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The global prevalence of Metabolic Syndrome (MetS) is continuously rising and exposure to environmental toxicants such as arsenic could be contributing to this rapid surge. In this study, we have assessed the effects of prenatal arsenic exposure on insulin resistance and MetS parameters in a mouse model, and an underlying mechanism was identified. We found that prenatal arsenic exposure promotes insulin resistance and adipocyte dysfunction which leads to the early onset of MetS in male offspring. Primary adipocytes isolated from 20-week-old arsenic-exposed offspring showed hypertrophy, elevated basal lipolysis, and impaired insulin response along with enhanced expression of Tumor necrosis factor-alpha (TNF-α). TNF-α levels were consistently high at gestational day 15.5 (GD15.5) as well as primary adipocytes of 6-week-old arsenic-exposed male offspring. Along with TNF-α, downstream p-JNK1/2 levels were also increased, which led to inhibitory phosphorylation of IRS1and reduced GLUT4 translocation upon insulin stimulation in adipocytes. Insulin response and downstream signaling were restored upon TNF-α inhibition, confirming its central role. The persistent overexpression of TNF-α in adipocytes of arsenic-exposed mice resulted from diminished EZH2 occupancy and reduced H3K27me3 (gene silencing histone marks) at the TNF-α promoter. This further led to chromatin relaxation, recruitment of c-Jun and CBP/p300, formation of an enhanceosome complex, and TNF-α expression. Our findings show how prenatal arsenic exposure can epigenetically modulate TNF-α expression to promote adipocyte dysfunction and insulin resistance which contributes to the early onset of MetS in offspring.
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BACKGROUND: On September 1976, due to the explosion of an ammonia-washing column at the petrochemical plant in Manfredonia (Italy), 39 tonnes of arsenic were released into the atmosphere, contaminating the plants and the neighbourhoods close to it. The aim of this study is to present the results of a 45-year follow up of exposed workers with a focus on residential exposure. METHODS: We contacted Italian General Registries Offices and updated the vital status of persons involved in the clean-up activities following the disaster. The outcome of interest was the overall and cause-specific mortality. An accelerated failure time (AFT) approach was used when appropriate to model the risk of mortality. RESULTS: 1772 workers contributing 67,743 person years were considered in the analysis. For overall mortality, results of the age-adjusted AFT model show an accelerator factor of 0.89 (95%CI 0.80-0.99) among contract workers, which means a shortening of survival in comparison to the reference category (plastic area workers). When accounting for latency greater than 20 years, higher mortality rates for lung cancer were observed among workers residing in Manfredonia. DISCUSSION: An increased risk of mortality among workers who were more exposed to arsenic during the clean-up activities has been observed. In fact, a loss of 5 years of life among more exposed workers was calculated. Furthermore, the mortality rates of residents in Manfredonia were higher than those of workers residing elsewhere.
Subject(s)
Arsenic , Occupational Exposure , Humans , Arsenic/analysis , Arsenic/toxicity , Italy/epidemiology , Male , Occupational Exposure/adverse effects , Middle Aged , Female , Cohort Studies , Disasters , AdultABSTRACT
Exposure to inorganic arsenic (As) is recognized as a risk factor for non-melanoma skin cancer (NMSC). We followed up with 7000 adults for 6 years who were exposed to As. During follow-up, 2.2% of the males and 1.3% of the females developed basal cell carcinoma (BCC), while 0.4% of the male and 0.2% of the female participants developed squamous cell carcinoma (SCC). Using a panel of more than 400 cancer-related genes, we detected somatic mutations (SMs) in the first 32 NMSC samples (BCC = 26 and SCC = 6) by comparing paired (tissue-blood) samples from the same individual and then comparing them to the SM in healthy skin tissue from 16 participants. We identified (a) a list of NMSC-associated SMs, (b) SMs present in both NMSC and healthy skin, and (c) SMs found only in healthy skin. We also demonstrate that the presence of non-synonymous SMs in the top mutated genes (like PTCH1, NOTCH1, SYNE1, PKHD1 in BCC and TP53 in SCC) significantly affects the magnitude of differential expressions of major genes and gene pathways (basal cell carcinoma pathways, NOTCH signaling, IL-17 signaling, p53 signaling, Wnt signaling pathway). These findings may help select groups of patients for targeted therapy, like hedgehog signaling inhibitors, IL17 inhibitors, etc., in the future.
