypothetical mitigation scenarios by combining two extensive data sets from Araihazar Bangladesh: a blanket survey of 6595 wells over 25 km2 based on laboratory measurements and 943 paired kit and laboratory measurements from the same area. The results indicate that the decline in average arsenic exposure from relying on kit rather than laboratory data is modest in relation to the logistical and financial challenge of delivering exclusively laboratory data. The analysis further indicates that the 50 μg/L threshold used in Bangladesh to distinguish safe and unsafe wells, rather than the WHO guideline of 10 μg/L, is close to optimal in terms of average exposure reduction. We also show that providing kit data at the maximum possible resolution rather than merely classifying wells as unsafe or safe would be even better. These findings are relevant as the government of Bangladesh is about to launch a new blanket testing campaign of millions of wells using field kits. Plain Language Summary: Arsenic contaminates groundwater across much of Bangladesh, poisoning millions of people who rely on well water for drinking. Well‐switching programs have proved useful for lowering arsenic exposures. In well‐switching programs, households with high‐arsenic wells switch to nearby wells with low arsenic for drinking. However, several important questions remain for designing future well‐switching programs: Do inexpensive field kits provide sufficiently accurate arsenic concentration measurements for determining which wells are safe and which are unsafe? What arsenic concentration is the best threshold for designating wells as safe? In this analysis, we use two large datasets from Ariahazar Bangladesh, a district where the arsenic problem has been extensively studied. Our results indicate that the average decline in arsenic exposure for a switching program that is based on cheap kit measurements is comparable to that of a program that uses more accurate, but expensive and logistically challenging, laboratory measurements. We also show that the 50 μg/L threshold used in Bangladesh to distinguish safe and unsafe wells is close to the optimal value for reducing arsenic exposure. These findings will be useful to the government of Bangladesh that is about to launch a new blanket testing campaign of millions of wells using field kits. Key Points: Well‐switching based on kit or laboratory measurements produces similar reductions in arsenic exposureThe optimal well switching threshold for reducing arsenic exposure is near 50 μg/L, higher than the WHO guideline of 10 μg/LProviding actual kit readings instead of classifying wells as just "unsafe" or "safe" could lead to a higher reduction in arsenic exposure [ABSTRACT FROM AUTHOR]

The use of plant growth‐promoting bacteria (PGPB) to enhance plant growth and protection against heavy metal toxicity has been extensively studied. However, its potentiality to reduce arsenate toxicity, a threat to plant growth and metabolism, has been hardly investigated. Moreover, the toxic effect of arsenic oxide nanoparticles (As‐NPs) on plants and possible mechanisms for its alleviation has not yet been explored. In this study, the impact of the bioactive actinomycete Streptomyces spp. on the growth, physiology and stress‐related metabolites, such as sugars and proline, on As‐NPs‐stressed wheat and maize plants was investigated. Soil amendment with arsenic oxide nanoparticles (As‐NPs) induced the uptake and accumulation of As in the plants of both species, resulting in reduced growth and photosynthesis, but less marked in maize than in wheat plants. Under As‐NPs‐free conditions, Streptomyces spp. treatment markedly improved growth and photosynthesis in wheat only. The application of Streptomyces spp. reduced As accumulation, recovered the As‐NPs‐induced growth, photosynthesis inhibition, and oxidative damage in plants of both species. Wheat plants specifically accumulated soluble sugars, while both species accumulated proline. Under As‐NPs stress, the ornithine pathway of proline biosynthesis was more important in maize than in wheat plants, while the glutamine pathway was dominant in wheat ones. The addition of Streptomyces spp. further induced the accumulation of proline and starch in both plant species. Overall, despite a different response to Streptomyces spp. under nontoxic conditions, the amendment of as‐contaminated soil with Streptomyces spp. induced similar metabolic responses in the two tested species, which trigger stress recovery. [ABSTRACT FROM AUTHOR]

Arsenic is a well‐known environmental toxicant and carcinogen, which has been epidemiologically proved related to the increased hepatic disorders. Researches have shown that aseptic inflammation and abnormal immune response are associated with arsenic‐induced liver injury. However, the immunotoxic effects of liver have not been extensively characterized. Ginkgo biloba extract (GBE), a natural products of G. biloba leaves with proven anti‐inflammatory and potential immunoregulatory activities, was used as intervention agent to explore its protective effects on arsenic‐induced hepatotoxicity. Thus, the underlying mechanism of the immunotoxic effects on arsenic‐induced liver injury were investigated in 2.5, 5.0, and 10.0 mg/kg NaAsO2 of Wistar rats for 16 weeks. Subsequently, GBE was used as intervention agent in 50 mg/kg for 6 weeks after cessation of arsenic exposure. The ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL‐17A, IL‐6, TGF‐β1, and IL‐10 in serum and liver were detected. Meanwhile, the notable activation of aseptic inflammation‐related molecule TLR4 and its downstream targets MyD88 and NF‐κB in the liver were observed. In this work, we confirmed that subchronic exposed to arsenic triggered the infiltration of inflammatory cells in rat liver, coupled with obvious histopathological changes and aberrant hepatic serum biochemical parameters. Meanwhile, imbalanced immune response was verified by the notable abnormal ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL‐17A, IL‐6, TGF‐β1, and IL‐10 in serum and liver of arsenic exposed rats. Further, the level of TLR4, MyD88, and NF‐κB in liver both transcription and translation activity were raised. Subsequently, GBE markedly mitigated arsenic‐induced liver injury, most impressively, post treatment with GBE prominently suppressed the overactivated inflammatory‐related TLR4‐MyD88‐NF‐κB pathway and evidently decreased the secretion of inflammation cytokines. Meanwhile, the disturbance of pro‐ and anti‐inflammatory response was reversed. We concluded that the disruption of pro‐ and anti‐inflammatory T‐cells balance caused by cytokines mediated cell–cell interactions may be one of the mechanisms underlying arsenic‐induced liver injury and that GBE intervention exerts an evidence protective effects, which might be closely associated with the suppression of inflammatory‐related TLR4 pathway. [ABSTRACT FROM AUTHOR]

