title: Cadmium exposure and the epigenome: Exposure-associated patterns of DNA methylation in leukocytes from mother-baby pairs.
abstract: Cadmium (Cd) is prevalent in the environment yet understudied as a developmental toxicant. Cd partially crosses the placental barrier from mother to fetus and is linked to detrimental effects in newborns. Here we examine the relationship between levels of Cd during pregnancy and 5-methylcytosine (5mC) levels in leukocyte DNA collected from 17 mother-newborn pairs. The methylation of cytosines is an epigenetic mechanism known to impact transcriptional signaling and influence health endpoints. A methylated cytosine-guanine (CpG) island recovery assay was used to assess over 4.6 million sites spanning 16,421 CpG islands. Exposure to Cd was classified for each mother-newborn pair according to maternal blood levels and compared with levels of cotinine. Subsets of genes were identified that showed altered DNA methylation levels in their promoter regions in fetal DNA associated with levels of Cd (n = 61), cotinine (n = 366), or both (n = 30). Likewise, in maternal DNA, differentially methylated genes were identified that were associated with Cd (n = 92) or cotinine (n = 134) levels. While the gene sets were largely distinct between maternal and fetal DNA, functional similarities at the biological pathway level were identified including an enrichment of genes that encode for proteins that control transcriptional regulation and apoptosis. Furthermore, conserved DNA motifs with sequence similarity to specific transcription factor binding sites were identified within the CpG islands of the gene sets. This study provides evidence for distinct patterns of DNA methylation or "footprints" in fetal and maternal DNA associated with exposure to Cd.
authors.affiliation: Department of Environmental Sciences and Engineering; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Alison P
authors.initials: AP
authors.lastname: Sanders
authors.affiliation: Department of Environmental Sciences and Engineering; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Smeester
authors.affiliation: Curriculum in Toxicology; School of Medicine; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rojas
authors.affiliation: Center for Bioinformatics; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Tristan
authors.initials: T
authors.lastname: DeBussycher
authors.affiliation: Department of Biostatistics; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wu
authors.affiliation: Department of Biostatistics; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: Department of Biostatistics; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Laine
authors.affiliation: Department of Environmental Sciences and Engineering; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rager
authors.affiliation: Department of Obstetrics and Gynecology; Duke University; Durham, NC USA.
authors.forename: Geeta K
authors.initials: GK
authors.lastname: Swamy
authors.affiliation: Center for Human Genetics; Duke University Medical Center; Durham, NC USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Ashley-Koch
authors.affiliation: School of Natural Resources and Environment; Department of Pediatrics; University of Michigan; Ann Arbor, MI USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Lynn Miranda
authors.affiliation: Department of Environmental Sciences and Engineering; Gillings School of Global Public Health; University of North Carolina; Chapel Hill, NC USA; Curriculum in Toxicology; School of Medicine; University of North Carolina; Chapel Hill, NC USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
mesh_terms: D044503:5-Methylcytosine / Q000097:blood; D002104:Cadmium / Q000097:blood* / Q000633:toxicity; D003367:Cotinine / Q000097:blood; D018899:CpG Islands; D019175:DNA Methylation; D004785:Environmental Pollutants / Q000097:blood* / Q000633:toxicity; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D007231:Infant, Newborn; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011401:Promoter Regions, Genetic
chemical_list: D004785:Environmental Pollutants; D002104:Cadmium; D044503:5-Methylcytosine; D003367:Cotinine
keywords: cadmium; cigarette smoke; cord blood; epigenetics; heavy metal; maternal blood; methylation; pregnancy