RESUMO
Exposure through arsenic-contaminated air and food caused by the burning of coal is a major environmental public health concern in Guizhou Province of China. Previous studies have shown that immunological dysfunction is involved in the pathogenesis and carcinogenesis of arsenic; however, knowledge regarding effective prevention measures have not been fully examined. The effect of Ginkgo biloba extract (EGb761) on arsenic-induced skin damage of human immortalized keratinocyte cells (HaCaT) was first evaluated in this study. The results showed that 200 µg/mL EGb761 can reduce the expression of miR-155-5p, and the indicators reflecting arsenic-induced skin damage (Krt1, Krt6c and Krt10) in arsenic-exposed cells (P < 0.05), the expression levels of NF-AT1; the indicators reflecting arsenic-induced immunological dysfunction (IL-2, IFN-γ) in cells; and the levels of secreted IL-2 and IFN-γ in cell supernatants were significantly increased (P < 0.05). Further randomized controlled double-blind experiments showed that compared to the placebo control group, the expression level of miR-155-5p in the plasma of the Ginkgo biloba intervention group, the indicators in the serum reflecting arsenic-induced skin damage (Krt1, Krt6c, and Krt10) and the epithelial-mesenchymal transformation (EMT) vimentin were significantly reduced (P < 0.05), but the levels of NF-AT1 and the indicators reflecting arsenic-induced immunological dysfunction (IL-2, IFN-γ) and EMT (E-cadherin) in serum were significantly increased (P < 0.05). Our study provides some limited evidence that Ginkgo biloba L. can increase the expression of NF-AT1 by downregulating the level of miR-155-5p, alleviating immunological dysfunction, and decreasing the expression of EMT biomarkers, thus indirectly improving arsenic-induced skin damage.
Assuntos
Intoxicação por Arsênico/tratamento farmacológico , Queratinócitos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Dermatopatias/tratamento farmacológico , Adulto , Idoso , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/complicações , Intoxicação por Arsênico/genética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Método Duplo-Cego , Feminino , Ginkgo biloba , Humanos , Interferon gama/sangue , Interferon gama/genética , Interleucina-2/sangue , Interleucina-2/genética , Queratinócitos/metabolismo , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Fatores de Transcrição NFATC/sangue , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Dermatopatias/sangue , Dermatopatias/induzido quimicamente , Dermatopatias/genéticaRESUMO
BACKGROUND: Arsenic poisoning affects millions of people. The inorganic forms of arsenic are more toxic. Treatment for arsenic poisoning relies on chelation of extracellularly circulating arsenic molecules by 2,3-dimecaptosuccinic acid (DMSA). As a pharmacological intervention, DMSA is unable to chelate arsenic molecules from intracellular spaces. The consequence is continued toxicity and cell damage in the presence of DMSA. A two-pronged approach that removes extracellular arsenic, while protecting from the intracellular arsenic would provide a better pharmacotherapeutic outcome. In this study, Coenzyme Q10 (CoQ10), which has been shown to protect from intracellular organic arsenic, was administered separately or with DMSA; following oral exposure to sodium meta-arsenite (NaAsO2) - a very toxic trivalent form of inorganic arsenic. The aim was to determine if CoQ10 alone or when co-administered with DMSA would nullify arsenite-induced toxicity in mice. METHODS: Group one represented the control; the second group was treated with NaAsO2 (15 mg/kg) daily for 30 days, the third, fourth and fifth groups of mice were given NaAsO2 and treated with 200 mg/kg CoQ10 (30 days) and 50 mg/kg DMSA (5 days) either alone or in combination. RESULTS: Administration of CoQ10 and DMSA resulted in protection from arsenic-induced suppression of RBCs, haematocrit and hemoglobin levels. CoQ10 and DMSA protected from arsenic-induced alteration of WBCs, basophils, neutrophils, monocytes, eosinophils and platelets. Arsenite-induced dyslipidemia was nullified by administration of CoQ10 alone or in combination with DMSA. Arsenite induced a drastic depletion of the liver and brain GSH; that was significantly blocked by CoQ10 and DMSA alone or in combination. Exposure to arsenite resulted in significant elevation of liver and kidney damage markers. The histological analysis of respective organs confirmed arsenic-induced organ damage, which was ameliorated by CoQ10 alone or when co-administered with DMSA. When administered alone, DMSA did not prevent arsenic-driven tissue damage. CONCLUSIONS: Findings from this study demonstrate that CoQ10 and DMSA separately or in a combination, significantly protect against arsenic-driven toxicity in mice. It is evident that with further pre-clinical and clinical studies, an adjunct therapy that incorporates CoQ10 alongside DMSA may find applications in nullifying arsenic-driven toxicity.