This study investigates the effect of static magnetic field (SMF) pre‐treatment in ameliorating arsenic (As) toxicity in soybean plants in relation to growth, photosynthesis and water transport through leaf venation. Soybean (Glycine max variety JS‐9560) seeds pre‐treated with SMF (200 mT for 1 h) were grown in four levels of arsenate‐polluted soil (As(V); 0, 5, 10 and 50 mg kg−1) in order to find out the impact of magnetopriming on plant tolerance against As toxicity. Quantitative image analysis of soybean leaf venation showed a narrowing in the width of midrib with increasing As(V) contamination in non‐primed seeds. The morphological variations are also supported by the physiological parameters such as reduction in efficiency of photosystem II, plant performance index, stomatal conductance and photosynthetic rate in the presence of As(V) for non‐primed seeds. However, remarkable increase was observed in all the measured parameters by SMF pre‐treatment at all the concentrations of As(V) used. Even for the highest concentration of As(V) (50 mg kg−1 soil), SMF pre‐treatment caused significant enhancement in plant height (40%), area of third trifoliate leaves (40%), along with increase in width of the midrib (17%) and minor vein (13%), contributing to increase in the water uptake, that resulted in higher primary photochemistry of PSII (12%), performance index (50%), stomatal conductance (57%) and photosynthetic rate (33%) as compared to non‐primed ones. Consequently, magnetopriming of dry seeds can be effectively used as pretreatment for reduction of As toxicity in soybean plants. [ABSTRACT FROM AUTHOR]

Metal toxicity in crop plants is a matter of scientific concern. Therefore, in recent years efforts have been made to minimize metal toxicity in crop plants. Out of various strategies, priming of seedlings with certain chemicals, like e.g. donors of signaling molecules, nutrients, metabolites or plant hormones has shown encouraging results. However, mechanisms related with the priming‐induced mitigation of metal toxicity are still poorly known. Hence, we have tested the potential of 2‐oxoglutarate (2‐OG) priming in enhancing the arsenate (AsV) toxicity tolerance in tomato seedlings along with deciphering the probable role of nitric oxide (NO) in accomplishing this task. Arsenate decreased growth, endogenous NO and nitric oxide synthase‐like activity but enhanced the accumulation of As, which collectively led to root cell death. Arsenate toxicity also decreased some photosynthetic characteristics (i.e. Fv/Fm, qP, Fv/F0 and Fm/F0, and total chlorophyll content) but enhanced NPQ. However, priming with 2‐OG alleviated the toxic effect of AsV on growth, endogenous NO, cell death and photosynthesis. Moreover, arsenate inhibited the activities of enzymes of nitrogen metabolism (i.e. nitrate reductase, nitrite reductase, glutamine synthetase and glutamine 2‐oxoglutarate aminotransferase) but increased the activity of glutamate dehydrogenase and NH4+ content. Superoxide radicals, hydrogen peroxide, lipid peroxidation, protein oxidation and membrane damage increased upon AsV exposure, but the antioxidant enzymes (i.e. superoxide dismutase, catalase and glutathione‐S‐transferase) showed differential responses. Overall, our results showed that 2‐OG is capable of alleviating AsV toxicity in tomato seedlings but the involvement of endogenous NO is probably required. [ABSTRACT FROM AUTHOR]

Anatomically modern human being is a relatively young species (~300 000 years old) with small amounts of genetic variation contained within them. The vast majority of its existence was spent in Eastern Africa, migration out of the region began around 100 000 YBP. Sub‐Saharan African populations have the greatest amount of human genetic variation. However, migration allowed populations to accumulate genomic variation associated with living in the arctic, higher altitudes, disease resistance, living on high fat or starchy foods, surviving toxic arsenic‐rich environments, lactase persistence, changing skin pigmentation, gaining thicker hair, and changing height and body mass index. Understanding these aspects of human evolution forces us to reconsider our notion of the "normal." Thus, normal for our species includes having dark melanic skin, brown eyes, and brown tightly curled hair. Derived features include lighter skin (~10 000 YBP), blue eyes (~6000 YBP), and blond straight hair (~6000 YBP). Yet in reality, "normal" has no meaning for a species that inhabits such a broad geographic range. Natural selection and genetic drift have genetically differentiated human populations in ways that impact our morphological and physiological traits. The genomic differentiation is small and does not allow any unambiguous classification of human populations into biological races. Despite these now well‐established facts of human variation, significant confusion associated with Eurocentric notions of the normal still persist in both the lay public and various professions such as biomedical research and clinical practice. [ABSTRACT FROM AUTHOR]

