Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic in Utero

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Abstract

Background: There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation.

Objectives: In this study we aimed to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure.

Methods: DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24–28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord blood and in utero arsenic exposure; we also examined the association between methylation at individual CpG loci and arsenic exposure levels.

Results: We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8 ⁺ T lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG islands ( p = 0.009). Of those in CpG islands ( n = 44), most (75%) exhibited higher methylation levels in the highest exposed group compared with the lowest exposed group. Also, several CpG loci exhibited a linear dose-dependent relationship between methylation and arsenic exposure.

Conclusions: Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes.

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Most cited references 49

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Rice consumption contributes to arsenic exposure in US women.

Margaret R. Karagas, Diane Gilbert-Diamond, David F Gruber … (2011)

Emerging data indicate that rice consumption may lead to potentially harmful arsenic exposure. However, few human data are available, and virtually none exist for vulnerable periods such as pregnancy. Here we document a positive association between rice consumption and urinary arsenic excretion, a biomarker of recent arsenic exposure, in 229 pregnant women. At a 6-mo prenatal visit, we collected a urine sample and 3-d dietary record for water, fish/seafood, and rice. We also tested women's home tap water for arsenic, which we combined with tap water consumption to estimate arsenic exposure through water. Women who reported rice intake (n = 73) consumed a median of 28.3 g/d, which is ∼0.5 cup of cooked rice each day. In general linear models adjusted for age and urinary dilution, both rice consumption (g, dry mass/d) and arsenic exposure through water (μg/d) were significantly associated with natural log-transformed total urinary arsenic (βrice = 0.009, βwater = 0.028, both P 2 cups/d. Rice arsenic content and speciation also vary, with some strains predominated by dimethylarsinic acid, particularly those grown in the United States. Our findings along with others indicate that rice consumption should be considered when designing arsenic reduction strategies in the United States.

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Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study

Yu Chen, Joseph Graziano, Faruque Parvez … (2011)

Objective To evaluate the association between arsenic exposure and mortality from cardiovascular disease and to assess whether cigarette smoking influences the association. Design Prospective cohort study with arsenic exposure measured in drinking water from wells and urine. Setting General population in Araihazar, Bangladesh. Participants 11 746 men and women who provided urine samples in 2000 and were followed up for an average of 6.6 years. Main outcome measure Death from cardiovascular disease. Results 198 people died from diseases of circulatory system, accounting for 43% of total mortality in the population. The mortality rate for cardiovascular disease was 214.3 per 100 000 person years in people drinking water containing <12.0 µg/L arsenic, compared with 271.1 per 100 000 person years in people drinking water with ≥12.0 µg/L arsenic. There was a dose-response relation between exposure to arsenic in well water assessed at baseline and mortality from ischaemic heart disease and other heart disease; the hazard ratios in increasing quarters of arsenic concentration in well water (0.1-12.0, 12.1-62.0, 62.1-148.0, and 148.1-864.0 µg/L) were 1.00 (reference), 1.22 (0.65 to 2.32), 1.35 (0.71 to 2.57), and 1.92 (1.07 to 3.43) (P=0.0019 for trend), respectively, after adjustment for potential confounders including age, sex, smoking status, educational attainment, body mass index (BMI), and changes in urinary arsenic concentration since baseline. Similar associations were observed when baseline total urinary arsenic was used as the exposure variable and for mortality from ischaemic heart disease specifically. The data indicate a significant synergistic interaction between arsenic exposure and cigarette smoking in mortality from ischaemic heart disease and other heart disease. In particular, the hazard ratio for the joint effect of a moderate level of arsenic exposure (middle third of well arsenic concentration 25.3-114.0 µg/L, mean 63.5 µg/L) and cigarette smoking on mortality from heart disease was greater than the sum of the hazard ratios associated with their individual effect (relative excess risk for interaction 1.56, 0.05 to 3.14; P=0.010). Conclusions Exposure to arsenic in drinking water is adversely associated with mortality from heart disease, especially among smokers.

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Effects of arsenic exposure on DNA methylation and epigenetic gene regulation.

John Reichard, Alvaro Puga (2010)

Arsenic is a nonmutagenic human carcinogen that induces tumors through unknown mechanisms. A growing body of evidence suggests that its carcinogenicity results from epigenetic changes, particularly in DNA methylation. Changes in gene methylation status, mediated by arsenic, have been proposed to activate oncogene expression or silence tumor suppressor genes, leading to long-term changes in the activity of genes controlling cell transformation. Mostly descriptive, and often contradictory, studies have demonstrated that arsenic exposure is associated with both hypo- and hyper-methylation at various genetic loci in vivo or in vitro. This ambiguity has made it difficult to assess whether the changes induced by arsenic are causally involved in the transformation process or are simply a reflection of the altered physiology of rapidly dividing cancer cells. Here, we discuss the evidence supporting changes in DNA methylation as a cause of arsenic carcinogenesis and highlight the strengths and limitations of these studies, as well as areas where consistencies and inconsistencies exist.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Journal ID (iso-abbrev): Environ. Health Perspect

Journal ID (publisher-id): EHP

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Electronic): 11 June 2013

Publication date (Print): August 2013

Volume: 121

Issue: 8

Pages: 971-977

Affiliations

[1 ]Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA

[2 ]Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, USA

[3 ]Department of Public Health, Oregon State University, Corvallis, Oregon, USA

[4 ]Department of Pharmacology and Toxicology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA

Author notes

Address correspondence C.J. Marsit, Department of Pharmacology and Toxicology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, 7650 Remsen, Hanover, NH 03755 USA. Telephone: (603) 650-1825. E-mail: Carmen.J.Marsit@ 123456Dartmouth.edu

Article

Publisher ID: ehp.1205925

DOI: 10.1289/ehp.1205925

PMC ID: 3733676

PubMed ID: 23757598

SO-VID: d224df4e-4750-4cb4-a121-3dd2df327c3d

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, properly cited.

Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic in Utero

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Most cited references 49

Rice consumption contributes to arsenic exposure in US women.

Arsenic exposure from drinking water and mortality from cardiovascular disease in Bangladesh: prospective cohort study

Effects of arsenic exposure on DNA methylation and epigenetic gene regulation.

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