RESUMO
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
Prenatal exposure to inorganic arsenic (iAs) is detrimental to the health of newborns and increases the risk of disease development later in life. Here we examined a subset of newborn cord blood leukocyte samples collected from subjects enrolled in the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico, who were exposed to a range of drinking water arsenic concentrations (0.456-236 µg/l). Changes in iAs-associated DNA 5-methylcytosine methylation were assessed across 424,935 CpG sites representing 18,761 genes and compared with corresponding mRNA expression levels and birth outcomes. In the context of arsenic exposure, a total of 2919 genes were identified with iAs-associated differences in DNA methylation. Site-specific analyses identified DNA methylation changes that were most predictive of gene expression levels where CpG methylation within CpG islands positioned within the first exon, the 5' untranslated region and 200 bp upstream of the transcription start site yielded the most significant association with gene expression levels. A set of 16 genes was identified with correlated iAs-associated changes in DNA methylation and mRNA expression and all were highly enriched for binding sites of the early growth response (EGR) and CCCTC-binding factor (CTCF) transcription factors. Furthermore, DNA methylation levels of 7 of these genes were associated with differences in birth outcomes including gestational age and head circumference.These data highlight the complex interplay between DNA methylation, functional changes in gene expression and health outcomes and underscore the need for functional analyses coupled to epigenetic assessments.
Assuntos
5-Metilcitosina/sangue , Intoxicação por Arsênico/genética , Arsênio/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Sangue Fetal/citologia , Leucócitos/efeitos dos fármacos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Poluentes Químicos da Água/efeitos adversos , Regiões 5' não Traduzidas , Intoxicação por Arsênico/sangue , Cefalometria , Estudos de Coortes , Ilhas de CpG , Epigenômica/métodos , Éxons , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Cabeça/crescimento & desenvolvimento , Humanos , Recém-Nascido , Leucócitos/química , México , Gravidez , Resultado da Gravidez , RNA Mensageiro/metabolismo , Medição de RiscoRESUMO
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
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
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
Intoxicação por Arsênico/sangue , Água Potável/química , Exposição Ambiental/estatística & dados numéricos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Argentina , Biomarcadores Tumorais/sangue , Exposição Ambiental/efeitos adversos , Exposição Ambiental/análise , Métodos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , População Rural/estatística & dados numéricosRESUMO
Arsenic (As) is a toxic semi-metal of wide distribution in nature. People living in regions where drinking water contains large quantities of arsenic, have an unusually high likelihood of developing blood-vessel diseases, but little is known about the mechanisms involved, i.e. the blood rheologic alterations that would contribute to the circulatory obstruction. Erythrocytes are the main target cells for arsenic compounds systemically absorbed and their cell membrane is the first place against the toxic. In this paper we have examined the in vitro effect of arsenic (As(V)) on the rheologic properties of human erythrocytes in relation with membrane fluidity and internal microviscosity. According to our present results, As(V) treatment produces oxidative degradation of membrane lipids and alteration of internal microviscosity. These red blood cells (RBCs) membrane and cytoplasmic structural damage consequently alters RBCs rheologic properties: an alteration of the RBCs discoid shape to stomatocytes, a diminution of erythrocyte deformability and an enhancement of osmotic fragility and cell aggregability. These effects impaired blood fluid behaviour that contribute to obstruct peripheral circulation and provides anemia, both clinic evidences typical of arsenic cronic intoxication.
Assuntos
Intoxicação por Arsênico/sangue , Eritrócitos/efeitos dos fármacos , Adulto , Viscosidade Sanguínea/efeitos dos fármacos , Agregação Eritrocítica/efeitos dos fármacos , Deformação Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/efeitos dos fármacos , Eritrócitos/metabolismo , Hemorreologia/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Fluidez de Membrana/efeitos dos fármacos , Lipídeos de Membrana/metabolismo , Fragilidade Osmótica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doenças Vasculares/induzido quimicamenteRESUMO
We assessed the relationships between chronic arsenic (As) exposure, human papilloma virus (HPV) contact and non-melanoma skin cancer (NMSC) by means of a dermatology clinic-based case-control study (42 cases and 48 controls) in Region Lagunera, Mexico, where chronic As poisoning is endemic. Exposure was determined through detailed history of residence in the As-contaminated area and measurement of As levels in drinking water and urine. We used a consensus epitope from the central region of L1 protein of the HPV family to determine antibodies against HPV. A history of As exposure and HPV seropositivity were associated with increased NMSC risks. A history of exposure to high levels of As increased the risk for NMSC (OR = 4.53; P = 0.11) in the group of seronegative HPV patients. A positive response to HPV significantly increased the OR for NMSC to 9.04 (P = 0.01) when history showed exposure to low levels of As. Interestingly, the OR was significantly increased to 16.5 (P = 0.001) when both exposure to high levels of As and HPV seropositivity were present. In addition, the presence of NMSC increased the OR (5.45; P = 0.03) for a positive response to HPV when history showed exposure to low levels of As, but the OR was increased to 8.0 (P = 0.005) in the cases with high exposure levels. Thus, HPV infection could constitute an additional risk factor for NMSC development in humans chronically exposed to As. However, further studies with additional populations are needed to determine the interaction between HPV and As exposure in NMSC.