Societal Impact Statement: The inoculation with arbuscular mycorrhizal (AM) fungi shows great potential to increase the tolerance of host plants toward toxic arsenic. In many Asian countries and elsewhere, crops are increasingly being irrigated with arsenic‐contaminated groundwater, which causes loss of yield and the risk that arsenic enters the food chain. Greenhouse cultivation experiments demonstrated that AM fungi are able to increase the arsenic tolerance in crop plants, but the results are highly variable. This meta‐analysis demonstrates that AM fungi significantly reduce the arsenic concentration, and at the same time, positively modify the nutrient supply and the biomass in host crops that are grown under arsenic stress. Thus, the inoculation with AM fungi represents a promising approach to alleviate the negative effects of arsenic on crop growth, which deserves to be developed in future studies. Summary: Recent greenhouse experiments showed that the inoculation of crop plants with arbuscular mycorrhizal (AM) fungi does not only improve plant nutrition but also shows great potential to increase the host plants' tolerance toward the toxic metalloid arsenic (As). This approach could alleviate negative effects of crop plants grown under As stress, which causes substantial loss of yield and the risk of As entering the food chain. This is especially relevant in Asian countries and elsewhere where As subsequently accumulates in soil due to irrigation with As‐polluted groundwater. Overall effects of AM fungi symbiosis on seven crop plants grown under As stress were assessed by a meta‐analysis that included 299 studies obtained from 27 independent publications. Biomass, concentrations of As and phosphorus (P), and P/As ratios in plant tissue were used to evaluate the effects of AM fungi in host crops. Inoculation with AM fungi reduced As concentrations in tissue of host plants by 19% on average, while it increased the P/As ratio and biomass at the same time by 64% and 53%, respectively. With the exception of Helianthus annuus, AM effects were highly significant in all crop plants. The meta‐analysis results illustrate that AM fungi are able to significantly reduce As concentration, and at the same time, positively modify the nutrient supply and the biomass in host crops. These promising results strongly encourage the implementation of field trials as a next step toward the development of AM fungi‐based approaches to alleviate the negative effects of As stress on crop growth. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common neoplasm and the primary cause‐related mortality in developed and in most of nondeveloped countries. Epidemiological studies have demonstrated that even at low arsenic doses, the lungs are one of the main target organs and that chronic arsenic exposure has been associated with an increase in lung cancer development. Among the risk factors for cancer, arsenic methylation efficiency (As3MT) and the clearance of arsenic from cells by two members of the ATP‐binding cassette (ABC) transporter family (multidrug resistance protein 1 [MRP1] and P‐glycoprotein [P‐gp]) play an important role in processing of arsenic and decreasing its intracellular levels. This study aimed to evaluate the association between chronic exposure to arsenic with polymorphism of three proteins involved in arsenic metabolism and efflux of the metalloid in subjects with lung cancer. Polymorphism in As3MT, MRP1, and P‐gp modified the arsenic metabolism increasing significantly the AsV urinary levels. A significant association between MRP1 polymorphisms with an increase in the risk for cancer was found. The high inorganic arsenic urinary levels registered in the studied subjects suggest a reduction in the efficiency of As3MT, MRP1, and P‐gp firstly because of gene polymorphisms and secondarily because of high internal inorganic arsenic levels. MRP1 polymorphism was associated with a twofold increase in the risk of lung cancer. Polymorphism in As3MT, MRP1 and P‐gp modified the arsenic metabolism increasing significantly the AsV urinary levels. A significant association between MRP1 polymorphisms with an increase in the risk for cancer was found. The high inorganic arsenic urinary levels registered in the studied subjects suggest a reduction in the efficiency of As3MT, MRP1 and P‐gp firstly because of gene polymorphisms and secondarily because of high internal inorganic arsenic levels. MRP1polymorphism was associated with twofold increase in the risk of lung cancer. [ABSTRACT FROM AUTHOR]

Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis, but the molecular mechanisms by which this occurs are complex and elusive. It is not known if miRNAs are involved in arsenic‐induced liver fibrosis. We found that in the livers of mice exposed to arsenite, there were elevated levels of microRNA‐21 (miR‐21), phosphorylated mammalian target of rapamycin (p‐mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite‐induced miR‐21, p‐mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP‐1 monocytes (THP‐M), which caused secretion of fibrogenic cytokines, including transforming growth factor‐β1. Coculture of arsenite‐treated, THP‐M with LX‐2 cells induced α‐SMA and collagen I in the LX‐2 cells and resulted in the activation of these cells. Downregulation of miR‐21 in THP‐M inhibited arsenite‐induced M2 polarization and activation of LX‐2 cells, but cotransfection with PTEN siRNA or a miR‐21 inhibitor reversed this inhibition. Moreover, knockout of miR‐21 in mice attenuated liver fibrosis and M2 polarization compared with WT mice exposed to arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher hair arsenic levels, and levels of miR‐21 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR‐21 regulation of PTEN, which is involved in the activation of hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown mechanism for arsenicosis‐induced fibrosis. [ABSTRACT FROM AUTHOR]

Arsenic is a contaminant found in many foods and drinking water. Exposure to arsenic during development can cause improper neuronal progenitor cell development, differentiation, and function, while in vitro studies have determined that acute arsenic exposure to stem and progenitor cells reduced their ability to differentiate. In the current study, P19 mouse embryonal stem cells were exposed continuously to 0.1‐μM (7.5 ppb) arsenic for 32 weeks. A cell lineage array examining messenger RNA (mRNA) changes after 8 and 32 weeks of exposure showed that genes involved in pluripotency were increased, whereas those involved in differentiation were reduced. Therefore, temporal changes of select pluripotency and neuronal differentiation markers throughout the 32‐week chronic arsenic exposure were investigated. Sox2 and Oct4 mRNA expression were increased by 1.9‐ to 2.5‐fold in the arsenic‐exposed cells, beginning at Week 12. Sox2 protein expression was similarly increased starting at Week 16 and remained elevated by 1.5‐fold to sixfold. One target of Sox2 is N‐cadherin, whose expression is a hallmark of epithelial–mesenchymal transitions (EMTs). Exposure to arsenic significantly increased N‐cadherin protein levels beginning at Week 20, concurrent with increased grouping of N‐cadherin positive cells at the perimeter of the embryoid body. Expression of Zeb1, which helps increase the expression of Sox2, was also increased started at Week 16. In contrast, Gdf3 mRNA expression was reduced by 3.4‐ to 7.2‐fold beginning at Week 16, and expression of its target protein, phospho‐Smad2/3, was also reduced. These results suggest that chronic, low‐level arsenic exposure may delay neuronal differentiation and maintain pluripotency. Arsenic is a contaminant found in drinking water, and exposure to arsenic can impair cellular differentiation. P19 mouse embryonal stem cells were exposed to 0.1‐μM (7.5 ppb) arsenic for 32 weeks. The results indicate that transcripts involved in differentiation were reduced starting at Week 16, including Gdf3, a marker of early neuronal differentiation. In contrast, expression of pluripotency markers, including Sox2 and Zeb1, and their target proteins, such as N‐cadherin, was increased. [ABSTRACT FROM AUTHOR]

The transcriptional regulators of arsenic‐induced gene expression remain largely unknown. Sulfur assimilation is tightly linked with arsenic detoxification. Here, we report that mutant alleles in the SLIM1 transcription factor are substantially more sensitive to arsenic than cadmium. Arsenic treatment caused high levels of oxidative stress in the slim1 mutants, and slim1 alleles were impaired in both thiol accumulation and sulfate accumulation. We further found enhanced arsenic accumulation in roots of slim1 mutants. Transcriptome analyses indicate an important role for SLIM1 in arsenic‐induced tolerance mechanisms. The present study identifies the SLIM1 transcription factor as an essential component in arsenic tolerance and arsenic‐induced gene expression. Our results suggest that the severe arsenic sensitivity of the slim1 mutants is caused by altered redox status. [ABSTRACT FROM AUTHOR]

