Amphibian tolerance to arsenic: microbiome-mediated insights.

Amphibians are often recognized as bioindicators of healthy ecosystems. The persistence of amphibian populations in heavily contaminated environments provides an excellent opportunity to investigate rapid vertebrate adaptations to harmful contaminants. Using a combination of culture-based challenge assays and a skin permeability assay, we tested whether the skin-associated microbiota may confer adaptive tolerance to tropical amphibians in regions heavily contaminated with arsenic, thus supporting the adaptive microbiome principle and immune interactions of the amphibian mucus. At lower arsenic concentrations (1 and 5 mM As3+), we found a significantly higher number of bacterial isolates tolerant to arsenic from amphibians sampled at an arsenic contaminated region (TES) than from amphibians sampled at an arsenic free region (JN). Strikingly, none of the bacterial isolates from our arsenic free region tolerated high concentrations of arsenic. In our skin permeability experiment, where we tested whether a subset of arsenic-tolerant bacterial isolates could reduce skin permeability to arsenic, we found that isolates known to tolerate high concentrations of arsenic significantly reduced amphibian skin permeability to this metalloid. This pattern did not hold true for bacterial isolates with low arsenic tolerance. Our results describe a pattern of environmental selection of arsenic-tolerant skin bacteria capable of protecting amphibians from intoxication, which helps explain the persistence of amphibian populations in water bodies heavily contaminated with arsenic.

Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10-4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10-2, p = 2.8 × 10-2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10-2, p = 3.2 × 10-2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10-1, p = 3.4 × 10-2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10-2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10-4-3.1 × 10-3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10-3-2.8 × 10-3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10-3), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10-4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.

Analysis of arsenic-modulated expression of hypothalamic estrogen receptor, thyroid receptor, and peroxisome proliferator-activated receptor gamma mRNA and simultaneous mitochondrial morphology and respiration rates in the mouse.

Arsenic has been identified as an environmental toxicant acting through various mechanisms, including the disruption of endocrine pathways. The present study assessed the ability of a single intraperitoneal injection of arsenic, to modify the mRNA expression levels of estrogen- and thyroid hormone receptors (ERα,ß; TRα,ß) and peroxisome proliferator-activated receptor gamma (PPARγ) in hypothalamic tissue homogenates of prepubertal mice in vivo. Mitochondrial respiration (MRR) was also measured, and the corresponding mitochondrial ultrastructure was analyzed. Results show that ERα,ß, and TRα expression was significantly increased by arsenic, in all concentrations examined. In contrast, TRß and PPARγ remained unaffected after arsenic injection. Arsenic-induced dose-dependent changes in state 4 mitochondrial respiration (St4). Mitochondrial morphology was affected by arsenic in that the 5 mg dose increased the size but decreased the number of mitochondria in agouti-related protein- (AgRP), while increasing the size without affecting the number of mitochondria in pro-opiomelanocortin (POMC) neurons. Arsenic also increased the size of the mitochondrial matrix per host mitochondrion. Complex analysis of dose-dependent response patterns between receptor mRNA, mitochondrial morphology, and mitochondrial respiration in the neuroendocrine hypothalamus suggests that instant arsenic effects on receptor mRNAs may not be directly reflected in St3-4 values, however, mitochondrial dynamics is affected, which predicts more pronounced effects in hypothalamus-regulated homeostatic processes after long-term arsenic exposure.

Phosphate Uptake and Its Relation to Arsenic Toxicity in Lactobacilli.

The use of probiotic lactobacilli has been proposed as a strategy to mitigate damage associated with exposure to toxic metals. Their protective effect against cationic metal ions, such as those of mercury or lead, is believed to stem from their chelating and accumulating potential. However, their retention of anionic toxic metalloids, such as inorganic arsenic, is generally low. Through the construction of mutants in phosphate transporter genes (pst) in Lactiplantibacillus plantarum and Lacticaseibacillus paracasei strains, coupled with arsenate [As(V)] uptake and toxicity assays, we determined that the incorporation of As(V), which structurally resembles phosphate, is likely facilitated by phosphate transporters. Surprisingly, inactivation in Lc. paracasei of PhoP, the transcriptional regulator of the two-component system PhoPR, a signal transducer involved in phosphate sensing, led to an increased resistance to arsenite [As(III)]. In comparison to the wild type, the phoP strain exhibited no differences in the ability to retain As(III), and there were no observed changes in the oxidation of As(III) to the less toxic As(V). These results reinforce the idea that specific transport, and not unspecific cell retention, plays a role in As(V) biosorption by lactobacilli, while they reveal an unexpected phenotype for the lack of the pleiotropic regulator PhoP.

