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The toxicity of arsenic has challenged life for billions of years, but the timing of when complex organisms first evolved strategies to cope with this threat remains elusive. Here, we study 2.1-billion-year-old (Ga) Francevillian macrofossils, some of Earth’s earliest complex life forms, to establish their biogenicity and to ascertain how they managed arsenic toxicity. The studied specimens thrived in low-arsenic marine waters, yet displayed strikingly high levels of arsenic, which was actively sequestered in specialized compartments in their bodies to mitigate toxicity. Upon their death, arsenic was released and incorporated into pyrite nuclei. The patterns observed in the fossils are distinct from abiotic concretions but similar to some seen in later eumetazoans, reinforcing their biological affinity. Our findings highlight that early complex life faced significant arsenic stress, even in low-concentration marine environments, which prompted the development of essential survival mechanisms. Arsenic incorporation into pyrite nuclei reveals that the 2.1-billion-year-old Francevillian biota actively detoxified arsenic by sequestration in specialized body compartments.

Arsenic, distributed pervasively in the natural environment, is an extremely toxic substance which can severely impair the normal functions of living cells. Research on the genetic mechanisms of arsenic metabolism is of great importance for remediating arsenic-contaminated environments. Many organisms, including bacteria, have developed various strategies to tolerate arsenic, by either detoxifying this harmful element or utilizing it for energy generation. This review summarizes arsenic detoxification as well as arsenic respiratory metabolic pathways in bacteria and discusses novel arsenic resistance pathways in various bacterial strains. This knowledge provides insights into the mechanisms of arsenic biotransformation in bacteria. Multiple detoxification strategies among bacteria imply possible functional relationships among different arsenic detoxification/metabolism pathways. In addition, this review sheds light on the bioremediation of arsenic-contaminated environments and prevention of antibiotic resistance.

Arsenic (As) contamination affects hundreds of millions of people globally. Although the number of patients with chronic As exposure is large, the symptoms and long-term clinical courses of the patients remain unclear. In addition to reviewing the literature on As contamination and toxicity, we provide useful clinical information on medical care for As-exposed patients. Further, As metabolite pathways, toxicity, speculated toxicity mechanisms, and clinical neurological symptoms are documented. Several mechanisms that seem to play key roles in As-induced neurotoxicity, including oxidative stress, apoptosis, thiamine deficiency, and decreased acetyl cholinesterase activity, are described. The observed neurotoxicity predominantly affects peripheral nerves in sensory fibers, with a lesser effect on motor fibers. A sural nerve biopsy showed the axonal degeneration of peripheral nerves mainly in small myelinated and unmyelinated fibers. Exposure to high concentrations of As causes severe central nervous system impairment in infants, but no or minimal impairment in adults. The exposure dose–response relationship was observed in various organs including neurological systems. The symptoms caused by heavy metal pollution (including As) are often nonspecific. Therefore, in order to recognize patients experiencing health problems caused by As, a multifaceted approach is needed, including not only clinicians, but also specialists from multiple fields.

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RARα. Mechanistically, we found that HDAC3 deacetylated PML-RARα at lysine 394, which reduced PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RARα ubiquitylation and degradation and reduced the expression of PML-RARα in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.

Arsenic contamination in a water system is an urgent environmental problem that has caused severe endemic arsenicosis in south and southeast Asian countries. It is well known that microbially mediated arsenic metabolism can enhance arsenic mobility, bioavailability, and toxicity. Here, for the first time, we applied the Illumina high-throughput metagenomic and metatranscriptomic approaches to study the distribution, diversity, abundance, and expression of microbial arsenic metabolism genes in activated sludge and five coastal sediments. An average depth of ~2.6 Gb clean data for each sample was finally obtained for BLAST analysis after quality filtration and normalization. The results revealed that: (1) highly diverse arsenic metabolism-like genes were found and the overall abundance varied from 0.18 % to 0.26 % in the six metagenomic data sets; (2) arsenic metabolism-like genes were expressed with extremely low levels or no expression at all in activated sludge; and (3) the distribution, diversity, and abundance of aioA -like, arrA -like, arsB -like, ACR3 -like, and arsM -like genes varied significantly in the six surveyed environments. This study provided a novel perspective on understanding the ecology of arsenic metabolism in different water environments using high-throughput sequencing technique.