Arsenic (As) contamination and accumulation in rice is a serious concern causing severe oxidative damage. Melatonin acts as a protective agent in plant defence against multiple abiotic stresses. The mechanism of antioxidant function of melatonin during As stress in rice genotypes is less studied.In this study, hydroponically‐grown As‐susceptible (Khitish) and As‐tolerant (Muktashri) rice cultivars, subjected to 150 µm arsenate stress, were supplemented with exogenously applied melatonin (20 µm) to examine the plant defence mechanism.Melatonin (Mel) increased root and shoot length, fresh and dry weight, chlorophyll a and b content and activated reducing power and free radical scavenging capacity in both rice cultivars. The role of Mel in the sensitive variety appeared to be more prominent with respect to reduced water saturation deficit by reducing endogenous As and H2O2 accumulation, and enhancing overall antioxidant capacity by imposing reduced requirement of catalase for ROS detoxification, and restoring As‐inhibited activity of glutathione‐S‐transferase, glutathione peroxidase and dehydroascorbate reductase. In contrast, melatonin treatment in the tolerant cultivar required reduced involvement of ascorbate peroxidase to deal with As toxicity, and complemented the stress‐mediated inhibition of guaiacol peroxidase activity. Isozyme profiling also established extensive varietal differences with regard to induction of new isoform(s) by Mel during As treatment.This study provides clear insights into mechanistic details of the regulation of antioxidative enzymes by melatonin in contrasting rice genotypes, which may prove helpful in generating As tolerance in susceptible rice varieties grown in marginalized soils, thereby improving crop yield and productivity. [ABSTRACT FROM AUTHOR]

Arsenic in groundwater caused the black‐foot disease (BFD) in many countries in the 1950–1960s. It is of great importance to develop a feasible method for removal of arsenic from contaminated groundwater in BFD endemic areas. Photocatalytic oxidation of As(III) to less toxic As(V) is, therefore, of significance for preventing any arsenic‐related disease that may occur. By in situ synchrotron X‐ray absorption spectroscopy, the formation of As(V) is related to the expense of As(III) disappearance during photocatalysis by TiO2 nanotubes (TNTs). Under UV/Vis light irradiation, the apparent first‐order rate constant for the photocatalytic oxidation of As(III) to As(V) is 0.0148 min−1. It seems that As(III) can be oxidized with photo‐excited holes while the not‐recombined electrons may be scavenged with O2 in the channels of the well defined TNTs (an opening of 7 nm in diameter). In the absence of O2, on the contrary, As(III) can be reduced to As(0), to some extent. Cu(II) (CuO), as an electron acceptor, was impregnated on the TNTs surfaces in order to gain a better understanding of electron transfer during photocatalysis. It appears that As(III) can be oxidized to As(V) while Cu(II) is reduced to Cu(I) and Cu(0). The molecular‐scale data are very useful in revealing the oxidation states and interconversions of arsenic during the photocatalytic reactions. This work has implications in that the toxicity of arsenic in contaminated groundwater or wastewater can be effectively decreased via solar‐driven photocatalysis, which may facilitate further treatments by coagulation. [ABSTRACT FROM AUTHOR]

Arsenic stress causes rapid transcriptional responses in plants. However, transcriptional regulators of arsenic‐induced gene expression in plants remain less well known. To date, forward genetic screens have proven limited for dissecting arsenic response mechanisms. We hypothesized that this may be due to the extensive genetic redundancy present in plant genomes. To overcome this limitation, we pursued a forward genetic screen for arsenite tolerance using a randomized library of plants expressing >2,000 artificial microRNAs (amiRNAs). This library was designed to knock‐down diverse combinations of homologous gene family members within sub‐clades of transcription factor and transporter gene families. We identified six transformant lines showing an altered response to arsenite in root growth assays. Further characterization of an amiRNA line targeting closely homologous CBF and ERF transcription factors show that the CBF1,2 and 3 transcription factors negatively regulate arsenite sensitivity. Furthermore, the ERF34 and ERF35 transcription factors are required for cadmium resistance. Generation of CRISPR lines, higher‐order T‐DNA mutants and gene expression analyses, further support our findings. These ERF transcription factors differentially regulate arsenite sensitivity and cadmium tolerance. The transcription factors (TFs) mediating resistance to arsenic and cadmium (Cd) remain largely unknown. A redundancy‐ and lethality‐circumventing amiRNA screen uncovers CBFs as negative regulators of arsenite sensitivity and the ERF34 and 35 TFs as positive regulators mediating Cd resistance. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) is generally well tolerated for treatment of APL. We present a patient with severe watery diarrhea and pancreatitis thought to be due to ATO toxicity in the setting of obesity and acute kidney injury. Future studies evaluating ATO levels in patients experiencing toxicities may help guide dose modifications. [ABSTRACT FROM AUTHOR]

Arsenic is an established human carcinogen that can induce DNA damage; however, the precise mechanism remains unknown. Histone modification is of great significance in chemical toxicity and carcinogenesis. To investigate the role of histone H3K9me2 in arsenic‐induced DNA damage, HaCaT cells were exposed to sodium arsenite in this study, and the results showed that the enrichment level of H3K9me2 at the N‐methylated purine‐DNA‐glycosylase (MPG), X‐ray repair cross‐complementary gene 1 (XRCC1), and polyadenylate diphosphate ribose polymerase‐1 (PARP1) promoter regions of base‐excision repair (BER) genes was increased, which inhibited the expression of these BER genes, thereby inhibiting the repair of DNA damage and aggravating the DNA damage. Furthermore, the molecular mechanism by which H3K9me2 participates in the BER repair of arsenic‐induced DNA damage was verified based on functional loss and gain experiments. In addition, Ginkgo biloba extract can upregulate the expression of MPG, XRCC1, and PARP1 and ameliorate cell DNA damage by reducing the enrichment of H3K9me2 at repair gene promoter regions. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO2 ingestion could result in liver fibrosis and oxidative stress in Sprague–Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol‐requiring enzyme 1α (IRE1α)–endoplasmic reticulum (ER)‐stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO2 exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO2. In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4‐mediated ROS generation. [ABSTRACT FROM AUTHOR]