Assuntos
Antídotos/uso terapêutico , Intoxicação por Arsênico/tratamento farmacológico , Arsenitos/toxicidade , Quelantes/uso terapêutico , Substâncias Protetoras/uso terapêutico , Compostos de Sódio/toxicidade , Succímero/uso terapêutico , Ubiquinona/análogos & derivados , Animais , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/metabolismo , Intoxicação por Arsênico/patologia , Células Sanguíneas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Quimioterapia Combinada , Glutationa/metabolismo , Hematócrito , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Ubiquinona/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: The French national authority for health (Haute autorité de santé: HAS) and the French clinical toxicology society (Société de toxicologie clinique: STC) received a formal request from the French ministry for heath to elaborate recommendations for the screening of environmental overexposure to inorganic arsenic (iAs), for the medical management of overexposed patients and for the medical surveillance of exposed population. To allow these recommendations, preliminary literature retrieval and analysis were performed for identifying validated indicators of both exposure and early effects of iAs and their levels in the general population living in France. METHODS: Evaluations of inorganic arsenic toxicity conducted by national or international health agencies during the last 3 decades were all examined and analyzed. These evaluations were completed by literature retrieval through Medline and Scopus from January 2016 to December 2019. RESULTS AND CONCLUSIONS: The best biomonitoring indicator for iAs exposure is the sum of urine iAs, monmomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) concentrations (SAs). The upper limit of confidence interval of the 95th percentile of the distribution of this parameter in the general adult population living in France is 10 µg/g of creatinine, and is recommended as the limit value for the definition of overexposure. In less than 12 year-old children specific limit values are required, but not yet available. In their absence, SAs should exceed both 10 µg/g creatinine and 11 µg/L to be considered as indicating a probable overexposure to iAs. There are no useful biological indicators of iAs early effects. Non carcinogenic skin effects of inorganic arsenic (hyperpigmentation and keratosis) should be considered as the earliest deleterious effects of repeated environmental iAs exposure.
Assuntos
Intoxicação por Arsênico/diagnóstico , Arsênio/análise , Monitoramento Biológico/métodos , Exposição Ambiental/análise , Adulto , Intoxicação por Arsênico/sangue , Monitoramento Biológico/normas , Criança , Pré-Escolar , Estudos de Viabilidade , França , Humanos , Lactente , Recém-NascidoRESUMO
Arsenic is ubiquitous in the earth's crust, and human diseases are linked with exposures that are similar to dietary intake estimates. Metabolic methylation of inorganic arsenic facilitates excretion of pentavalent metabolites and decreases acute toxicity; however, tissue binding of trivalent arsenic intermediates is evidence for concomitant metabolic activation. Pregnant and fetal CD-1 mice comprise a key animal model for arsenic carcinogenesis since adult-only exposures have minimal effects. This study evaluated inorganic arsenic and its metabolites in pentavalent and trivalent states in blood and tissues from maternal and fetal CD-1 mice after repeated administration of arsenite through drinking water. After 8 days of exposure, DMA species were ubiquitous in dams and fetuses. Despite the presence of MMAIII in dams, none was observed in any fetal sample. This difference may be important in assessing fetal susceptibility to arsenic toxicity because MMA production has been linked with human disease. Binding of DMAIII in fetal tissues provided evidence for metabolic activation, although the role for such binding in arsenic toxicity is unclear. This study provides links between administered dose, metabolism, and internal exposures from a key animal model of arsenic toxicity to better understand risks from human exposure to environmental arsenic.
Assuntos
Intoxicação por Arsênico/metabolismo , Arsenitos/metabolismo , Água Potável/análise , Gravidez/metabolismo , Compostos de Sódio/metabolismo , Poluentes Químicos da Água/metabolismo , Animais , Animais Recém-Nascidos/sangue , Arsênio/sangue , Arsênio/química , Arsênio/metabolismo , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/embriologia , Intoxicação por Arsênico/etiologia , Arsenitos/química , Feminino , Feto/metabolismo , Humanos , Masculino , Exposição Materna/efeitos adversos , Camundongos , Gravidez/sangue , Compostos de Sódio/química , Poluentes Químicos da Água/sangue , Poluentes Químicos da Água/químicaRESUMO
BACKGROUND: Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. OBJECTIVES: To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. METHODS: The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N=80 women) and DNA methylation (N=93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. RESULTS: U-As concentrations, ranging 10-1251µg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. CONCLUSIONS: Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.
