Inorganic arsenic (iAs)-induced urothelial carcinoma (UC) develops into a poor-prognosis malignancy. Arsenic-induced oxidative stress contributes to circadian rhythm disruption altered metabolism. Glutamine anaplerosis is a common metabolic feature of rapidly proliferating malignant cells, in which glutaminase (GLS) is a key enzyme in this process. Therefore, this study intends to determine if arsenic-induced oxidative stress can alter circadian rhythms and promote glutamine anaplerosis. Exonic expression of core circadian molecules (CLOCK, ARNTL, and NR1D1) and GLS in varying grades of UC were assessed using 423 bladder cancer samples from the TCGA Urothelial Bladder Cancer (BLCA) dataset. The levels of circadian proteins and metabolic markers in 44 UC patients from non-black foot disease (BFD) and BFD areas were detected by immunohistochemistry. In vitro and in vivo experiments elucidated the regulatory mechanisms of arsenic-mediated circadian disturbance and metabolic alteration. Public database analysis showed that ARNTL, NR1D1, and GLS exhibited greater expression in more high-grade UC. Strong immunoreactivity for BMAL1, GLS, and low levels of NR1D1 were found in malignant urothelial lesions, especially in arsenic-exposed UC. Arsenic-induced overexpression of BMAL1 and GLS involves activation of NADH: quinone oxidoreductase 1 (NQO1), continuously altering the NADH oscillations to promote glutamate metabolism in SV-HUC-1, T24 and BFTC-905 cells. These phenomenon were also demonstrated in the urothelium of arsenic-exposed animals. The present findings highlight the potential clinical significance of BMAL1 and GLS in UC in the BFD region. Furthermore, these results suggest that arsenic interferes with circadian rhythm and glutamine anaplerosis by NADH oscillatory imbalance in urothelial cells and urothelial cancer cells, predisposing them to malignant development.

Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N6-methyladenosine (m6A) modification is known to modulate pri-miRNA processing. However, whether m6A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m6A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m6A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m6A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m6A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What\'s more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m6A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.

The knowledge about co-transport of goethite and As3+ to investigate the effect of goethite colloids on As3+ transport under various degrees of seawater intrusion, particular extremely conditions, in groundwater environment is still limited. The main objective is to investigate the influence of seawater intrusion on the sorption, migration, and reaction of As3+and goethite colloids into sand aquifer media under anoxic conditions by using the bench-scale and reactive geochemical modeling. The research consisted of two parts as follows: 1) column transport experiments consisting of 8 columns, which were packed by using synthesis groundwater at IS of 0.5, 50, 200, and 400 mM referring to the saline of seawater system in the study area, and 2) reactive transport modeling, the mathematical model (HYDRUS-1D) was applied to describe the co-transport of As3+ and goethite. Finally, to explain the interaction of goethite and As3+, the Derjaguin-Landau-Verwey-Overbeek (DLVO) calculation was considered to support the experimental results and HYDRUS-1D model. The results of column experiments showed goethite colloids can significantly inhibit the mobility of As3+ under high IS conditions (>200 mM). The Rf of As3+ bound to goethite grows to higher sizes (47.5 and 65.0 μm for 200 and 400 mM, respectively) of goethite colloid, inhibiting As3+ migration through the sand columns. In contrast, based on Rf value, goethite colloids transport As3+ more rapidly than a solution with a lower IS (0.5 and 50 mM). The knowledge gained from this study would help to better understand the mechanisms of As3+ contamination in urbanized coastal groundwater aquifers and to assess the transport of As3+ in groundwater, which is useful for groundwater management, including the optimum pumping rate and long-term monitoring of groundwater quality.

Various stress conditions, such as heat stress (HS) and oxidative stress, can cause biomolecular condensates represented by stress granules (SGs) via liquid-liquid phase separation. We have previously shown that Hsp90 forms aggregates in response to HS and that Hsp90 aggregates transiently co-localize with SGs as visualized by Pabp. Here, we showed that arsenite, one of the well-described SG-inducing stimuli, induces Hsp90 aggregates distinct from conventional SGs in fission yeast. Arsenite induced Hsp90 granules in a dose-dependent manner, and these granules were significantly diminished by the co-treatment with a ROS scavenger N-acetyl cysteine (NAC), indicating that ROS are required for the formation of Hsp90 granules upon arsenite stress. Notably, Hsp90 granules induced by arsenite do not overlap with conventional SGs as represented by eIF4G or Pabp, while HS-induced Hsp90 granules co-localize with SGs. Nrd1, an RNA-binding protein known as a HS-induced SG component, was recruited into Hsp90 aggregates but not to the conventional SGs upon arsenite stress. The non-phosphorylatable eIF2α mutants significantly delayed the Hsp90 granule formation upon arsenite treatment. Importantly, inhibition of Hsp90 by geldanamycin impaired the Hsp90 granule formation and reduced the arsenite tolerance. Collectively, arsenite stimulates two types of distinct aggregates, namely conventional SGs and a novel type of aggregates containing Hsp90 and Nrd1, wherein Hsp90 plays a role as a center for aggregation, and stress-specific compartmentalization of biomolecular condensates.

Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.