Long‐term arsenic exposure can promote cancer through epigenetic mechanisms, and arsenite methyltransferase (AS3MT) plays an important role in this process. However, the expression patterns and mechanisms of AS3MT in arsenic carcinogenesis remain unclear. In this study, we found that the AS3MT was overexpressed in arsenic exposed population, non‐small cell lung cancer (NSCLC) tissues, and A549 cells with sodium arsenite (NaAsO2) treatment for 48 hours. Besides, the level of AS3MT expression was positively correlated with the concentrations of urinary total arsenic (tAs), inorganic arsenic (iAs), methanearsonic acid (MMA), and dimethylarsinic acid (DMA) in all subjects. Functional experiments demonstrated that siRNA‐mediated knockdown of AS3MT significantly inhibited proliferation of A549 cells. Mechanism investigation revealed that silencing of AS3MT inhibited proliferation by increasing mRNA expression levels of p21 and E2F1, and inhibiting CDK1, CDK2, CDK4, CDK6, Cyclin A2, Cyclin E1, Cyclin E2, and PCNA mRNA expression. Therefore, arsenic increased AS3MT expression in vivo and in vitro, which could directly act on the cell and affect the progression of NSCLC by regulating cell cycle genes. [ABSTRACT FROM AUTHOR]

Long‐term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic‐induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L‐02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic‐induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N‐methylpurine‐DNA glycosylase [MPG], XRCC1 and poly(ADP‐ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic‐induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning. Arsenic poisoning can lead to abnormal DNA damage and repair, which is related to the regulation of histone methylation. JHDM2A is the histone demethylase that specifically removes the methyl group from histone lysine H3K9, which is overexpressed in various tumors. After inhibition of JHDM2A, it can increase the expression of H3K9me2 and inhibit the proliferation of cancer cells. Our study shows that arsenic can upregulate JHDM2A and aggravate DNA damage, and JHDM2A inhibition can reduce levels of DNA damage. [ABSTRACT FROM AUTHOR]

Rice is a major dietary source of the toxic metal, cadmium (Cd). Previous studies reported that the rice transporter, OsNRAMP1, (Natural resistance‐associated macrophage protein 1) could transport iron (Fe), Cd and arsenic (As) in heterologous yeast assays. However, the in planta function of OsNRAMP1 remains unknown. Here, we showed that OsNRAMP1 was able to transport Cd and manganese (Mn) when expressed in yeast, but did not transport Fe or As. OsNRAMP1 was mainly expressed in roots and leaves and encoded a plasma membrane‐localized protein. OsNRAMP1 expression was induced by Cd treatment and Fe deficiency. Immunostaining showed that OsNRAMP1 was localized in all root cells, except the central vasculature, and in leaf mesophyll cells. The knockout of OsNRAMP1 resulted in significant decreases in root uptake of Cd and Mn and their accumulation in rice shoots and grains, and increased sensitivity to Mn deficiency. The knockout of OsNRAMP1 had smaller effects on Cd and Mn uptake than knockout of OsNRAMP5, while knockout of both genes resulted in large decreases in the uptake of the two metals. Taken together, OsNRAMP1 contributes significantly to the uptake of Mn and Cd in rice, and the functions of OsNRAMP1 and OsNRAMP5 are similar but not redundant. Rice is the major dietary source of the toxic metal cadmium. Understand how rice takes up Cd is important. Two previous studies showed that OsNRAMP1 could transport iron (Fe), Cd and arsenic (As) in heterologous yeast assays, but its in planta function remains unknown. Here, we functionally characterize OsNRAMP1 and show that the transporter contributes significantly to the uptake of Cd and Mn in rice, but not the uptake of Fe or As. OsNRAMP1 and OsNRAMP5 play similar but non‐redundant functions. Our study sheds light on the mechanisms of Cd and Mn uptake by rice. [ABSTRACT FROM AUTHOR]

In 1955, an outbreak of arsenic poisoning caused by the ingestion of arsenic‐contaminated Morinaga Dry Milk occurred in western Japan. This study aimed to assess the mortality and cancer incidence risk among Japanese individuals who were poisoned during this time as infants. In total, 6223 survivors (mean age at enrollment, 27.5 y) who had ingested contaminated milk when they were aged ≤ 2 y participated in this study. Follow‐up was conducted from 1982 to 2018 (mean follow‐up duration, 30.3 y). Standardized mortality ratio (SMR) and standardized incidence ratio (SIR) were used to compare mortality and cancer incidence rates of subjects with the respective Japanese population rates, and 95% confidence intervals (95% CIs) of the SMR and SIR were also calculated. In total, 561 deaths and 524 new cancer cases were observed. A statistically significant increase in mortality rate was observed for all causes (SMR, 1.15; 1.01‐1.19), nervous system disease (2.83, 1.62‐4.19), respiratory disease (2.02, 1.37‐2.62), genitourinary system disease (2.25, 1.10‐3.73), and traffic accident (2.03, 1.14‐3.04). In contrast, a significant decrease in cancer incidence rate was observed for all cancers (SIR, 0.96; 0.84‐0.99), stomach cancer (0.77, 0.57‐0.92), colon cancer (0.63, 0.41‐0.85), rectum cancer (0.69, 0.43‐0.95), and breast cancer (0.72, 0.52‐0.89). Liver cancer showed a high mortality rate (SMR, 1.68; 1.06‐2.31). In this study, after the long‐term follow‐up we revealed overall and cause‐specific mortality and cancer incidence risk among survivors who ingested arsenic‐contaminated dry milk as infants. [ABSTRACT FROM AUTHOR]

Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic‐induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated‐ER stress plays an important role in Life‐and‐Death decision of cells. The current study was to investigate whether NaAsO2 utilizes oxidative stress integrated‐ER stress signaling to exert pro‐apoptotic activity in L‐02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO2‐induced apoptosis by enhancing construction of the death‐inducing signaling complex (DISC). NaAsO2‐sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO2 increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R‐like ER kinase (PERK)‐eukaryotic translation initiation 2α (eIF2α)‐activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO2‐induced CHOP and DR5 expressions. In addition, the antioxidant N‐acetyl‐l‐cysteine (NAC) treatment led to amelioration of NaAsO2‐induced production of reactive oxygen species (ROS) and some ER stress‐ and apoptosis‐ related protein levels and cell viability. Taken together, the results indicate that ROS‐mediated PERK‐eIF2α‐ATF4 pathway activated by NaAsO2 is the critical upstream event for subsequent apoptosis induction via regulating CHOP‐DR5 signaling in L‐02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic‐induced hepatotoxicity. [ABSTRACT FROM AUTHOR]

BACKGROUND The polishing process plays a key role in determining the beneficial quality of rice. However, the effects of polishing on human exposure to essential and toxic elements are not well reported. This study evaluated the effects of polishing on the levels of essential and toxic elements in rice grains and evaluated the status of their daily intake using probabilistic assessment. RESULTS: The levels of essential elements decreased as the degree of polishing increased. The highest reduction percentages of essential elements [24% of copper (Cu), 26% of nickel (Ni), and 52% of manganese (Mn)] were found after the first polishing step. The highest zinc (Zn) reduction (15%) was found after the fourth polishing step. For toxic elements, polishing significantly reduced the arsenic (As) concentration (15–31%) from that of the whole grains, of which 26% was removed after the first step. CONCLUSION: Polishing removed both essential and toxic elements from rice grains. The highest losses of Cu, Mn, Ni, and As were found after the first polishing step since these elements generally localize in the aleurone layers of rice grains. The last polishing step caused a significant Zn reduction from the grain. Polishing had no significant effect on the cadmium (Cd) concentration in grains. The consumption of all types of rice could not supply sufficient amounts of all microelements except Mn to maintain optimum health. Both As and Cd intake levels were lower than the benchmarks of toxic health effects. Thus, the potential health impacts of both of these elements in rice can be neglected. © 2020 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Arsenic toxicity is a significant health problem featured with several incidents of male reproductive dysfunctions. We studied the protective effects of a casein‐ and pea‐enriched formulated high‐protein diet (FHPD) on arsenic‐mediated testicular dysfunctions in rats. Adult male rats sustained on either a benchmark diet (n = 8) or an isocaloric FHPD (n = 8) were gavaged with arsenic trioxide (3mg/kg body wt/rat/day) for 30 consecutive days. A vehicle‐fed group (n = 8) maintained on the standard diet served as control. The arsenic‐treated group continued on the standard diet had a significantly reduced testicular and accessory sex organs weights. They exhibited decreased count, motility, viability and disrupted plasma membrane integrity of caudal spermatozoa with a higher incidence of gross morphological anomalies and DNA damage. Attenuated steroidogenic enzyme activities and low serum testosterone level vouched for a compromised state of testicular steroidogenesis. An increased testicular malondialdehyde and protein carbonyl contents coupled with impaired activities of antioxidant enzymes and free radical scavengers mirrored a situation of exacerbated testicular oxidative imbalance and disrupted redox homeostasis. FHPD, by and large, countermanded testicular steroidogenesis and antioxidant defence system and revoked the ill effects of arsenic. We conclude that specific protein‐enriched diet may serve as prospective weaponry in encountering the arsenic‐threatened testicular functions. [ABSTRACT FROM AUTHOR]

Arsenic (As) is a widespread metalloid contaminant, and its internal exposure is demonstrated to cause serious detrimental health problems. Albeit considerable studies are performed to interrogate the molecular mechanisms responsible for As‐induced toxicities, the exact mechanisms are not fully understood yet, especially at the epigenetic regulation level. In the present study, it is identified that long non‐coding RNA (lncRNA) urothelial cancer associated 1 (UCA1) alleviates As‐induced G2/M phase arrest in human liver cells. Intensive mechanistic investigations illustrate that UCA1 interacts with enhancer of zeste homolog 2 (EZH2) and accelerates the latter's protein turnover rate under normal and As‐exposure conditions. The phosphorylation of EZH2 at the Thr‐487 site by cyclin dependent kinase 1 (CDK1) is responsible for As‐induced EZH2 protein degradation, and UCA1 enhances this process through increasing the interaction between CDK1 and EZH2. As a consequence, the cell cycle regulator nuclear factor of activated T cells 2 (NFATc2), a downstream target of EZH2, is upregulated to resist As‐blocked cell cycle progress and cytotoxicity. In conclusion, the findings decipher a novel prosurvival signaling pathway underlying As toxicity from the perspective of epigenetic regulation: UCA1 facilitates the ubiquitination of EZH2 to upregulate NFATc2 and further antagonizes As‐induced cell cycle arrest. [ABSTRACT FROM AUTHOR]

Fertilizers containing phosphate (PO43−) are commonly used within the agricultural industry and are known to increase the bioavailability and mobility of metalloids like arsenic (As). This may increase plant uptake of As and hence pose a risk to human health. Arsenic and antimony (Sb) often co‐occur in contaminated soils; however, little is known about the interactions between As and Sb with PO43− on their bioavailability, accumulation, and toxicity in plants. The present study investigated individual and combined As and Sb–contaminated soils across 2 soil PO43− concentrations using a commonly consumed leafy vegetable, choy sum (Brassica chinensis var. parachinensis). Increased soil PO43− had no clear influence on the bioavailability of As or Sb (derived from a sequential extraction procedure). At high PO43− concentration, B. chinensis accumulated higher amounts of As in the shoots and roots in both individual and co‐contaminated soil, whereas Sb accumulation increased only when Sb was the only contaminant. When As was the only contaminant, the translocation of As from roots to shoots decreased as soil PO43− increased. Increased soil PO43− had no influence on Sb translocation from root to shoot. Although As was toxic (impaired growth) at low PO43− soil concentration, no toxicity was observed in the high‐PO43− soil. No toxicity was observed for Sb in either low‐ or high‐PO43− soils. Increased soil PO43− concentration ameliorated or masked As toxicity to plant growth and led to higher As concentration in the plant's edible parts. The addition of high soil PO43− concentrations ameliorated or masked As toxicity to plant growth in both individually and As + Sb co‐contaminated soil; however, the plant's edible parts accumulated higher As and Sb concentrations. Environ Toxicol Chem 2020;39:1233–1243. © 2020 SETAC [ABSTRACT FROM AUTHOR]