Assuntos
Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/genética , Metilação de DNA/fisiologia , Água Potável/efeitos adversos , Adolescente , Adulto , Argentina/epidemiologia , Arsênio/administração & dosagem , Arsênio/toxicidade , Intoxicação por Arsênico/epidemiologia , Criança , Metilação de DNA/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Arsenic is a common environmental and occupational toxicant with dramatic species differences in its susceptibility and metabolism. Mouse strain variability may provide a better understanding of the arsenic pathological profile but is largely unknown. Here we investigated oxidative lesion induced by acute arsenic exposure in the two frequently used mouse strains C57BL/6J and 129X1/SvJ in classical gene targeting technique. A dose of 5 mg/kg body weight arsenic led to a significant alteration of blood glutathione towards oxidized redox potential and increased hepatic malondialdehyde content in C57BL/6J mice, but not in 129X1/SvJ mice. Hepatic antioxidant enzymes were induced by arsenic in transcription in both strains and many were higher in C57BL/6J than 129X1/SvJ mice. Arsenic profiles in the liver, blood and urine and transcription of genes encoding enzymes involved in arsenic biomethylation all indicate a higher arsenic methylation capacity, which contributes to a faster hepatic arsenic excretion, in 129X1/SvJ mice than C57BL/6J mice. Taken together, C57BL/6J mice are more susceptible to oxidative hepatic injury compared with 129X1/SvJ mice after acute arsenic exposure, which is closely associated with arsenic methylation pattern of the two strains.
Assuntos
Intoxicação por Arsênico/sangue , Arsenitos/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Compostos de Sódio/toxicidade , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Animais , Intoxicação por Arsênico/patologia , Intoxicação por Arsênico/urina , Arsenitos/farmacocinética , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Biotransformação , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sódio/farmacocinética , Especificidade da Espécie , Transcrição GênicaRESUMO
Arsenic (+3 oxidation state) methyltransferase is the key enzyme in the methylation pathway for inorganic arsenic. We have recently shown that As3mt knockout (KO) has a profound effect on metabolomic profiles in mice. Phosphatidylcholine species (PCs) were the largest group of metabolites altered in both plasma and urine. The present study used targeted analysis to investigate the KO-associated changes in PC profiles in the liver, the site of PC synthesis. Results show that As3mt KO has a systemic effect on PC metabolism and that this effect is sex dependent.
Assuntos
Intoxicação por Arsênico/enzimologia , Arsênio/toxicidade , Carcinógenos Ambientais/toxicidade , Fígado/efeitos dos fármacos , Metiltransferases/metabolismo , Neoplasias/induzido quimicamente , Fosfatidilcolinas/metabolismo , Animais , Arsênio/farmacocinética , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/metabolismo , Intoxicação por Arsênico/fisiopatologia , Arsenitos/administração & dosagem , Biotransformação , Carcinógenos Ambientais/farmacocinética , Feminino , Fígado/enzimologia , Fígado/metabolismo , Masculino , Metilação/efeitos dos fármacos , Metiltransferases/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/sangue , Neoplasias/etiologia , Neoplasias/metabolismo , Fosfatidilcolinas/sangue , Caracteres SexuaisRESUMO
OBJECTIVE: This study aimed to evaluate the prevalence of skin lesions, which is a health effect of chronic arsenic (As) exposure, and determine the hair/blood arsenic concentrations of people living in Kutahya villages who are using and drinking tap water with a high concentration of arsenic. MATERIALS AND METHODS: A total of 303 people were included in the present cross-sectional study. A prepared questionnaire form was used to collect the participants' information and environmental history. Skin examination was performed on all participants. Hair, blood and water samples were analyzed using atomic absorption spectroscopy. The cumulative arsenic index (CAI) was calculated for all participants. RESULTS: Villages were divided into two groups according to the arsenic level (<20 µg/L, Group I; >20 µg/L, Group II) in their water. The prevalence of skin lesions, hair and blood arsenic level, and CAI were found to be higher in the Group II participants. There was a positive association between body arsenic levels and CAI in the participants of each group. CONCLUSIONS: The number of skin lesions and arsenic concentrations in body samples were found to increase with the water arsenic level and exposure time. We hope that sharing this study's results with local administrators will help accelerate the rehabilitation of water sources in Kutahya.