Subject(s)
Arsenic , Mutation , Skin Neoplasms , Transcriptome , Humans , Skin Neoplasms/genetics , Arsenic/toxicity , Female , Mutation/genetics , Male , Transcriptome/genetics , Transcriptome/drug effects , Middle Aged , Carcinoma, Basal Cell/genetics , Carcinoma, Squamous Cell/genetics , Adult , Gene Expression Profiling , Aged , Gene Expression Regulation, Neoplastic/drug effectsABSTRACT
BACKGROUND: Melanoma is a highly malignant tumor. Moreover, its prevalence is increasing at a rapid rate year after year. Currently, UV light is the leading cause of melanoma, although numerous other risk factors exist, including arsenic. The link between arsenic and the likelihood of developing melanoma has long been debated. As a result, we conducted a meta-analysis of the available data to investigate the association between arsenic exposure and melanoma. METHODS: We identified seven non-randomized controlled studies with 41,949 participants by searching the Chinese CNKI, Embase, PubMed, and Cochrane Library databases. We then used random-effects or fixed-effects models to evaluate the pooled odds ratios (OR) and their 95% confidence intervals (CI). Subgroup analyses were also carried out with different included regions. RESULTS: Participants in the study who were exposed to arsenic had a somewhat higher chance of developing melanoma than those who were not (OR = 1.47, 95% CI 1.01-2.13). A subgroup analysis was also carried out for the US region, and the findings were not statistically significant (OR = 1.40, 95% CI 0.94-2.07). CONCLUSION: This meta-analysis shows that arsenic exposure relates to an increased risk of melanoma.
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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.
Subject(s)
Arsenic , DNA Methylation , Epigenesis, Genetic , Telomere Shortening , Humans , Adult , Arsenic/adverse effects , Arsenic/toxicity , Female , DNA Methylation/drug effects , Telomere Shortening/drug effects , Male , Child , Adolescent , Young Adult , Middle Aged , Mitosis/drug effects , Mitosis/genetics , Skin/pathology , Skin/drug effects , Skin Diseases/chemically induced , Skin Diseases/genetics , Skin Diseases/pathology , Skin Neoplasms/genetics , Skin Neoplasms/chemically induced , Skin Neoplasms/pathologyABSTRACT
BACKGROUND: Arsenic (As) is a risk factor associated with glycemic alterations. However, the mechanisms of action and metabolic aspects associated with changes in glycemic profiles have not yet been completely elucidated. Therefore, in this review, we aimed to investigate the metabolic aspects of As and its mechanism of action associated with glycemic changes. METHODS: We searched the PubMed (MEDLINE) and Google Scholar databases for relevant articles published in English. A combination of free text and medical subject heading keywords and search terms was used to construct search equations. The search yielded 466 articles; however, only 50 were included in the review. RESULTS: We observed that the relationship between As exposure and glycemic alterations in humans may be associated with sex, smoking status, body mass index, age, occupation, and genetic factors. The main mechanisms of action associated with changes induced by exposure to As in the glycemic profile identified in animals are increased oxidative stress, reduced expression of glucose transporter type 4, induction of inflammatory factor expression and dysfunction of pancreatic ß cells. CONCLUSIONS: Therefore, As exposure may be associated with glycemic alterations according to inter-individual differences.
Subject(s)
Arsenic , Animals , Humans , Risk Factors , PubMed , Body Mass Index , Blood Glucose/metabolismABSTRACT
Exposure to arsenic during gestation has lasting health-related effects on the developing fetus, including an increase in the risk of metabolic disease later in life. Epigenetics is a potential mechanism involved in this process. Ten-eleven translocation 2 (TET2) has been widely considered as a transferase of 5-hydroxymethylcytosine (5hmC). Here, mice were exposed, via drinking water, to arsenic or arsenic combined with ascorbic acid (AA) during gestation. For adult offspring, intrauterine arsenic exposure exhibited disorders of glucose metabolism, which are associated with DNA hydroxymethylation reprogramming of hepatic nuclear factor 4 alpha (HNF4α). Further molecular structure analysis, by SEC-UV-DAD, SEC-ICP-MS, verified that arsenic binds to the cysteine domain of TET2. Mechanistically, arsenic reduces the stability of TET2 by binding to it, resulting in the decrease of 5hmC levels in Hnf4α and subsequently inhibiting its expression. This leads to the disorders of expression of its downstream key glucose metabolism genes. Supplementation with AA blocked the reduction of TET2 and normalized the 5hmC levels of Hnf4α, thus alleviating the glucose metabolism disorders. Our study provides targets and methods for the prevention of offspring glucose metabolism abnormalities caused by intrauterine arsenic exposure.