Schwertmannite (Sch) holds a great promise as an iron material for remediating Arsenic (As)-contaminated paddy soils, due to its extremely high immobilization capacities for both arsenate [As(V)] and arsenite [As(III)]. However, there is still limited knowledge on the mineral phase transformation of this metastable iron-oxyhydroxysulfate mineral in paddy soils, particularly under different water management regimes including aerobic, intermittent flooding, and continuous flooding, and how its phase transformation impacts the migration of As in paddy soils. In this study, a membrane coated with schwertmannite was first developed to directly reflect the phase transformation of bulk schwertmannite applied to paddy soils. A soil incubation experiment was then conducted to investigate the mineral phase transformation of schwertmannite in paddy soils under different water management regimes and its impact on the migration of As in paddy soil. Our findings revealed that schwertmannite can persist in the paddy soil for 90 days in the aerobic group, whereas in the continuous flooding and intermittent flooding groups, schwertmannite transformed into goethite, with the degree or rate of mineral phase transformation being 5% Sch >1% Sch > control. These results indicated that water management practices and the amount of schwertmannite applied were the primary factors determining the occurrence and degree of mineral transformation of schwertmannite in paddy soil. Moreover, despite undergoing phase transformation, schwertmannite still significantly reduced the porewater As (As(III) and As(V)), and facilitated the transfer of non-specifically adsorbed As (F1) and specifically adsorbed As (F2) to amorphous iron oxide-bound As (F3), effectively reducing the bioavailability of soil As. These findings contribute to a better understanding of the mineralogical transformation of schwertmannite in paddy soils and the impact of mineral phase transformation on the retention of As in soil, which carry important implications for the application of schwertmannite in remediating As-contaminated paddy soils.

Contamination of ground water and soil with toxic metalloids like arsenic (As) poses a serious hazard to the global agricultural food production. One of the best ways to restrict entry of As into the food chain is selection of germplasms which accrue extremely low level of As in grains. Here, we screened diverse maize genotypes under high arsenite (100 μM AsIII) stress and identified PMI-PV-9 and PMI-PV-3 as AsIII-tolerant and -sensitive maize genotype respectively. Expression of genes associated with As uptake, vacuolar sequestration, biosynthesis of phytochelatins, root-to-shoot translocation, in vivo ROS generation, fine tuning of antioxidant defense system, DNA and membrane damage, H2O2 and superoxide anion (O2•-) levels were compared among the selected genotypes. PMI-PV-9 plants performed much better than PMI-PV-3 in terms of plant growth with no visible symptom of As toxicity. Susceptibility of PMI-PV-3 to AsIII stress may be attributed to comparatively low expression of genes involved in phytochelatins (PCs) biosynthesis. Concomitant decrease in ABCC1 expression might be another key factor for futile sequestration of AsIII into root vacuoles. Moreover, up-regulation of ZmNIP3;1 might contribute in high root-to-leaf As translocation. Substantial spike in H2O2, O2•- and MDA levels indicates that PMI-PV-3 plants have experienced more oxidative stress than PMI-PV-9 plants. Appearance of prominent deep brown and dark blue spots/stripes on leaves as revealed after DAB and NBT staining respectively suggest severe oxidative burst in PMI-PV-3 plants. Marked reduction in DHAR and MDAR activity rendered PMI-PV-3 cells to recycle ascorbate pool ineffectively, which might have exacerbated their susceptibility to AsIII stress. In a nutshell, incompetent PCs mediated detoxification system and disruption of cellular redox homeostasis owing to feeble antioxidant defence system resulting oxidative burst might be the prime reasons behind reduced performance of PMI-PV-3 plants under AsIII stress.

Arsenic poisoning of groundwater is one of the most critical environmental hazards on Earth. Therefore, the practical and proper treatment of arsenic in water requires more attention to ensure safe drinking water. The World Health Organization (WHO) sets guidelines for 10 μg/L of arsenic in drinking water, and direct long-term exposure to arsenic in drinking water beyond this value causes severe health hazards to individuals. Numerous studies have confirmed the adverse effects of arsenic after long-term consumption of arsenic-contaminated water. Here, technologies for the remediation of arsenic from water are highlighted for the purpose of understanding the need for a single-point solution for the treatment of As(III)-contaminated water. As(III) species are neutral at neutral pH; the solution requires transformation technology for its complete removal. In this critical review, emphasis was placed on single-step technologies with multiple functions to remediate arsenic from water.

The indigenous halophilic arsenite-resistant bacterium Halomonas elongata strain SEK2 isolated from the high saline soil of Malek Mohammad hole, Lut Desert, Iran, could tolerate high concentrations of arsenate (As5+) and arsenite (As3+) up to 800 and 40 mM in the SW-10 agar medium, respectively. The isolated strain was able to tolerate considerable concentrations of other toxic heavy metals and oxyanions, including Cadmium (Cd2+), Chromate (Cr6+), lead (Pb2+), and selenite (Se4+), regarding the high salinity of the culture media (with a total salt concentration of 10% (w/v)), the tolerance potential of the isolate SEK2 was unprecedented. The bioremoval potential of the isolate SEK2 was examined through the Silver diethyldithiocarbamate (SDDC) method and demonstrated that the strain SEK2 could remove 60% of arsenite from arsenite-containing growth medium after 48 h of incubation without converting it to arsenate. The arsenite adsorption or uptake by the halophilic bacterium was investigated and substantiated through Fourier-transform infrared spectroscopy (FTIR), Scanning Electron Microscope (SEM), and Energy Dispersive X-ray (EDX) analyses. Furthermore, Transmission electron microscope (TEM) analysis revealed ultra-structural alterations in the presence of arsenite that could be attributed to intracellular accumulation of arsenite by the bacterial cell. Genome sequencing analysis revealed the presence of arsenite resistance as well as other heavy metals/oxyanion resistance genes in the genome of this bacterial strain. Therefore, Halomonas elongata strain SEK2 was identified as an arsenite-resistant halophilic bacterium for the first time that could be used for arsenite bioremediation in saline arsenite-polluted environments.

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.