SUMOylation modification of FTO facilitates oxidative damage response of arsenic by IGF2BP3 in an m6A-dependent manner.

N6-methyladenosine (m6A) is the most common form of internal post-transcriptional methylation observed in eukaryotic mRNAs. The abnormally increased level of m6A within the cells can be catalyzed by specific demethylase fat mass and obesity-associated protein (FTO) and stay in a dynamic and reversible state. However, whether and how FTO regulates oxidative damage via m6A modification remain largely unclear. Herein, by using both in vitro and in vivo models of oxidative damage induced by arsenic, we demonstrated for the first time that exposure to arsenic caused a significant increase in SUMOylation of FTO protein, and FTO SUMOylation at lysine (K)- 216 site promoted the down-regulation of FTO expression in arsenic target organ lung, and therefore, remarkably elevating the oxidative damage via an m6A-dependent pathway by its specific m6A reader insulin-like growth factor-2 mRNA-binding protein-3 (IGF2BP3). Consequently, these findings not only reveal a novel mechanism underlying FTO-mediated oxidative damage from the perspective of m6A, but also imply that regulation of FTO SUMOylation may serve as potential approach for treatment of oxidative damage.

Sea-level rise and arsenic-rich soils: A toxic relationship.

In the United States, dangerously high arsenic (As) levels have been found in drinking water wells in more than 25 states, potentially exposing 2.1 million people to drinking water high in As; a known carcinogen. The anticipated sea-level rise (SLR) is expected to alter soil biogeochemical and hydrological conditions, potentially impacting their ability to sequester As. In our study of coastal Wilmington, DE, an area projected to experience a 1 -meter SLR by 2100, we examined the spatial distribution, speciation, and release possibilities of As due to SLR. To understand the complex dynamics at play, we employed a comprehensive approach, including bulk and micro X-ray absorption spectroscopy measurements, hydrological pattern evaluation, and macroscopic stirred-flow experiments. Our results suggest that introducing reducing and saline conditions can increase As release in both river water and seawater inundation scenarios, most likely due to ionic competition and the dissolution of As-bearing Fe/Mn oxides. Regardless of the salinity source, the released As concentrations consistently exceeded the EPA threshold for drinking water. Our results provide valuable insights for developing appropriate remedial and management strategies for this site and numerous others facing similar environmental challenges. ENVIRONMENTAL IMPLICATION: With nearly two hundred million individuals living within coastal flood plains and with two million square kilometers of land and one trillion dollars' worth of assets lying less than 1 m above current sea level, sea-level rise (SLR) is one of the significant socio-economic threats associated with global warming. Arsenic is a prevalent contaminant in coastal areas impacted by industrial activities, many of which are susceptible to being impacted by SLR. This study examines SLR's impact on arsenic fate and speciation in a densely populated coastline in Wilmington, DE, expecting 1 meter of SLR by 2100.

Effects of arsenic on gut microbiota and its bioaccumulation and biotransformation in freshwater invertebrate.