Subject(s)
Arsenic , Ascorbic Acid , Dioxygenases , Glucose Metabolism Disorders , Animals , Mice , Arsenic/toxicity , Ascorbic Acid/therapeutic use , Dioxygenases/metabolism , DNA , DNA Methylation , DNA-Binding Proteins , Glucose/metabolism , Glucose Metabolism Disorders/chemically induced , Glucose Metabolism Disorders/genetics , Glucose Metabolism Disorders/metabolism , Liver/metabolismABSTRACT
INTRODUCTION: Arsenic has been ranked as the most hazardous substance by the U.S. Agency for Toxic Substances and Disease Registry. Environmental arsenic exposure-evoked health risks have become a vital public health concern worldwide owing to the widespread existence of arsenic. Multi-omics is a revolutionary technique to data analysis providing an integrated view of bioinformation for comprehensively and systematically understanding the elaborate mechanism of diseases. OBJECTIVES: This study aimed at uncovering the potential contribution of liver-microbiota-gut axis in chronic inorganic arsenic exposure-triggered biotoxicity in chickens based on multi-omics technologies. METHODS: Forty Hy-Line W-80 laying hens were chronically exposed to sodium arsenite with a dose-dependent manner (administered with drinking water containing 10, 20, or 30 mg/L arsenic, respectively) for 42 d, followed by transcriptomics, serum non-targeted metabolome, and 16S ribosomal RNA gene sequencing accordingly. RESULTS: Arsenic intervention induced a serious of chicken liver dysfunction, especially severe liver fibrosis, simultaneously altered ileal microbiota populations, impaired chicken intestinal barrier, further drove enterogenous lipopolysaccharides translocation via portal vein circulation aggravating liver damage. Furtherly, the injured liver disturbed bile acids (BAs) homoeostasis through strongly up-regulating the BAs synthesis key rate-limiting enzyme CYP7A1, inducing excessive serum total BAs accumulation, accompanied by the massive synthesis of primary BA-chenodeoxycholic acid. Moreover, the concentrations of secondary BAs-ursodeoxycholic acid and lithocholic acid were markedly repressed, which might involve in the repressed dehydroxylation of Ruminococcaceae and Lachnospiraceae families. Abnormal BAs metabolism in turn promoted intestinal injury, ultimately perpetuating pernicious circle in chickens. Notably, obvious depletion in the abundance of four profitable microbiota, Christensenellaceae, Ruminococcaceae, Muribaculaceae, and Faecalibacterium, were correlated tightly with this hepato-intestinal circulation process in chickens exposed to arsenic. CONCLUSION: Our study demonstrates that chronic inorganic arsenic exposure evokes liver-microbiota-gut axis disruption in chickens and establishes a scientific basis for evaluating health risk induced by environmental pollutant arsenic.
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Benchmark dose (BMD) methodology has been employed as a default dose-response modeling approach to determine the toxicity value of chemicals to support regulatory chemical risk assessment. Especially, a relatively standardized BMD analysis framework has been established for modeling toxicological data regarding the formats of input data, dose-response models, definitions of benchmark response, and model uncertainty consideration. However, the BMD approach has not been well developed for epidemiological data mainly because of the diverse designs of epidemiological studies and various formats of data reported in the literature. Although most of the epidemiological BMD analyses were developed to solve a particular question, the methods proposed in two recent studies are able to handle cohort and case-control studies using summary data with consideration of adjustments for confounders. Therefore, the purpose of the present study is to investigate and compare the "effective count"-based BMD modeling approach and adjusted relative risk (RR)-based BMD analysis approach to identify an appropriate BMD modeling framework that can be generalized for analyzing published data of prospective cohort studies for BMD analysis. The two methods were applied to the same set of studies that investigated the association between bladder and lung cancer and inorganic arsenic exposure for BMD estimation. The results suggest that estimated BMDs and BMDLs are relatively consistent; however, with the consideration of established common practice in BMD analysis, modeling adjusted RR values as continuous data for BMD estimation is a more generalizable approach harmonized with the BMD approach using toxicological data.
