RESUMO
Exposure to inorganic arsenic (iAs) in drinking water is a global public health concern and is associated with a range of health outcomes, including immune dysfunction. Children are a particularly sensitive population to the effects of inorganic arsenic, yet the biological mechanisms underlying adverse health outcomes are understudied. Here we used a proteomic approach to examine the effects of iAs exposure on circulating serum protein levels in a cross-sectional children's cohort in Mexico. To identify iAs-associated proteins, levels of total urinary arsenic (U-tAs) and its metabolites were determined and serum proteins assessed for differences in expression. The results indicate an enrichment of Tumor Necrosis Factor-(TNF)-regulated immune and inflammatory response proteins that displayed decreased expression levels in relation to increasing U-tAs. Notably, when analyzed in the context of the proportions of urinary arsenic metabolites in children, the most robust response was observed in relation to the monomethylated arsenicals. This study is among the first serum proteomics assessment in children exposed to iAs.
Assuntos
Arsênio/toxicidade , Proteínas Sanguíneas/análise , Exposição Ambiental/efeitos adversos , Arsênio/urina , Arsenicais/urina , Criança , Feminino , Humanos , Masculino , México , Proteômica , Transdução de SinaisRESUMO
Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in Gómez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure.
Assuntos
Arsênio , Metabolômica , Arsenicais , Exposição Ambiental , Feminino , Humanos , Recém-Nascido , México , GravidezRESUMO
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
BACKGROUND: Exposure to inorganic arsenic (iAs) from drinking water is a global public health problem, yet much remains unknown about the extent of exposure in susceptible populations. OBJECTIVES: We aimed to establish the Biomarkers of Exposure to ARsenic (BEAR) prospective pregnancy cohort in Gómez Palacio, Mexico, to better understand the effects of iAs exposure on pregnant women and their children. METHODS: Two hundred pregnant women were recruited for this study. Concentrations of iAs in drinking water (DW-iAs) and maternal urinary concentrations of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) were determined. Birth outcomes were analyzed for their relationship to DW-iAs and to the concentrations and proportions of maternal urinary arsenicals. RESULTS: DW-iAs for the study subjects ranged from < 0.5 to 236 µg As/L. More than half of the women (53%) had DW-iAs that exceeded the World Health Organization's recommended guideline of 10 µg As/L. DW-iAs was significantly associated with the sum of the urinary arsenicals (U-tAs). Maternal urinary concentrations of MMAs were negatively associated with newborn birth weight and gestational age. Maternal urinary concentrations of iAs were associated with lower mean gestational age and newborn length. CONCLUSIONS: Biomonitoring results demonstrate that pregnant women in Gómez Palacio are exposed to potentially harmful levels of DW-iAs. The data support a relationship between iAs metabolism in pregnant women and adverse birth outcomes. The results underscore the risks associated with iAs exposure in vulnerable populations.
Assuntos
Arsênio/toxicidade , Tamanho Corporal , Poluentes Ambientais/toxicidade , Idade Gestacional , Exposição Materna/estatística & dados numéricos , Adulto , Arsênio/metabolismo , Arsênio/urina , Biomarcadores/metabolismo , Água Potável/química , Poluentes Ambientais/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , México , Gravidez , Estudos ProspectivosRESUMO
Exposure to inorganic arsenic (iAs) early in life is associated with adverse health effects in infants, children, and adults, and yet the biological mechanisms that underlie these effects are understudied. The objective of this research was to examine the proteomic shifts associated with prenatal iAs exposure using cord blood samples isolated from 50 newborns from Gómez Palacio, Mexico. Levels of iAs in maternal drinking water (DW-iAs) and the sum of iAs and iAs metabolites in maternal urine (U-tAs) were determined. Cord blood samples representing varying iAs exposure levels during the prenatal period (DW-iAs ranging from <1 to 236 µg As/l) were analyzed for altered expression of proteins associated with U-tAs using a high throughput, antibody-based method. A total of 111 proteins were identified that had a significant association between protein level in newborn cord blood and maternal U-tAs. Many of these proteins are regulated by tumor necrosis factor and are enriched in functionality related to immune/inflammatory response and cellular development/proliferation. Interindividual differences in proteomic response were observed in which 30 newborns were "activators," displaying a positive relationship between protein expression and maternal U-tAs. For 20 "repressor" newborns, a negative relationship between protein expression level and maternal U-tAs was observed. The activator/repressor status was significantly associated with maternal U-tAs and head circumference in newborn males. These results may provide a critical groundwork for understanding the diverse health effects associated with prenatal arsenic exposure and highlight interindividual responses to arsenic that likely influence differential susceptibility to adverse health outcomes.
Assuntos
Arsênio/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Proteoma/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Poluentes Químicos da Água/toxicidade , Arsênio/urina , Água Potável/análise , Água Potável/normas , Feminino , Sangue Fetal/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Recém-Nascido , Masculino , Exposição Materna/efeitos adversos , México , Análise Multivariada , Gravidez , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Análise de Regressão , Poluentes Químicos da Água/urinaRESUMO
Inorganic arsenic (iAs) is an environmental toxicant currently poisoning millions of people worldwide, and chronically exposed individuals are susceptible to arsenicosis or arsenic poisoning. Using a state-of-the-art technique to map the methylomes of our study subjects, we identified a large interactome of hypermethylated genes that are enriched for their involvement in arsenic-associated diseases, such as cancer, heart disease, and diabetes. Notably, we have uncovered an arsenic-induced tumor suppressorome, a complex of 17 tumor suppressors known to be silenced in human cancers. This finding represents a pivotal clue in unraveling a possible epigenetic mode of arsenic-induced disease.