This study aimed to investigate the impact of arsenic stress on the gut microbiota of a freshwater invertebrate, specifically the apple snail (Pomacea canaliculata), and elucidate its potential role in arsenic bioaccumulation and biotransformation. Waterborne arsenic exposure experiments were conducted to characterize the snail's gut microbiomes. The results indicate that low concentration of arsenic increased the abundance of gut bacteria, while high concentration decreased it. The dominant bacterial phyla in the snail were Proteobacteria, Firmicutes, Bacteroidota, and Actinobacteriota. In vitro analyses confirmed the critical involvement of the gut microbiota in arsenic bioaccumulation and biotransformation. To further validate the functionality of the gut microbiota in vivo, antibiotic treatment was administered to eliminate the gut microbiota in the snails, followed by exposure to waterborne arsenic. The results demonstrated that antibiotic treatment reduced the total arsenic content and the proportion of arsenobetaine in the snail's body. Moreover, the utilization of physiologically based pharmacokinetic modeling provided a deeper understanding of the processes of bioaccumulation, metabolism, and distribution. In conclusion, our research highlights the adaptive response of gut microbiota to arsenic stress and provides valuable insights into their potential role in the bioaccumulation and biotransformation of arsenic in host organisms. ENVIRONMENTAL IMPLICATION: Arsenic, a widely distributed and carcinogenic metalloid, with significant implications for its toxicity to both humans and aquatic organisms. The present study aimed to investigate the effects of As on gut microbiota and its bioaccumulation and biotransformation in freshwater invertebrates. These results help us to understand the mechanism of gut microbiota in aquatic invertebrates responding to As stress and the role of gut microbiota in As bioaccumulation and biotransformation.

Transporters and phytohormones analysis reveals differential regulation of ryegrass (Lolium perenne L.) in response to cadmium and arsenic stresses.

Cadmium (Cd) and arsenic (As) are two highly toxic heavy metals and metalloids that coexist in many situations posing severe threats to plants. Our investigation was conducted to explore the different regulatory mechanisms of ryegrass (Lolium perenne L.) responding to individual and combined Cd and As stresses in hydroponics. Results showed that the ryegrass well-growth phenotype was not affected by Cd stress of 10 mg·L-1. However, As of 10 mg·L-1 caused rapid water loss, proline surge, and chlorosis in shoots, suggesting that ryegrass was highly sensitive to As. Transcriptomic analysis revealed that the transcription factor LpIRO2 mediated the upregulation of ZIP1 and YSL6 that played an important role in Cd tolerance. We found that the presence of As caused the overexpression of LpSWT12, a process potentially regulated by bHLH14, to mitigate hyperosmolarity. Indoleacetic acid (IAA) and abscisic acid (ABA) contents and expression of their signaling-related genes were significantly affected by As stress rather than Cd. We predict a regulatory network to illustrate the interaction between transporters, transcription factors, and signaling transduction, and explain the antagonism of Cd and As toxicity. This present work provides a research basis for plant protection from Cd and As pollution.

The mitochondria-targeted antioxidant MitoQ ameliorates inorganic arsenic-induced DCs/Th1/Th2/Th17/Treg differentiation partially by activating PINK1-mediated mitophagy in murine liver.

Inorganic arsenic is a well-established environmental toxicant linked to acute liver injury, fibrosis, and cancer. While oxidative stress, pyroptosis, and ferroptosis are known contributors, the role of PTEN-induced kinase 1 (PINK1)-mediated mitophagy in arsenic-induced hepatic immunotoxicity remains underexplored. Our study revealed that acute arsenic exposure prompts differentiation of hepatic dendritic cells (DCs) and T helper (Th) 1, Th2, Th17, and regulatory T (Treg) cells, alongside increased transcription factors and cytokines. Inorganic arsenic triggered liver redox imbalance, leading to elevated alanine transaminase (ALT), hydrogen peroxide (H2O2), malondialdehyde (MDA), and activation of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway. PINK1-mediated mitophagy was initiated, and its inhibition exacerbates H2O2 accumulation while promoting DCs/Th1/Th2/Treg differentiation in the liver of arsenic-exposed mice. Mitoquinone (MitoQ) pretreatment relieved arsenic-induced acute liver injury and immune imbalance by activating Nrf2/HO-1 and PINK1-mediated mitophagy. To our knowledge, this is the first report identifying PINK1-mediated mitophagy as a protective factor against inorganic arsenic-induced hepatic DCs/Th1/Th2 differentiation. This study has provided new insights on the immunotoxicity of inorganic arsenic and established a foundation for exploring preventive and therapeutic strategies targeting PINK1-mediated mitophagy in acute liver injury. Consequently, the application of mitochondrial antioxidant MitoQ may offer a promising treatment for the metalloid-induced acute liver injury.

Co-exposure of arsenic and polystyrene-nanoplastics induced kidney injury by disrupting mitochondrial homeostasis and mtROS-mediated ferritinophagy and ferroptosis.

