title: Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes.
abstract: 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.
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rojas
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rager
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Lisa
authors.initials: L
authors.lastname: Smeester
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Bailey
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Drobná
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Marisela
authors.initials: M
authors.lastname: Rubio-Andrade
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stýblo
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: García-Vargas
authors.affiliation: *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico *Curriculum in Toxicology, Department of Environmental Sciences and Engineering, Department of Nutrition and Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina and Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango, Mexico rfry@unc.edu.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
mesh_terms: D020121:5' Untranslated Regions; D044503:5-Methylcytosine / Q000097:blood*; D001151:Arsenic / Q000009:adverse effects*; D020261:Arsenic Poisoning / Q000097:blood / Q000235:genetics*; D002508:Cephalometry; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D057890:Epigenomics / Q000379:methods; D005091:Exons; D005260:Female; D005312:Fetal Blood / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006257:Head / Q000254:growth & development; D006801:Humans; D007231:Infant, Newborn; D007962:Leukocytes / Q000737:chemistry / Q000187:drug effects*; D018811:Maternal Exposure / Q000009:adverse effects*; D008800:Mexico; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D018570:Risk Assessment; D014874:Water Pollutants, Chemical / Q000009:adverse effects*
chemical_list: D020121:5' Untranslated Regions; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D044503:5-Methylcytosine; D001151:Arsenic
keywords: DNA methylation; arsenic; epigenetics; gene expression; prenatal exposure