Assuntos
Intoxicação por Arsênico/diagnóstico , Arsênio/efeitos adversos , Arsênio/análise , Biomarcadores/análise , Cabelo/química , Dermatopatias/diagnóstico , Poluentes Químicos da Água/análise , Adulto , Idoso , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/etiologia , Estudos Transversais , Água Potável/análise , Exposição Ambiental , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dermatopatias/sangue , Dermatopatias/etiologia , Espectrofotometria Atômica , Poluentes Químicos da Água/efeitos adversosRESUMO
Blood uric acid has been recognized as a putative marker for cardiovascular diseases (CVDs). CVDs are the major causes of arsenic-related morbidity and mortality. However, the association of arsenic exposure with plasma uric acid (PUA) levels in relation to CVDs has not yet been explored. This study for the first time demonstrated the associations of arsenic exposure with PUA levels and its relationship with hypertension. A total of 483 subjects, 322 from arsenic-endemic and 161 from non-endemic areas in Bangladesh were recruited as study subjects. Arsenic concentrations in the drinking water, hair and nails of the study subjects were measured by inductively coupled plasma mass spectroscopy. PUA levels were measured using a colorimetric method. We found that PUA levels were significantly (p<0.001) higher in males and females living in arsenic-endemic areas than those in non-endemic area. Arsenic exposure (water, hair and nail arsenic) levels showed significant positive correlations with PUA levels. In multiple regression analyses, arsenic exposure levels were found to be the most significant contributors on PUA levels among the other variables that included age, body mass index, blood urea nitrogen, and smoking. There were dose-response relationships between arsenic exposure and PUA levels. Furthermore, diastolic and systolic blood pressure showed significant positive correlations with PUA levels. Finally, the average PUA levels were significantly higher in the hypertensive group than those in the normotensive group in both males and females living in arsenic-endemic areas. These results suggest that arsenic exposure-related elevation of PUA levels may be implicated in arsenic-induced CVDs.
Assuntos
Arsênio/toxicidade , Água Potável/efeitos adversos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Ácido Úrico/sangue , Poluentes Químicos da Água/toxicidade , Adolescente , Adulto , Arsênio/administração & dosagem , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/epidemiologia , Bangladesh/epidemiologia , Biomarcadores/sangue , Estudos Transversais , Feminino , Cabelo/química , Cabelo/efeitos dos fármacos , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Unhas/química , Unhas/efeitos dos fármacos , Poluentes Químicos da Água/administração & dosagem , Abastecimento de Água/normas , Adulto JovemRESUMO
Chronic arsenicosis induced by excessive arsenic intake can cause damages to multi-organ systems, skin cancer and various internal cancers. However, the key metabolic changes and biomarkers which can reflect these changes remain unclear resulting in a lack of effective prevention and treatments. The aim of this study is to determine the impact of chronic arsenic exposure on the metabolism of organism, and find the metabolites changes by using metabolomic techniques. Thirty male Wistar rats were randomly divided into three groups. The arsenite was administered in water, and the doses were 0, 10, and 50mg/L, respectively. The exposure lasted for 6 months. The endogenous metabolite profile of serum was investigated by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Partial least squares discriminant analysis (PLS-DA) enabled clusters to be visualized. Nine serum principal metabolites contributing to the clusters were identified, which were CPA (18:2(9Z,12Z)/0:0), LysoPC (14:0), LysoPC (18:4 (6Z,9Z,12Z,15Z)), LysoPC (P-18:0), l-palmitoylcarnitine, LysoPC (20:2(11Z,14Z)) in positive ESI mode and deoxygcholylglycine, LysoPE (0:0/20:2(11Z,14Z)), 15(S)-hydroxyeicosatrienoic acid in negative ESI. These changes of metabolites in rats suggested the changed metabolism in rats exposed to arsenic. These findings may further aid diagnose and serve as targets for therapeutic intervention of arsenicosis.