Subject(s)
Benchmarking , Lung Neoplasms , Humans , Prospective Studies , Dose-Response Relationship, Drug , Risk Assessment/methodsABSTRACT
With the comprehensive implementation of prevention and control measures for endemic fluorosis and endemic arsenicosis in China, and in accordance with the World Health Organization (WHO) recommended drinking water standards and the Chinese standards of allowable daily fluoride intake and limit values of arsenic content in drinking water, Chinese residents have entered the era of low-dose fluoride and arsenic exposure. However, there have been few studies focused on the long-term health effects of exposure to low-dose fluoride and arsenic both domestically and internationally. Further more, study on non-target organs of fluoride and arsenic has been neglected. The conclusions are also inconsistent, and there is an urgent need for systematic study to clarify them. Accordingly, this paper proposes to establish a cohort of people exposed to low-dose fluoride and arsenic, systematically carry out study on the long-term health effects and mechanisms of low-dose fluoride and arsenic exposure, and promote China's prevention and control experience to the "the Belt and Road" countries, in order to provide a scientific basis for the formulation of prevention and control strategies and measures for endemic fluorosis and endemic arsenicosis under the new situation in China.
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Arsenic is a widely distributed environmental toxic substance in nature. Chronic arsenic exposure can cause permanent damage to the liver, resulting in the death of poisoned patients. However, the mechanism of liver damage caused by arsenic poisoning is yet unclear. Here, four different concentrations of sodium arsenite (NaAsO2) (0 mg/L (control group), 25 mg/L, 50 mg/L, and 100 mg/L group)were established to induce liver injury in rats. Taking this into account, the relationship and potential mechanisms of oxidative stress, Bcl-2/adenovirus E1B-19-kDa-interacting protein 3 (BNIP3), and inhibition of autophagy flux in liver injury caused by arsenic poisoning were studied. The results indicated that long-term exposure to NaAsO2 could induce oxidative stress, leading to high expression of BNIP3, thereby impaired autophagy flux, and ultimately resulting in liver damage. This research provides an important basis for future research on liver damage caused by chronic arsenic exposure and prevention and treatment with BNIP3 as the target.
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Background: Arsenic exposure is closely related to keratosis and cutaneous carcinoma, but a few studies have focused on patients with psoriasis presenting carcinoma after long-term medication of arsenic-containing traditional Chinese medicine (TCM). Case description: We presented a psoriasis patient showing multiple cutaneous carcinoma arising from arsenic containing TCM. A 60-year-old gentleman with psoriasis for nearly 30 years presented to our department with severe keratosis in hands, trunk and feet. He received oral administration of realgar (with As4S4 as the major component) for at least 15 years. There were keratotic plaques, ulcer and exudate in the middle finger and forefinger of left hand, and middle finger, forefinger and ring finger of the right hand. Moreover, brown papule was seen in right sole, together with keratotic plaques and ulcer in the left heel. Pathological analysis revealed basal cell carcinoma (BCC) in the anterior chest, right hand and right foot, Bowen disease in left hand and right hand, as well as squamous cell carcinomas (SCC) in right hand. Conclusion: This is a rare arsenic-exposure psoriasis patient showed coexistence of Bowen disease in left hand and right hand, BCC in the thoracic site, right hand and right foot, as well as SCC in right hand.
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Arsenic is ubiquitous in soil and water environments and is consistently at the top of the Agency for Toxic Substances Disease Registry (ATSDR) substance priority list. It has been shown to induce toxicity even at low levels of exposure. One of the major routes of exposure to arsenic is through drinking water. This review presents current information related to the distribution of arsenic in the environment, the resultant impacts on human health, especially related to diabetes, which is one of the most prevalent chronic diseases, regulation of arsenic in drinking water, and approaches for treatment of arsenic in drinking water for both public utilities and private wells. Taken together, this information points out the existing challenges to understanding both the complex health impacts of arsenic and to implementing the treatment strategies needed to effectively reduce arsenic exposure at different scales.
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Introduction: Approximately 200 million people worldwide are affected by arsenic toxicity emanating from the consumption of drinking water containing inorganic arsenic above the prescribed maximum contaminant level. The current investigation deals with the role of prenatal arsenic exposure in modulating the gut microbial community and functional pathways of the host. Method: 16S rRNA-based next-generation sequencing was carried out to understand the effects of in utero 0.04 mg/kg (LD) and 0.4 mg/kg (HD) of arsenic exposure. This was carried out from gestational day 15 (GD-15) until the birth of pups to understand the alterations in bacterial diversity. Results: The study focused on gestational exposure to arsenic and the altered gut microbial community at phyla and genus levels, along with diversity indices. A significant decrease in firmicutes was observed in the gut microbiome of mice treated with arsenic. Functional analysis revealed that a shift in genes involved in crucial pathways such as insulin signaling and non-alcoholic fatty liver disease pathways may lead to metabolic diseases in the host. Discussion: The present investigation may hypothesize that in utero arsenic exposure can perturb the gut bacterial composition significantly as well as the functional pathways of the gestationally treated pups. This research paves the way to further investigate the probable mechanistic insights in the field of maternal exposure environments, which may play a key role in epigenetic modulations in developing various disease endpoints in the progeny.