Arsenic (As) and polystyrene nanoplastics (PSNPs) co-exposure induced biotoxicity and ecological risks have attracted wide attention. However, the combined effects of As and PSNPs on the kidney and their underlying mechanisms of toxicities remain to be explored. Here, we investigated the effects of As and PSNPs co-exposure on structure and function in mice kidney, and further explored the possible mechanisms. In this study, we identified that co-exposure to As and PSNPs exhibited conspicuous renal structural damage and pathological changes, accompanied by renal tissue fibrosis (increased protein expression of Collagen I and α-SMA and deposition of collagen fibers), whereas alone exposure to As or PSNPs does not exhibit nephrotoxicity. Subsequently, our results further showed that combined action of As and PSNPs induced mitochondrial oxidative damage and impaired mitochondrial dynamic balance. Furthermore, co-treatment with As and PSNPs activated NCOA4-mediated ferritinophagy and ferroptosis in mice kidney and TCMK-1 cells, which was confirmed by the changes in the expression of ferritinophagy and ferroptosis related indicators (NCOA4, LC3, ATG5, ATG7, FTH1, FTL, GPX4, SLC7A11, FSP1, ACSL4 and PTGS2). Meaningfully, pretreatment with the mtROS-targeted scavenger Mito-TEMPO significantly attenuated As and PSNPs co-exposure induced mitochondrial damage, ferritinophagy and ferroptosis. In conclusion, these findings demonstrated that mtROS-dependent ferritinophagy and ferroptosis are important factors in As and PSNPs co-exposure induced kidney injury and fibrosis. This study provides a new insight into the study of combined toxicity of nanoplastics and heavy metal pollutants.

Resveratrol alleviates inorganic arsenic-induced ferroptosis in chicken brain via activation of the Nrf2 signaling pathway.

Inorganic arsenic (iAs) is a well-recognized environmental pollutant that induces severe brain injury in humans and animals. The antioxidant, anti-inflammatory, and anti-ferroptotic effects of resveratrol (Res) were demonstrated in multiple animal experiments. In order to investigate the protective effect of Res on iAs-induced chicken brain injury, the 40 chickens (19-d-old, female) brain injury model was established by oral administration of iAs (30 mg/L NaAsO2) for 6 weeks. All chickens had free access to both food and water during the experiment. The biochemical indices, hematoxylin-eosin staining, and related protein levels of oxidative stress, inflammation and ferroptosis were then determined. Our results indicated that Res (1000 mg/kg) alleviated the iAs-induced brain injury after 6 weeks of oral administration, primarily by reducing the interleukin-1ß mRNA expression and nuclear factor kappa B and malondialdehyde level, and increasing the antioxidant enzyme activity and the mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, our study demonstrates that Res effectively inhibits iAs-induced oxidative stress and ferroptosis by mediating the Nrf2 signaling pathway, thereby alleviating iAs-induced brain injury in chickens. This is the first time that the amelioration effects of Res on the iAs-induced brain have been investigated from multiple perspectives.

Essential and Toxic Elements in Infant Cereal in Brazil: Exposure Risk Assessment.

Infant cereals, one of the first solid foods introduced to infants, have been reported to pose risks to human health because they contain toxic elements and an excess of essential elements. The objective of this study was to assess the cancer and non-cancer risk of exposure to essential and toxic elements in infant cereal in Brazil. In our analyses, we included data from 18 samples of infant cereals made from different raw materials and estimated the incremental lifetime cancer risks and non-cancer hazard quotients (HQs) for their consumption. Rice cereal is particularly concerning because it is immensely popular and usually contains high levels of inorganic arsenic. In addition to arsenic, we assessed aluminum, boron, barium, cadmium, chromium, copper, lead, manganese, nickel, selenium, silver, strontium, and zinc. The cancer risk was highest for rice cereal, which was also found to have an HQ > 1 for most of the tested elements. Inorganic As was the element associated with the highest cancer risk in infant cereal. All of the infant cereals included in this research contained at least one element with an HQ > 1. The essential and non-essential elements that presented HQ > 1 more frequently were zinc and cadmium, respectively. The cancer and non-cancer risks could potentially be decreased by reducing the amount of toxic and essential elements (when in excess), and public policies could have a positive influence on risk management in this complex scenario.