Critical priority pathogens have globally disseminated beyond clinical settings, thereby threatening wildlife. Andean Condors (Vultur gryphus) are essential for ecosystem health and functioning, but their populations are globally near threatened and declining due to anthropogenic activities. During a microbiological and genomic surveillance study of critical priority antibiotic‐resistant pathogens, we identified pandemic lineages of multidrug‐resistant extended‐spectrum β‐lactamase (ESBL)‐producing Escherichia coli colonizing Andean Condors admitted at two wildlife rehabilitation centres in South America. Genomic analysis revealed the presence of genes encoding resistance to hospital and healthcare agents among international E. coli clones belonging to sequence types (STs) ST162, ST602, ST1196 and ST1485. In this regard, the resistome included genes conferring resistance to clinically important cephalosporins (i.e., CTX‐M‐14, CTX‐M‐55 and CTX‐M‐65 ESBL genes), heavy metals (arsenic, mercury, lead, cadmium, copper, silver), pesticides (glyphosate) and domestic/hospital disinfectants, suggesting a link with anthropogenic environmental pollution. On the other hand, the presence of virulence factors, including the astA gene associated with outbreak of childhood diarrhoea and extra‐intestinal disease in animals, was identified, whereas virulent behaviour was confirmed using the Galleria mellonella infection model. E. coli ST162, ST602, ST1196 and ST1485 have been previously identified in humans and food‐producing animals worldwide, indicating that a wide resistome could contribute to rapid adaptation and dissemination of these clones at the human–animal–environment interface. Therefore, these results highlight that Andean Condors have been colonized by critical priority pathogens, becoming potential environmental reservoirs and/or vectors for dissemination of virulent and antimicrobial‐resistant bacteria and/or their genes, in associated ecosystems and wildlife. [ABSTRACT FROM AUTHOR]

Trivalent arsenic (As(III)) is recently found to be an immunomodulatory agent. As(III) has therapeutic potential in several autoimmune and inflammatory diseases in vivo. In vitro, it selectively induces apoptosis of immune cells due to different sensitivity. At a non-toxic level, As(III) shows its multifaceted nature by inducing either pro- or anti-inflammatory functions of immune subsets. These effects are exerted by either As(III)-protein interactions or as a consequence of As(III)-induced homeostasis imbalance. The immunomodulatory properties also show synergistic effects of As(III) with cancer immunotherapy. In this review, we summarize the immunomodulatory effects of As(III), focusing on the effects of As(III) on immune subsets in vitro, on mouse models of immune-related diseases, and the role of As(III) in cancer immunotherapy. Updates of the mechanisms of action, the pioneer clinical trials, dosing, and adverse events of therapeutic As(III) are also provided. [ABSTRACT FROM AUTHOR]

Arsenic (As) can contaminate air, soil, water, and organisms through mobilization of natural mineralogical deposits or anthropogenic actions. Inorganic‐As compounds are more toxic and widely available in aquatic environments, including drinking water reservoir catchments. Since little is known about its effects on prepubertal mammals, the present study focused on it. Hence, As was administered through drinking water to male Wistar rats from postnatal day 23 to 53. Negative control group received vehicle only (filtered water); As 1 group received AsNaO2 at 0.01 mg L−1 and As2 group received AsNaO2 at 10 mg L−1. It was investigated hepatic and renal toxicity of AsNaO2 (ie, histopathology and apoptosis analysis), as well as its mutagenicity (ie, micronucleus test in liver and bone marrow), cytotoxicity (ie, frequency and type of erythrocytes in blood), and genotoxicity (ie, comet assay in blood). Also, As determination was performed in hepatic and renal tissues. Data obtained revealed that immature organisms present a pattern of arsenic accumulation similar to that observed in adults, suggesting similarity in metabolic processes. In addition, liver showed to be an important target tissue for As toxicity in these experimental conditions, exhibiting infiltrate of defense cells, DNA damages, and increased apoptosis rates. [ABSTRACT FROM AUTHOR]

Human adenoviruses (HAdV) are associated with clinical symptoms such as gastroenteritis, keratoconjunctivitis, pneumonia, hepatitis, and encephalitis. In the absence of protective immunity, as in allogeneic bone marrow transplant patients, HAdV infections can become lethal. Alarmingly, various outbreaks of highly pathogenic, pneumotropic HAdV types have been recently reported, causing severe and lethal respiratory diseases. Effective drugs for treatment of HAdV infections are still lacking. The repurposing of drugs approved for other indications is a valuable alternative for the development of new antiviral therapies and is less risky and costly than de novo development. Arsenic trioxide (ATO) is approved for treatment of acute promyelocytic leukemia. Here, it is shown that ATO is a potent inhibitor of HAdV. ATO treatment blocks virus expression and replication by reducing the number and integrity of promyelocytic leukemia (PML) nuclear bodies, important subnuclear structures for HAdV replication. Modification of HAdV proteins with small ubiquitin‐like modifiers (SUMO) is also key to HAdV replication. ATO reduces levels of viral SUMO‐E2A protein, while increasing SUMO‐PML, suggesting that ATO interferes with SUMOylation of proteins crucial for HAdV replication. It is concluded that ATO targets cellular processes key to HAdV replication and is relevant for the development of antiviral intervention strategies. [ABSTRACT FROM AUTHOR]