Assuntos
Intoxicação por Arsênico/metabolismo , Animais , Intoxicação por Arsênico/sangue , Arsenitos/intoxicação , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Masculino , Espectrometria de Massas/métodos , Metabolômica , Ratos , Ratos WistarRESUMO
Chronic exposure to inorganic arsenic (InAs) through drinking water is a major problem worldwide. InAs undergoes hepatic methylation to form mono- and dimethyl arsenical species (MMA and DMA, respectively), facilitating arsenic elimination. Both reactions are catalyzed by arsenic (+3 oxidation state) methyltransferase (AS3MT) using S-adenosylmethionine (SAM) as the methyl donor, yielding the methylated product and S-adenosylhomocysteine (SAH), a potent product-inhibitor of AS3MT. SAM biosynthesis depends on folate- and cobalamin-dependent one-carbon metabolism. With the use of samples from 353 participants in the Folate and Oxidative Stress Study, our objective was to test the hypotheses that blood SAM and SAH concentrations are associated with arsenic methylation and that these associations differ by folate and cobalamin nutritional status. Blood SAM and SAH were measured by HPLC. Arsenic metabolites in blood and urine were measured by HPLC coupled to dynamic reaction cell inductively coupled plasma MS. In linear regression analyses, SAH was not associated with any of the arsenic metabolites. However, log(SAM) was negatively associated with log(% urinary InAs) (ß: -0.11; 95% CI: -0.19, -0.02; P = 0.01), and folate and cobalamin nutritional status significantly modified associations between SAM and percentage of blood MMA (%bMMA) and percentage of blood DMA (%bDMA) (P = 0.02 and P = 0.01, respectively). In folate- and cobalamin-deficient individuals, log(SAM) was positively associated with %bMMA (ß: 6.96; 95% CI: 1.86, 12.05; P < 0.01) and negatively associated with %bDMA (ß: -6.19; 95% CI: -12.71, 0.32; P = 0.06). These findings suggest that when exposure to InAs is high, and methyl groups are limiting, SAM is used primarily for MMA synthesis rather than for DMA synthesis, contributing additional evidence that nutritional status may explain some of the interindividual differences in arsenic metabolism and, consequently, susceptibility to arsenic toxicity.
Assuntos
Arsênio/sangue , Arsenicais/sangue , Exposição Ambiental , Ácido Fólico/sangue , S-Adenosilmetionina/sangue , Vitamina B 12/sangue , Adulto , Idoso , Arsênio/toxicidade , Arsênio/urina , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/urina , Arsenicais/urina , Bangladesh , Estudos Transversais , Água Potável , Feminino , Homocisteína/sangue , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Estresse Oxidativo , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/urinaRESUMO
Arsenic is carcinogenic, possibly partly through epigenetic mechanisms. We evaluated the effects of arsenic exposure and metabolism on DNA methylation. Arsenic exposure and methylation efficiency in 202 women in the Argentinean Andes were assessed from concentrations of arsenic metabolites in urine (inorganic arsenic, methylarsonic acid [MMA], and dimethylarsinic acid [DMA]), measured by HPLC-ICPMS. Methylation of CpGs of the tumor suppressor gene p16, the DNA repair gene MLH1, and the repetitive elements LINE1 was measured by PCR pyrosequencing of blood DNA. Genotyping (N = 172) for AS3MT was performed using Sequenom™, and gene expression (N = 90) using Illumina DirectHyb HumanHT-12 v3.0. Median arsenic concentration in urine was 230 µg L(-1) (range 10.1-1251). In linear regression analysis, log(2)-transformed urinary arsenic concentrations were positively associated with methylation of p16 (ß = 0.14, P = 0.0028) and MLH1 (ß = 0.28, P = 0.0011), but not with LINE1. Arsenic concentrations were of borderline significance negatively correlated with expression of p16 (r(s) = -0.20; P = 0.066)), but not with MLH1. The fraction of inorganic arsenic was positively (ß = 0.026; P = 0.010) and DMA was negatively (ß = -0.017, P = 0.043) associated with p16 methylation with no effect of MMA. Carriers of the slow-metabolizing AS3MT haplotype were associated with more p16 methylation (P = 0.022). Arsenic exposure was correlated with increased methylation, in blood, of genes encoding enzymes that suppress carcinogenesis, and the arsenic metabolism efficiency modified the degree of epigenetic alterations.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Intoxicação por Arsênico/genética , Arsênio/análise , Metilação de DNA/efeitos dos fármacos , Exposição Ambiental/análise , Genes p16/efeitos dos fármacos , Proteínas Nucleares/genética , Adolescente , Adulto , Argentina , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/metabolismo , Intoxicação por Arsênico/urina , Feminino , Marcadores Genéticos/genética , Haplótipos , Humanos , Metiltransferases/genética , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Estatísticas não Paramétricas , Abastecimento de ÁguaRESUMO
Water-soluble nanoparticles of curcumin were synthesized, characterized and applied as a stable detoxifying agent for arsenic poisoning. Chitosan nanoparticles of less than 50 nm in diameter containing curcumin were prepared. The particles were characterized by TEM, DLS and FT-IR. The therapeutic efficacy of the encapsulated curcumin nanoparticles (ECNPs) against arsenic-induced toxicity in rats was investigated. Sodium arsenite (2mg/kg) and ECNPs (1.5 or 15 mg/kg) were orally administered to male Wistar rats for 4 weeks to evaluate the therapeutic potential of ECNPs in blood and soft tissues. Arsenic significantly decreased blood δ-aminolevulinic acid dehydratase (δ-ALAD) activity, reduced glutathione (GSH) and increased blood reactive oxygen species (ROS). These changes were accompanied by increases in hepatic total ROS, oxidized glutathione, and thiobarbituric acid-reactive substance levels. By contrast, hepatic GSH, superoxide dismutase and catalase activities significantly decreased on arsenic exposure, indicative of oxidative stress. Brain biogenic amines (dopamine, norepinephrine and 5-hydroxytryptamine) levels also showed significant changes on arsenic exposure. Co-administration of ECNPs provided pronounced beneficial effects on the adverse changes in oxidative stress parameters induced by arsenic. The results indicate that ECNPs have better antioxidant and chelating potential (even at the lower dose of 1.5 mg/kg) compared to free curcumin at 15 mg/kg. The significant neurochemical and immunohistochemical protection afforded by ECNPs indicates their neuroprotective efficacy. The formulation provides a novel therapeutic regime for preventing arsenic toxicity.