Effects of multiple metals exposure on abnormal liver function: The mediating role of low-density lipoprotein cholesterol.

Equilibration of metal metabolism is critical for normal liver function. Most epidemiological studies have only concentrated on the influence of limited metals. However, the single and synergistic impact of multiple-metal exposures on abnormal liver function (ALF) are still unknown. A cross-sectional study involving 1493 Chinese adults residing in Shenzhen was conducted. Plasma concentrations of 13 metals, including essential metals (calcium, copper, cobalt, iron, magnesium, manganese, molybdenum, zinc, and selenium) and toxic metals (aluminum, cadmium, arsenic, and thallium) were detected by the inductively coupled plasma spectrometry (ICP-MS). ALF was ascertained as any observed abnormality from albumin, alanine transaminase, aspartate transaminase, γ-glutamyl transpeptidase, and direct bilirubin. Diverse statistical methods were used to evaluate the single and mixture effect of metals, as well as the dose-response relationships with ALF risk, respectively. Mediation analysis was conducted to evaluate the role of blood lipids in the relation of metal exposure with ALF. The average age of subjects was 59.7 years, and 56.7 % were females. Logistic regression and the least absolute shrinkage and selection operator (LASSO) penalized regression model consistently suggested that increased levels of arsenic, aluminum, manganese, and cadmium were related to elevated risk of ALF; while magnesium and zinc showed protective effects on ALF (all p-trend < 0.05). The grouped weighted quantile sum (GWQS) regression revealed that the WQS index of essential metals and toxic metals showed significantly negative or positive relationship with ALF, respectively. Aluminum, arsenic, cadmium, and manganese showed linear whilst magnesium and zinc showed non-linear dose-response relationships with ALF risk. Mediation analysis showed that LDL-c mediated 4.41 % and 14.74 % of the relationship of plasma cadmium and manganese with ALF, respectively. In summary, plasma aluminum, arsenic, manganese, cadmium, magnesium, and zinc related with ALF, and LDL-c might underlie the pathogenesis of ALF associated with cadmium and manganese exposure. This study may provide critical public health significances in liver injury prevention and scientific evidence for the establishment of environmental standard.

Unraveling the genetics of arsenic toxicity with cellular morphology QTL.

The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene-environment) interactions. However, risk assessment in laboratory mice typically involves isogenic strains and therefore, does not account for these known genetic effects. In this context, genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening because they provide a way to introduce genetic variation in risk assessment without increasing animal use. Cell lines from genetic reference populations of laboratory mice offer genetic diversity, power for genetic mapping, and potentially, predictive value for in vivo experimentation in genetically matched individuals. To explore this further, we derived a panel of fibroblast lines from a genetic reference population of laboratory mice (the Diversity Outbred, DO). We then used high-content imaging to capture hundreds of cell morphology traits in cells exposed to the oxidative stress-inducing arsenic metabolite monomethylarsonous acid (MMAIII). We employed dose-response modeling to capture latent parameters of response and we then used these parameters to identify several hundred cell morphology quantitative trait loci (cmQTL). Response cmQTL encompass genes with established associations with cellular responses to arsenic exposure, including Abcc4 and Txnrd1, as well as novel gene candidates like Xrcc2. Moreover, baseline trait cmQTL highlight the influence of natural variation on fundamental aspects of nuclear morphology. We show that the natural variants influencing response include both coding and non-coding variation, and that cmQTL haplotypes can be used to predict response in orthogonal cell lines. Our study sheds light on the major molecular initiating events of oxidative stress that are under genetic regulation, including the NRF2-mediated antioxidant response, cellular detoxification pathways, DNA damage repair response, and cell death trajectories.

Toxicological profile and potential health concerns through metals and trace elements exposure in brick kiln workers from Lahore, Pakistan.