Background: Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. Objectives: We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+ III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMTla and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods: Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 fig/L] and in rural Bangladesh [n = 361; U-As, 100 ug/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. Results: Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p > < 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (% MMA), and the most frequent haplotype in Argentina was associated with a lower % MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. Conclusions: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

BackgroundPrenatal exposure to arsenic and mercury have been associated with adverse pregnancy outcomes that might be in part mediated by dynamic modification of imprinting gene that are emerging mechanism.ObjectivesThe objective of this study was to examine the impacts of paternal exposure to arsenic and co-exposure to arsenic and mercury on human sperm DNA methylation status of imprinting genes, respectively.MethodsA total of 352 male subjects (23–52 years old) were recruited and demographic data were obtained through questionnaires. Urinary arsenic and mercury levels were measured using hydride generation-atomic fluorescence spectrometer. Multivariate regression model was employed to investigate the relationship between urinary arsenic levels and sperm DNA methylation status at H19, Meg3 and Peg3, measured by pyrosequencing, and evaluating the interaction with mercury.ResultsAfter adjusting potential confounds factors by multivariate regression model, the results indicated a significantly positive relationship between urinary arsenic levels and the methylation status of Meg3 at both mean level (β =  + 0.125, p < 0.001) and all individual CpGs, i.e., CpG1 (β =  + 0.094, p < 0.001), CpG2 (β =  + 0.132, p < 0.001), CpG3 (β =  + 0.121, p < 0.001), CpG4 (β =  + 0.142, p < 0.001), CpG5 (β =  + 0.111, p < 0.001), CpG6 (β =  + 0.120, p < 0.001), CpG7 (β =  + 0.143, p < 0.001), CpG8 (β =  + 0.139, p < 0.001) of Meg3 DMRs. The interaction effects analysis indicated the interaction effects of arsenic and mercury on Meg3 were not existing.ConclusionsPaternal nonoccupational exposure to arsenic induces the altered DNA methylation status of Meg3 in human sperm DNA. In addition, the interaction effects of arsenic and mercury on Meg3 were not existing. These findings would implicate the sensibility of sperm epigenome for environmental pollutions.

Background Prenatal inorganic arsenic (iAs) exposure is associated with pregnancy outcomes. Maternal capabilities of arsenic biotransformation and elimination may influence the susceptibility of arsenic toxicity. Therefore, we examined the determinants of arsenic metabolism of pregnant women in Bangladesh who are exposed to high levels of arsenic. Methods In a prospective birth cohort, we followed 1613 pregnant women in Bangladesh and collected urine samples at two prenatal visits: one at 4–16 weeks, and the second at 21–37 weeks of pregnancy. We measured major arsenic species in urine, including iAs (iAs%) and methylated forms. The proportions of each species over the sum of all arsenic species were used as biomarkers of arsenic methylation efficiency. We examined the difference in arsenic methylation using a paired t-test between first and second visits. Using linear regression, we examined determinants of arsenic metabolism, including age, BMI at enrollment, education, financial provider income, arsenic exposure level, and dietary folate and protein intake, adjusted for daily energy intake. Results Comparing visit 2 to visit 1, iAs% decreased 1.1% ( p  <  0.01), and creatinine-adjusted urinary arsenic level (U-As) increased 21% (95% CI: 15, 26%; p  <  0.01). Drinking water arsenic concentration was positively associated with iAs% at both visits. When restricted to participants with higher adjusted urinary arsenic levels (adjusted U-As > 50 μg/g-creatinine) gestational age at measurement was strongly associated with DMA% (β = 0.38, p <  0.01) only at visit 1. Additionally, DMA% was negatively associated with daily protein intake (β = − 0.02, p <  0.01) at visit 1, adjusting for total energy intake and other covariates. Conclusions Our findings indicate that arsenic metabolism and adjusted U-As level increase during pregnancy. We have identified determinants of arsenic methylation efficiency at visit 1.