Assuntos
Intoxicação por Arsênico/tratamento farmacológico , Arsênio/toxicidade , Curcumina/administração & dosagem , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Arsênio/farmacocinética , Intoxicação por Arsênico/sangue , Aminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Curcumina/farmacologia , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Distribuição TecidualRESUMO
Arsenic is an environmental toxicant, free-radical generator, carcinogenic agent, and aging promoter. Recently, blood samples were analyzed from individuals (control- male 12, female 13; arsenic-exposed- male 16, female 14; and exposed to ≥100 µg/L As, ≥10 y) with dermatological symptoms in few affected villages in Eastern India to unravel their hematopoietic, metabolic, and antioxidant profiles. White blood cells recovered from buffy coat were used for DNA fragmentation test. Present observation suggests that significant number of individuals developed pigmentation and palmoplantar hyperkeratosis with black-brownish patch on their body and many of those developed carcinomas. Hematopoietic data show a significant increase in eosinophil and decrease in monocyte count in either sex. Though insignificant, an increase in neutrophil in female and lymphocyte count in male arsenic-exposed individuals are supported by the earlier report on sex dimorphic immune sensitization. Significant increase in serum alanine transaminase in both sexes and bilirubin only in male suggests the eventuality of hepatic disintegration. Arsenic exposure significantly decreased serum amylase in female. A significant decrease in antioxidant components like catalase, soluble thiol, and recently recognized uric acid worsened the situation by generating free radicals as observed in significant rise in malondialdehyde level, which finally increased DNA fragmentation and arsenic-associated mutagenesis and carcinogenesis. This could attribute to lowering in immune competence and related necrotic and/or apoptotic manifestations.
Assuntos
Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/patologia , Arsênio/toxicidade , Água Potável/química , Dermatopatias/induzido quimicamente , Poluentes Químicos da Água/toxicidade , Antioxidantes/metabolismo , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Índia , Masculino , Redes e Vias Metabólicas/efeitos dos fármacos , Dermatopatias/sangue , Dermatopatias/patologiaRESUMO
Monoisoamyl DMSA (MiADMSA), a lipophilic chelating agent has emerged as a promising drug for the treatment of arsenic. The present study aimed at exploring the optimum dose and route of administration for achieving maximum arsenic elimination with minimal side effects. We also carried out a pharmacokinetic analysis of this drug to support arsenic chelation. Rats were exposed to arsenic (25 ppm) for 6 months and later received MiADMSA (50 or 100 mg/kg) orally and via i.p. route for 5 days. Oxidative stress parameters and arsenic levels in soft tissues, liver function test and histopathology of liver and kidney were performed. Plasma kinetic of MiADMSA (plasma-free drug and total drug) at 50 and 100 mg/kg p.o. was carried out. Arsenic exposure resulted in significant oxidative stress and hepatotoxicity. MiADMSA at 50 mg/kg dose administered orally provided about 45% and 75% protection against oxidative stress and in lowering body arsenic burden, respectively, against 25% and 40% via i.p. route. Pharmacokinetic analysis supported prolonged availability of the drug through oral administration. Collectively, these findings led us to conclude that oral administration of MiADMSA was more effective than intraperitoneal administration and that the minimum effective dose with least side effects was 50 mg/kg.