This study examined levels of lead (Pb), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), and arsenic (As) in blood, hair, and nails of 18 brick kiln workers from three brick kiln units located around a metropolitan city, Lahore, Pakistan. All the trace elements except Hg and As were detected in the studied matrices of Brick kiln workers. In general, brick kiln workers reflect the highest concentration of Pb, followed by Cd, Cr, and Cu. Of the pollutants analyzed, Pb has the highest mean (min-max) concentrations at 0.35 (0.09-0.65) in blood (µg/mL), 0.34 (0.14-0.71) in hairs (µg/g), and 0.44 (0.32-0.59) in nails (µg/g) of brick kiln workers. Following Pb, the trend was Cd 0.17 (0.10-0.24), Cu 0.11(0.03-0.27), and Cr 0.07 (0.04-0.08) in blood (µg/mL), followed by Cr 0.11(0.05-0.20), Cd 0.09 (0.03-0.13), and Cu 0.08 (0.04-0.16) in hairs (µg/g) and Cu 0.16 (0.05-0.36), Cd 0.13 (0.11-0.17), and Cr 0.10 (0.05-0.14) in nails (µg/g) respectively. Relatively higher concentrations of metals and other trace elements in blood depicts recent dietary exposure. The difference of trace elements except Pb was non-significant (P > 0.05) among studied matrices of workers as well as between Zigzag and traditional exhaust-based brick kilns. The concentrations of Pb, Cd and Cr in blood of brick kilns workers are higher than the values reported to cause health problems in human populations. It is concluded that chronic exposure to metals and other trace elements may pose some serious health risks to brick kiln workers which needs to be addressed immediately to avoid future worst-case scenarios.

Integrative investigation of hematotoxic effects induced by low doses of lead, cadmium, mercury and arsenic mixture: In vivo and in silico approach.

The effect of the lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) mixture (MIX) on hematotoxicity development was investigated trough combined approach. In vivo subacute study (28 days) was performed on rats (5 per group): a control group and five groups orally exposed to increasing metal(loid) mixture doses, MIX 1- MIX 5 (mg/kg bw./day) (Pb: 0.003, 0.01, 0.1, 0.3, 1; Cd: 0.01, 0.03, 0.3, 0.9, 3; Hg: 0.0002, 0.0006, 0.006, 0.018, 0.06; As: 0.002, 0.006, 0.06, 0.18, 0.6). Blood was taken for analysis of hematological parameters and serum iron (Fe) analysis. MIX treatment increased thrombocyte/platelet count and MCHC and decreased Hb, HCT, MCV and MCH values compared to control, indicating the development of anemia and thrombocytosis. BMDIs with the narrowest width were identified for MCH [pg] (6.030E-03 - 1.287E-01 mg Pb/kg bw./day; 2.010E-02 - 4.290E-01 mg Cd/kg bw./day; 4.020E-04 - 8.580E-03 mg Hg/kg bw./day; 4.020E-03 - 8.580E-02 mg As/kg bw./day). In silico analysis showed target genes connected with MIX and the development of: anemia - ACHE, GSR, PARP1, TNF; thrombocytosis - JAK2, CALR, MPL, THPO; hematological diseases - FAS and ALAD. The main extracted pathways for anemia were related to apoptosis and oxidative stress; for thrombocytosis were signaling pathways of Jak-STAT and TPO. Changes in miRNAs and transcription factors enabled the mode of action (MoA) development based on the obtained results, contributing to mechanistic understanding and hematological risk related to MIX exposure.

Targeting OsNIP3;1 via CRISPR/Cas9: A strategy for minimizing arsenic accumulation and boosting rice resilience.

Arsenic (As) contamination in rice poses a significant threat to human health due to its toxicity and widespread consumption. Identifying and manipulating key genes governing As accumulation in rice is crucial for reducing this threat. The large NIP gene family of aquaporins in rice presents a promising target due to functional redundancy, potentially allowing for gene manipulation without compromising plant growth. This study aimed to utilize genome editing to generate knock-out (KO) lines of genes of NIP family (OsLsi1, OsNIP3;1) and an anion transporter family (OsLsi2), in order to assess their impact on As accumulation and stress tolerance in rice. KO lines were created using CRISPR/Cas9 technology, and the As accumulation patterns, physiological performance, and grain yield were compared against wild-type (WT) under As-treated conditions. KO lines exhibited significantly reduced As accumulation in grain compared to WT. Notably, Osnip3;1 KO line displayed reduced As in xylem sap (71-74%) and grain (32-46%) upon treatment. Additionally, these lines demonstrated improved silicon (23%) uptake, photosynthetic pigment concentrations (Chl a: 77%; Chl b: 79%, Total Chl: 79% & Carotenoid: 49%) overall physiological and agronomical performance under As stress compared to WT. This study successfully utilized genome editing for the first time to identify OsNIP3;1 as a potential target for manipulating As accumulation in rice without compromising grain yield or plant vigor.