Arsenic is a very potent toxicant. One major susceptibility factor for arsenic-related toxicity is the efficiency of arsenic metabolism. The efficiency, in turn, is associated with non-coding single nucleotide polymorphisms (SNPs) in the arsenic methyltransferase AS3MT on chromosome 10q24. However, the mechanism of action for these SNPs is not yet clarified. Here, we assessed the influence of genetic variation in AS3MT on DNA methylation and gene expression within 10q24, in people exposed to arsenic in drinking water. DNA was extracted from peripheral blood from women in the Argentinean Andes (N = 103) and from cord blood from new-borns in Bangladesh (N = 127). AS3MT SNPs were analyzed with Sequenom or Taqman assays. Whole genome epigenetic analysis with Infinium HumanMethylation450 BeadChip was performed on bisulphite-treated DNA. Whole genome gene expression analysis was performed with Illumina DirectHyb HumanHT-12 v4.0 on RNA from peripheral blood. Arsenic exposure was assessed by HPLC-ICPMS. In the Argentinean women, the major AS3MT haplotype, associated with more efficient arsenic metabolism, showed increased methylation of AS3MT (p = 10(-6)) and also differential methylation of several other genes within about 800 kilobasepairs: CNNM2 (p<10(-16)), NT5C2 (p<10(-16)), C10orf26 (p = 10(-8)), USMG5 (p = 10(-5)), TRIM8 (p = 10(-4)), and CALHM2 (p = 0.038) (adjusted for multiple comparisons). Similar, but weaker, associations between AS3MT haplotype and DNA methylation in 10q24 were observed in cord blood (Bangladesh). The haplotype-associated altered CpG methylation was correlated with reduced expression of AS3MT and CNNM2 (r(s) = -0.22 to -0.54), and with increased expression of NT5C2 and USMG5 (r(s) = 0.25 to 0.58). Taking other possibly influential variables into account in multivariable linear models did only to a minor extent alter the strength of the associations. In conclusion, the AS3MT haplotype status strongly predicted DNA methylation and gene expression of AS3MT as well as several genes in 10q24. This raises the possibility that several genes in this region are important for arsenic metabolism.

Chronic exposure to inorganic arsenic results in many cancers in susceptible persons. The metabolism of inorganic arsenic and genomic susceptibility are thought to be associated with cancer occurrence. This study aims to examine the interaction of genomic susceptibility markers and urinary methylation capacity indicators involved in inorganic arsenic metabolism with all-cancer occurrence. This study conducted a follow-up on 96 residents to determine their urinary inorganic arsenic metabolites and genomic assay from an arseniasis area. Among them, 24 cancer developed. Multivariable Cox proportional hazards model was used to determine and estimate the candidate independent variables for cancer development. The residents with high inorganic arsenic exposure, high primary methylation index (PMI; MMA/InAs) (but lower secondary methylation index (SMI)), and non-heterogeneity type of genomic markers, including GSTO1, AS3MT, and MPO, tend to develop cancers. Subjects with higher PMI are at higher risk of developing cancers (HR = 1.66; 95% CI = 1.30-2.12). Cancer occurrence was greater among the CC type of GSTO1 (HR = 3.33; 95% CI = 1.11-10.00), CC type of AS3MT (HR = 19.21; 95% CI = 1.16-318.80), and AA type of MPO (HR = 13.40; 95% CI = 1.26-142.40). After adjusting confounders, a mutually moderating effect was revealed between genomic markers and methylation capacity on cancer occurrence. This study found the hypermethylation responses to inorganic arsenic exposure and an array of genomic markers may increase the susceptibility of a wide range of organ cancers. The findings indicated a high-risk arsenic-exposed population to develop cancers. The phenotype of arsenic metabolism and genomic polymorphism suggested a potential preventive strategy for arsenic carcinogenesis.