Assuntos
Intoxicação por Arsênico/tratamento farmacológico , Quelantes/farmacologia , Succímero/análogos & derivados , Administração Oral , Animais , Arsênio/sangue , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/patologia , Quelantes/administração & dosagem , Quelantes/uso terapêutico , Doença Crônica , Cobre/sangue , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Dissulfeto de Glutationa/biossíntese , Rim/patologia , Fígado/patologia , Testes de Função Hepática , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Succímero/administração & dosagem , Succímero/farmacocinética , Succímero/uso terapêutico , Zinco/sangueRESUMO
Background: There is an association between arsenic exposure and prostatic cancer mortality. Aim: To analyze and to compare the serum levels of total prostatic specific antigen (TPSA) in asymptomatic men of a rural zone, exposed and not exposed to high concentrations of arsenic (As) in drinking water. Material and Methods: The study included 161 men that were subjected to a clinical evaluation, serum TPSA determination and a trans rectal ultrasonography. Exposed and non-exposed subjects were divided in groups GA, GB and GC according to TPSA levels (<4 ng/ml, 4.1-10 ng/ml and >10.1 ng/ml respectively). Results: Exposed and non-exposed subjects had similar TPSA levels. Among exposed subjects, 88.2, 8,8 and 3% were ascribed to groups GA, GB and GC respectively. The figures for non-exposed subjects were 90. 6, 6,3 and 3,1%. The area under the receiver operating characteristic (ROC) curve for TPSA in exposed and non-exposed subjects was 0.64 (95% confidence intervals (CI) 0.40-0.9) and 0.71 (95% CI 0.6-0.8) respectively. Conclusions: No differences in TPSA levels between subjects exposed and non-exposed to arsenic were observed in this study.
Assuntos
Humanos , Masculino , Pessoa de Meia-Idade , Intoxicação por Arsênico/sangue , Água Potável/química , Exposição Ambiental/estatística & dados numéricos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Argentina , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Métodos Epidemiológicos , População Rural/estatística & dados numéricos , Biomarcadores Tumorais/sangueRESUMO
Arsenic pollution is a major public health problem worldwide. Inorganic arsenic (iAs) is usually more harmful than organic ones. iAs pollution increases the risk of human diseases such as peripheral vascular disease and cancer. However, the toxicological effects of iAs in the brain are mostly unclear. Here, we investigated the toxic effects and possible mechanisms of iAs in the cerebrum of mice after exposure to iAs (0.5 and 5 ppm (mg/l) As(2)O(3), via the drinking water), which was the possible human exposed dose via the ingestion in iAs-contaminated areas, for 6 consecutive weeks. iAs dose-dependently caused an increase of LPO production in the plasma and cerebral cortex. iAs also decreased the reduced glutathione levels and the expressions of NQO1 and GPx mRNA in the cerebral cortex. These impairments in the cerebral cortex caused by iAs exposure were significantly correlated with the accumulation of As. Moreover, iAs induced the production of apoptotic cells and activation of caspase-3, up-regulation of Bax and Bak, and down-regulation of Mcl-1 in the cerebral cortex. Exposure to iAs also triggered the expression of ER stress-related genes, including GRP78, GRP94, and CHOP. Meanwhile, an increase of p38 activation and dephosphorylation of ERK1/2 were shown in the cerebral cortex as a result of iAs-exposed mice. These iAs-induced damages and apoptosis-related signals could be significantly reversed by NAC. Taken together, these results suggest that iAs-induced oxidative stress causes cellular apoptosis in the cerebrum, signaling of p38 and ERK1/2, and ER stress may be involved in iAs-induced cerebral toxicity.
Assuntos
Apoptose/efeitos dos fármacos , Intoxicação por Arsênico/metabolismo , Córtex Cerebral/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Óxidos/toxicidade , Acetilcisteína/uso terapêutico , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/patologia , Trióxido de Arsênio , Arsenicais/administração & dosagem , Arsenicais/metabolismo , Arsenicais/farmacocinética , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Relação Dose-Resposta a Droga , Chaperona BiP do Retículo Endoplasmático , Poluentes Ambientais/administração & dosagem , Poluentes Ambientais/metabolismo , Poluentes Ambientais/farmacocinética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Peróxidos Lipídicos/sangue , Peróxidos Lipídicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Oxirredução/efeitos dos fármacos , Óxidos/administração & dosagem , Óxidos/metabolismo , Óxidos/farmacocinética , RNA Mensageiro/metabolismo , Distribuição AleatóriaRESUMO
1. Gallium arsenide (GaAs), a semiconductor, exerts toxicity as a result of its constitutive moieties; that is, gallium and arsenic that becomes dissociated after exposure. The present study focuses on reducing arsenic concentration from the target organs using monoesters of meso 2,3-dimercaptosuccinic acid (DMSA) either individually or in combination. 2. Animals were exposed to GaAs (0.0014 mol/kg, orally for 8 weeks) and then treated with monoisoamyl DMSA (MiADMSA), monocyclohexyl DMSA (MchDMSA) or monomethyl DMSA (MmDMSA) either individually (0.3 mmol/kg, orally) or in combination (0.15 mmol/kg each, orally) for five consecutive days. 3. GaAs exposure significantly inhibited blood δ-aminolevulinic acid dehydrogenase (ALAD), suggesting alterations in the heme synthesis pathway. Whereas a significant increase in blood, liver and kidney reactive oxygen species accompanied by an increase in lipid peroxidation points to the involvement of oxidative stress in GaAs toxicity. 4. GaAs also significantly disturbed glutathione metabolism. Hepatic and renal catalase activity decreased significantly, whereas hepatic and renal superoxide dismutase activity, as well as serum transaminases activity, showed marginal increase. Treatment with MiADMSA in combination with MchDMSA showed better therapeutic efficacy compared with other treatments in the aforementioned variables. 5. Co-administration of MiADMSA with MchDMSA provided better therapeutic effects, including reduction of arsenic burden, compared with all other treatments.