Anthocyanins from blueberry ameliorated arsenic-induced memory impairment, oxidative stress, and mitochondrial-biosynthesis imbalance in rat hippocampal neurons.

In this study, blueberry anthocyanins extract (BAE) was used to investigate its protective effect on arsenic-induced rat hippocampal neurons damage. Arsenic exposure resulted in elevated levels of oxidative stress, decreased antioxidant capacity and increased apoptosis in rat hippocampal brain tissue and mitochondria. Immunohistochemical results showed that arsenic exposure also significantly decreased the expression of mitochondrial biosynthesis-related factors PGC-1α and TFAM. Treatment with BAE alleviated the decrease in antioxidant capacity, mitochondrial biogenesis related protein PGC-1α/NRF2/TFAM expression, and ATP production of arsenic induced hippocampal neurons in rats, and improved cognitive function in arsenic damaged rats. This study provides new insights into the detoxification effect of anthocyanins on the nervous system toxicity caused by metal exposure in the environment, indicating that anthocyanins may be a natural antioxidant against the nervous system toxicity caused by environmental metal exposure.

The plastid-localized lipoamide dehydrogenase 1 is crucial for redox homeostasis, tolerance to arsenic stress and fatty acid biosynthesis in rice.

Soil contamination with arsenic (As) can cause phytotoxicity and reduce crop yield. The mechanisms of As toxicity and tolerance are not fully understood. In this study, we used a forward genetics approach to isolate a rice mutant, ahs1, that exhibits hypersensitivity to both arsenate and arsenite. Through genomic resequencing and complementation tests, we identified OsLPD1 as the causal gene, which encodes a putative lipoamide dehydrogenase. OsLPD1 was expressed in the outer cell layer of roots, root meristem cells, and in the mesophyll and vascular tissues of leaves. Subcellular localization and immunoblot analysis demonstrated that OsLPD1 is localized in the stroma of plastids. In vitro assays showed that OsLPD1 exhibited lipoamide dehydrogenase (LPD) activity, which was strongly inhibited by arsenite, but not by arsenate. The ahs1 and OsLPD1 knockout mutants exhibited significantly reduced NADH/NAD+ and GSH/GSSG ratios, along with increased levels of reactive oxygen species and greater oxidative stress in the roots compared with wild-type (WT) plants under As treatment. Additionally, loss-of-function of OsLPD1 also resulted in decreased fatty acid concentrations in rice grain. Taken together, our finding reveals that OsLPD1 plays an important role for maintaining redox homeostasis, conferring tolerance to arsenic stress, and regulating fatty acid biosynthesis in rice.

Effect of arsenic on the risk of gestational diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Gestational diabetes mellitus (GDM) is a complication of pregnancy associated with numerous adverse outcomes. There may be a potential link between GDM and arsenic (As) exposure, but this hypothesis remains controversial. This meta-analysis summarizes the latest studies evaluating the association between As and GDM. METHODS: A comprehensive search of the PubMed, Embase, and Scopus databases up to September 2023 was performed. The pooled estimates with 95% CIs were presented using forest plots. Estimates were calculated with random effects models, and subgroup and sensitivity analyses were conducted to address heterogeneity. RESULTS: A total of 13 eligible studies involving 2575 patients with GDM were included in this meta-analysis. The results showed that women exposed to As had a significantly increased risk of GDM (OR 1.47, 95% CI: 1.11 to 1.95, P = 0.007). Subgroup analyses suggested that the heterogeneity might be attributed to the years of publication. In addition, sensitivity analysis confirmed the robust and reliable results. CONCLUSIONS: This analysis suggested that women exposed to As have a greater risk of GDM. However, the significant heterogeneity across studies requires careful interpretation. REGISTRATION: The PROSPERO registration ID is CRD42023461820.