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BACKGROUND: Gene-environment interactions contribute to metabolic disorders such as diabetes and dyslipidemia. In addition to affecting metabolic homeostasis directly, drugs and environmental chemicals can cause persistent alterations in metabolic portfolios across generations in a sex-specific manner. Here, we use inorganic arsenic (iAs) as a prototype drug and chemical to dissect such sex differences. METHODS: After weaning, C57BL/6 WT male mice were treated with 250 ppb iAs in drinking water (iAsF0) or normal water (conF0) for 6 weeks and then bred with 15-week-old, non-exposed females for 3 days in cages with only normal water (without iAs), to generate iAsF1 or conF1 mice, respectively. F0 females and all F1 mice drank normal water without iAs all the time. RESULTS: We find that exposure of male mice to 250 ppb iAs leads to glucose intolerance and insulin resistance in F1 female offspring (iAsF1-F), with almost no change in blood lipid profiles. In contrast, F1 males (iAsF1-M) show lower liver and blood triglyceride levels than non-exposed control, with improved glucose tolerance and insulin sensitivity. The liver of F1 offspring shows sex-specific transcriptomic changes, with hepatocyte-autonomous alternations of metabolic fluxes in line with the sex-specific phenotypes. The iAsF1-F mice show altered levels of circulating estrogen and follicle-stimulating hormone. Ovariectomy or liver-specific knockout of estrogen receptor α/ß made F1 females resemble F1 males in their metabolic responses to paternal iAs exposure. CONCLUSIONS: These results demonstrate that disrupted reproductive hormone secretion in alliance with hepatic estrogen signaling accounts for the sex-specific intergenerational effects of paternal iAs exposure, which shed light on the sex disparities in long-term gene-environment interactions.
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BACKGROUND: Arsenic exposure can cause adverse health effects. The effects of long-term low-to-moderate exposure and methylations remain unclear. OBJECTIVE: This study aims to examine the association between low-to-moderate arsenic exposure and urothelial tract cancers while considering the effects of methylation capacity. METHODS: In this study, 5,811 participants were recruited from an arseniasis area in Taiwan for inorganic arsenic metabolite analysis. This follow-up study was conducted between August 1995 and December 2017. We identified 85 urothelial tract cancers in these participants, including 49 bladder and 36 upper urothelial tract cancer cases. A Cox proportional hazards model was employed. RESULTS: The analyses revealed a significant association between concentrations of inorganic arsenic in water > 100 ug/L and bladder cancer occurrence, with a hazard ratio (HR) of 4.88 (95% CI 1.35-17.61). A monotonic trend was observed between concentrations of inorganic arsenic in water (from 0 to > 100 ug/L) and the incidence of urothelial tract cancer, including bladder cancer (p < 0.05) and upper urothelial tract cancers (p < 0.05). Participants with a lower primary methylation index or higher secondary methylation index had a prominent effect. CONCLUSIONS: Rigorous regulations and active interventions should be considered for populations with susceptible characteristics.
Subject(s)
Arsenic , Arsenicals , Urinary Bladder Neoplasms , Humans , Arsenic/toxicity , Follow-Up Studies , Urinary Bladder Neoplasms/chemically induced , Urinary Bladder Neoplasms/epidemiology , Arsenicals/adverse effects , WaterABSTRACT
BACKGROUND: Exposure to arsenic (As) is a major public health challenge worldwide. Chronic exposure to As can cause various human health effects, including skin diseases, cardiovascular disease, neurological disorders, and cancer. Studies have shown that As exposure can lead to disturbances in the balance of trace elements in the body. Moreover, As readily crosses the blood-brain barrier and can be enriched in the hippocampus and cortex, causing neurotoxic damage. At present, there are few reports on the effect of As on trace element levels in the central nervous system (CNS). Therefore, we sought to explore As-induced neurotoxicity and the effects of As on CNS trace element levels. METHODS: An As-induced neurological injury model in rats was established by feeding As chow for 90 days of continuous exposure, and 19 elements were detected in the hippocampus and cortex of As-exposed rats by inductively coupled plasma mass spectrometry. RESULTS: The results showed that the As levels in the hippocampus and cortex of As-exposed rats were significantly higher than those in the control group, The As levels in the cortex were significantly higher than in the hippocampus group. The levels of Cd, Ho, and Rb were increased in the hippocampus and decreased in Au, Ba, Ce, Cs, Pd, Se, Sr, and Tl in the As-exposed group, while the levels of Cd and Rb were increased and Se and Au were decreased in the cortex. Significant gender differences in the effects of As on hippocampal Cd, Ba, Rb, and Sr, and cortical Cd and Mo. CONCLUSION: It is suggested that elemental imbalance may be a risk factor for developing As toxicity plays a synergistic or antagonistic role in As-induced toxicity and is closely related to As-induced CNS damage.