Rationale: Accumulating evidence has linked prolonged exposure to heavy metals to cancer occurrence in the urinary system. However, the specific biological mechanisms responsible for the association of heavy metals with the unusually high incidence of upper tract urothelial carcinoma in Taiwan are complex and incompletely understood. Methods: To elucidate the specific biological mechanism and identify molecular indicators of the unusually high association of upper tract urothelial carcinoma with heavy metal exposure, protein expression following the treatment of T24 human bladder carcinoma and RT4 human bladder papilloma cell line models with arsenic (As) and cadmium (Cd) was studied. Proteomic changes in these cell models were integrated with data from a human bladder cancer (BLCA) tissue proteome to identify possible protein indicators of heavy metal exposure. Results: After mass spectrometry based proteomic analysis and verification by Western blotting procedures, we identified 66 proteins that were up‐regulated and 92 proteins that were down‐regulated in RT4 cell extracts after treatment with As or Cd. Some 52 proteins were up‐regulated and 136 proteins were down‐regulated in T24 cell extracts after treatment with Cd. We further confirmed that down‐expression of the PML (promyelocytic leukemia) protein was sustained for at least 75 days after exposure of bladder cells to As. Dysregulation of these cellular proteins by As was associated with three biological pathways. Immunohistochemical analyses of paraffin‐embedded BLCA tissue slides confirmed that PML protein expression was decreased in BLCA tumor cells compared with adjacent noncancerous epithelial cells. Conclusions: These data suggest that PML may play an important role in the pathogenesis of BLCA and may be an indicator of heavy metal exposure in bladder cells. [ABSTRACT FROM AUTHOR]

Summary: Arsenic is a toxin, ranking first on the Agency for Toxic Substances and Disease Registry and the Environmental Protection Agency Priority List of Hazardous Substances. Chronic exposure increases the risk of a broad range of human illnesses, most notably cancer; however, there is significant variability in arsenic‐induced disease among exposed individuals. Human genetics is a known component, but it alone cannot account for the large inter‐individual variability in the presentation of arsenicosis symptoms. Each part of the gastrointestinal tract (GIT) may be considered as a unique environment with characteristic pH, oxygen concentration, and microbiome. Given the well‐established arsenic redox transformation activities of microorganisms, it is reasonable to imagine how the GIT microbiome composition variability among individuals could play a significant role in determining the fate, mobility and toxicity of arsenic, whether inhaled or ingested. This is a relatively new field of research that would benefit from early dialogue aimed at summarizing what is known and identifying reasonable research targets and concepts. Herein, we strive to initiate this dialogue by reviewing known aspects of microbe–arsenic interactions and placing it in the context of potential for influencing host exposure and health risks. We finish by considering future experimental approaches that might be of value. [ABSTRACT FROM AUTHOR]

Arsenic is a ubiquitous environmental toxicant that has been associated with human respiratory diseases. In humans, arsenic exposure has been associated with increased risk of respiratory infection. Considering the existing epidemiological evidence and the well‐established impact of arsenic on epithelial cell biology, we posited that the effect of arsenic exposure in epithelial cells could enhance viral infection. In this study, we characterized influenza virus A/WSN/33 (H1N1) infection in Madin‐Darby Canine Kidney (MDCK) cells chronically exposed to low levels of sodium arsenite (75 ppb). We observed a 27.3‐fold increase in viral matrix (M2) protein (24 hours postinfection [p.i.]), a 1.35‐fold increase in viral mRNA levels, and a 126% increase in plaque area in arsenite‐exposed MDCK cells (48 hours p.i.). Arsenite exposure resulted in 114% increase in virus attachment‐positive cells (2 hours p.i.) and 224% increase in α‐2,3 sialic acid‐positive cells. Interestingly, chronic exposure to arsenite reduced the effect of the antiviral drug, oseltamivir in MDCK cells. We also found that exposure to sodium arsenite resulted in a 4.4‐fold increase in viral mRNA levels and significantly increased cytotoxicity in influenza A/Udorn/72 (H3N2) infected BEAS‐2B cells. This study suggests that chronic arsenite exposure could result in enhanced influenza infection in epithelial cells, and that this may be mediated through increased sialic acid binding. Finally, the decreased effectiveness of the anti‐influenza drug, oseltamivir, in arsenite‐exposed cells raises substantial public health concerns if this effect translates to arsenic‐exposed, influenza‐infected people. Arsenic exposure in humans has been associated with increased risk of respiratory infection, and research suggests that this may include increased susceptibility to influenza viral infection. To date, mechanistic research has focused on the immune system as the mediator of this effect of arsenic exposure. Here, we demonstrate that arsenic, at non‐cytotoxic concentrations, has the potential to alter epithelial cell biology to make cells more conducive to influenza infection, and less responsive to anti‐influenza drugs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Arsenic (As) is classified as a Group 1 human carcinogen, and the maximum arsenic contamination level allowed in drinking water is10 μg L−1. In this study, a genetic‐based whole‐cell biosensor for arsenic detection was constructed and engineered for rapid and more efficient arsenic detection. RESULTS: The promoter and repressor responsive to arsenic (ArsBR) were newly isolated from Bacillus cereus ATCC14579. The reporter gene was atsBA carrying formylglycine‐generating enzyme (FGE) and sulfatase, which provided a fluorescent product after reacting with 4‐methylumbelliferyl sulfate (4‐MUS). To improve the performance of the arsenic biosensor, firstly, more efficient Escherichia coli host strains were constructed, including the disruption of the arsenic efflux pump, multidrug efflux pump and arsenical‐resistant genes; secondly, a repressor (ArsBR) was engineered by an error‐prone polymerase chain reaction (PCR) technique, aiming to lower the detection limit; lastly, a single copy biosensor cassette in an E. coli chromosome was constructed. CONCLUSION: The stable and sensitive biosensor was able to detect As(III) at 5 μg L−1 and As(V) at 50 μg L−1 in 3.5 h with a very low fluorescent background. Moreover, the roles of all seven cysteine residues of the repressor were also investigated. Interestingly, the six cysteine residues Cys 28, 34, 36, 89, 90 and 100 are functionally involved in arsenic sensing, but not Cys 101. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]