Assuntos
Intoxicação por Arsênico/tratamento farmacológico , Arsênio/sangue , Arsenicais/farmacologia , Gálio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Succímero/farmacologia , Ácido Aminolevulínico/antagonistas & inibidores , Ácido Aminolevulínico/sangue , Animais , Intoxicação por Arsênico/sangue , Intoxicação por Arsênico/metabolismo , Catalase/metabolismo , Cobre/sangue , Gálio/sangue , Glutationa/metabolismo , Heme/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Succímero/análogos & derivados , Superóxido Dismutase/metabolismo , Transaminases/sangue , Transaminases/metabolismo , Zinco/sangueRESUMO
Induction of oxidative stress and inhibition of DNA repair are possible modes of arsenic-induced carcinogenesis. In West Bengal, India, several districts contain high levels of arsenic, which are far above the WHO-recommended standard. Prevention of arsenic-induced oxidative stress and induction of repair enzymes by curcumin, an active ingredient of turmeric, may be an effective strategy to combat the adverse effects of arsenic. This study aimed at observing the role of curcumin in reducing 8-hydroxy-20-deoxyguanosine formation and enhancing DNA repair capacity in the arsenic-exposed population of West Bengal. Chronically arsenic-exposed volunteers (n= 66), who were asymptomatic, were selected for this study. Our results indicated that curcumin suppressed the 8-hydroxy-20-deoxyguanosine level and OGG1 expression, which were increased by arsenic. Curcumin also induced DNA repair enzymes involved in both base excision repair and nonhomologous end-joining pathways. In this study, both the protein expression and genetic profile were observed for poly-ADP-ribose polymerase 1, DNA b polymerase, X ray repair cross complement 1, DNA ligase III, DNA protein kinase catalytic sub-unit, X ray repair cross-complement 4, DNA ligase IV, and topoisomerase II b. The results indicated that arsenic-inhibited DNA repair was induced by curcumin, both at protein and genetic levels. Thus, curcumin intervention may be a useful modality for the prevention of arsenic-induced carcinogenesis.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Intoxicação por Arsênico/tratamento farmacológico , Curcumina/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Intoxicação por Arsênico/sangue , Western Blotting , Ensaio Cometa , DNA Ligase Dependente de ATP , DNA Ligases/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , DNA Polimerase Dirigida por DNA/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas de XenopusRESUMO
BACKGROUND: There is an association between arsenic exposure and prostatic cancer mortality. AIM: To analyze and to compare the serum levels of total prostatic specific antigEn (TPSA) in asymptomatic men of a rural zone, exposed and not exposed to high concentrations of arsenic (As) in drinking water. MATERIAL AND METHODS: The study included 161 men that were subjected to a clinical evaluation, serum TPSA determination and a trans rectal ultrasonography. Exposed and non-exposed subjects were divided in groups GA, GB and GC according to TPSA levels (<4 ng/ml, 4.1-10 ng/ml and >10.1 ng/ml respectively). RESULTS: Exposed and non-exposed subjects had similar TPSA levels. Among exposed subjects, 88.2, 8,8 and 3% were ascribed to groups GA, GB and GC respectively. The figures for non-exposed subjects were 90. 6, 6,3 and 3,1%. The area under the receiver operating characteristic (ROC) curve for TPSA in exposed and non-exposed subjects was 0.64 (95% confidence intervals (CI) 0.40-0.9) and 0.71 (95% CI 0.6-0.8) respectively. CONCLUSIONS: No differences in TPSA levels between subjects exposed and non-exposed to arsenic were observed in this study.