Subject(s)
Arsenic , Trace Elements , Rats , Humans , Animals , Trace Elements/analysis , Arsenic/toxicity , Sex Factors , Cadmium , HippocampusABSTRACT
It is established that gut microbiota dysbiosis is implicated in arsenic (As)-induced neurotoxic process, however, the underlying mode of action remains largely unclear. Here, through remodeling gut microbiota on As-intoxicated pregnancy rats using fecal microbiota transplantation (FMT) from Control rats, neuronal loss and neurobehavioral deficits in offspring prenatally exposed to As were significantly alleviated after maternal FMT treatment. In prenatal As-challenged offspring after maternal FMT treatment, remarkably, suppressed expression of inflammatory cytokines in tissues (colon, serum, and striatum) were observed along with reversed mRNA and protein expression of tight junction related molecules in intestinal barrier and blood-brain barrier (BBB); Further, expression of serum lipopolysaccharide (LPS), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and nuclear transcription factor-κB (NF-κB) in colonic and striatal tissues were repressed with activation of astrocytes and microglia inhibited. In particular, tightly correlated and enriched microbiomes were identified such as higher-expressed g_Prevotella, g_UCG_005, and lower-expressed p_Desulfobacterota, g_Eubacterium_xylanophilum_group. Collectively, our results first demonstrated that reconstruction of normal gut microbiota by maternal FMT treatment alleviated prenatal As-induced overall inflammatory state and impairments of intestinal barrier and BBB integrity by impeding LPS-mediated TLR4/Myd88/NF-κB signaling pathway through microbiota-gut-brain axis, which provides a novel therapeutic avenue for developmental arsenic neurotoxicity.
Subject(s)
Arsenic , Fecal Microbiota Transplantation , Rats , Animals , Pregnancy , Female , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Brain-Gut Axis , Arsenic/toxicity , Arsenic/metabolism , NF-kappa B/metabolism , Lipopolysaccharides/toxicity , Myeloid Differentiation Factor 88/metabolismABSTRACT
Bladder cancer, prostate cancer, and kidney cancer, due to their high morbidity and mortality rates, result in significant economic and health care costs. Arsenic exposure affects the drinking water of millions of people worldwide. Long-term exposure to arsenic, even in low concentrations, increases the risk of developing various cancers. Smoking is also one of the leading causes of bladder, prostate and kidney cancers. Accordingly, this research reviews the relationship between arsenic exposure and smoking with three kinds of urinary tract cancers (bladder cancer, prostate cancer, and kidney cancer) due to their widespread concern for their negative impact on public health globally. In this review, we have gathered the most current information from scientific databases [PubMed, Scopus, Google Scholar, ISI web of science] regarding the relationship between arsenic exposure and tobacco smoking with the risk of bladder, prostate, and kidney cancer. In several studies, a significant relationship was determined between the incidence and mortality rate of the above-mentioned cancers in humans with arsenic exposure and tobacco smoking. The decrease or cessation of smoking and consumption of arsenic-free water significantly declined the incidence of bladder, prostate, and kidney cancers.
Subject(s)
Arsenic , Kidney Neoplasms , Prostatic Neoplasms , Urinary Bladder Neoplasms , Male , Humans , Smoking/adverse effects , Smoking/epidemiology , Urinary Bladder Neoplasms/chemically induced , Urinary Bladder Neoplasms/epidemiology , Tobacco Smoking , Kidney Neoplasms/chemically induced , Kidney Neoplasms/epidemiology , Arsenic/toxicity , Arsenic/analysis , Prostatic Neoplasms/complications , Environmental Exposure/adverse effectsABSTRACT
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 ß-endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of ß-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 (ß = -0.98, p = 0.04). CONCLUSION: Arsenic exposure is associated with pruritus, and ß-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis.