title: Maternal cadmium, iron and zinc levels, DNA methylation and birth weight.
abstract: BACKGROUND
  Cadmium (Cd) is a ubiquitous and environmentally persistent toxic metal that has been implicated in neurotoxicity, carcinogenesis and obesity and essential metals including zinc (Zn) and iron (Fe) may alter these outcomes. However mechanisms underlying these relationships remain limited.
  
  
  METHODS
  We examined whether maternal Cd levels during early pregnancy were associated with offspring DNA methylation at regulatory sequences of genomically imprinted genes and weight at birth, and whether Fe and Zn altered these associations. Cd, Fe and Zn were measured in maternal blood of 319 women ≤ 12 weeks gestation. Offspring umbilical cord blood leukocyte DNA methylation at regulatory differentially methylated regions (DMRs) of 8 imprinted genes was measured using bisulfite pyrosequencing. Regression models were used to examine the relationships among Cd, Fe, Zn, and DMR methylation and birth weight.
  
  
  RESULTS
  Elevated maternal blood Cd levels were associated with lower birth weight (p = 0.03). Higher maternal blood Cd levels were also associated with lower offspring methylation at the PEG3 DMR in females (β = 0.55, se = 0.17, p = 0.05), and at the MEG3 DMR in males (β = 0.72, se = 0.3, p = 0.08), however the latter association was not statistically significant. Associations between Cd and PEG3 and PLAGL1 DNA methylation were stronger in infants born to women with low concentrations of Fe (p < 0.05).
  
  
  CONCLUSIONS
  Our data suggest the association between pre-natal Cd and offspring DNA methylation at regulatory sequences of imprinted genes may be sex- and gene-specific. Essential metals such as Zn may mitigate DNA methylation response to Cd exposure. Larger studies are required.
authors.affiliation: Department of Surgery, Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA. adriana.vidal@cshs.org.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Vidal
authors.affiliation: Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA. vika245@gmail.com.|Department of Public Health, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA. vika245@gmail.com.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Semenova
authors.affiliation: Division of Water, Climate, and the Environment, School of Earth Sciences, The Ohio State University, Columbus, OH, 43210, USA. darrah.24@osu.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Darrah
authors.affiliation: Nicholas School of the Environment, Duke University, Research Drive, Durham, NC, 27710, USA. vengosh@duke.edu.
authors.forename: Avner
authors.initials: A
authors.lastname: Vengosh
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Research Drive, Durham, NC, 27710, USA. zhiqing.huang@duke.edu.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Environmental Public Health Division, U.S. Environmental Protection Agency, Chapel Hill, NC, 27599, USA. katherine.king@duke.edu.|Department of Community and Family Medicine and Duke Cancer Institute, Duke University School of Medicine, Erwin Drive, Durham, NC, 27710, USA. katherine.king@duke.edu.
authors.forename: Katherine
authors.initials: K
authors.lastname: King
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Research Drive, Durham, NC, 27710, USA. mnye@email.unc.edu.|University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, 450 West Drive, Chapel Hill, NC, 27599, USA. mnye@email.unc.edu.
authors.forename: Monica D
authors.initials: MD
authors.lastname: Nye
authors.affiliation: Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, UNC-Chapel Hill, Chapel Hill, NC, 27599, USA. rfry@unc.edu.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fry
authors.affiliation: Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA. daskaar@ncsu.edu.
authors.forename: David
authors.initials: D
authors.lastname: Skaar
authors.affiliation: Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA. rlmaguir@ncsu.edu.
authors.forename: Rachel
authors.initials: R
authors.lastname: Maguire
authors.affiliation: Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Duke University School of Medicine, Erwin Drive, Durham, NC, 27710, USA. amy.murtha@duke.edu.
authors.forename: Amy
authors.initials: A
authors.lastname: Murtha
authors.affiliation: Department of Community and Family Medicine and Duke Cancer Institute, Duke University School of Medicine, Erwin Drive, Durham, NC, 27710, USA. joellen.schildkraut@duke.edu.
authors.forename: Joellen
authors.initials: J
authors.lastname: Schildkraut
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University School of Medicine, Research Drive, Durham, NC, 27710, USA. susan.murphy@duke.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Department of Biological Sciences, Center for Human Health and the Environment, North Carolina State University, Raleigh, NC, 27695, USA. choyo@ncsu.edu.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hoyo
mesh_terms: D000328:Adult; D001724:Birth Weight / Q000187:drug effects*; D002104:Cadmium / Q000097:blood / Q000633:toxicity*; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D005312:Fetal Blood / Q000378:metabolism*; D005492:Folic Acid / Q000097:blood; D006801:Humans; D007223:Infant; D007501:Iron / Q000097:blood / Q000494:pharmacology*; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D011247:Pregnancy; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects; D055815:Young Adult; D015032:Zinc / Q000097:blood / Q000494:pharmacology*
chemical_list: D002104:Cadmium; D005492:Folic Acid; D007501:Iron; D015032:Zinc