title: Infant sex-specific placental cadmium and DNA methylation associations.
abstract: BACKGROUND
  Recent evidence suggests that maternal cadmium (Cd) burden and fetal growth associations may vary by fetal sex. However, mechanisms contributing to these differences are unknown.
  
  
  OBJECTIVE
  Among 24 maternal-infant pairs, we investigated infant sex-specific associations between placental Cd and placental genome-wide DNA methylation.
  
  
  METHODS
  We used ANOVA models to examine sex-stratified associations of placental Cd (dichotomized into high/low Cd using sex-specific Cd median cutoffs) with DNA methylation at each cytosine-phosphate-guanine site or region. Statistical significance was defined using a false discovery rate cutoff (<0.10).
  
  
  RESULTS
  Medians of placental Cd among females and males were 5 and 2 ng/g, respectively. Among females, three sites (near ADP-ribosylation factor-like 9 (ARL9), siah E3 ubiquitin protein ligase family member 3 (SIAH3), and heparin sulfate (glucosamine) 3-O-sulfotransferase 4 (HS3ST4) and one region on chromosome 7 (including carnitine O-octanoyltransferase (CROT) and TP5S target 1 (TP53TG1)) were hypomethylated in high Cd placentas. Among males, high placental Cd was associated with methylation of three sites, two (hypomethylated) near MDS1 and EVI1 complex locus (MECOM) and one (hypermethylated) near spalt-like transcription factor 1 (SALL1), and two regions (both hypomethylated, one on chromosome 3 including MECOM and another on chromosome 8 including rho guanine nucleotide exchange factor (GEF) 10 (ARHGEF10). Differentially methylated sites were at or close to transcription start sites of genes involved in cell damage response (SIAH3, HS3ST4, TP53TG1) in females and cell differentiation, angiogenesis and organ development (MECOM, SALL1) in males.
  
  
  CONCLUSIONS
  Our preliminary study supports infant sex-specific placental Cd-DNA methylation associations, possibly accounting for previously reported differences in Cd-fetal growth associations across fetal sex. Larger studies are needed to replicate and extend these findings. Such investigations may further our understanding of epigenetic mechanisms underlying maternal Cd burden with suboptimal fetal growth associations.
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, 1730 Minor Ave, Seattle, WA 98101, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA. Electronic address: april.mohanty@va.gov.
authors.forename: April F
authors.initials: AF
authors.lastname: Mohanty
authors.affiliation: Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, 4225 Roosevelt Way N.E., Suite #100, Seattle, WA 98105, USA. Electronic address: freddy@u.washington.edu.
authors.forename: Fred M
authors.initials: FM
authors.lastname: Farin
authors.affiliation: Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, 4225 Roosevelt Way N.E., Suite #100, Seattle, WA 98105, USA. Electronic address: tbammler@u.washington.edu.
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.affiliation: Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, 4225 Roosevelt Way N.E., Suite #100, Seattle, WA 98105, USA. Electronic address: jmacdon@uw.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: MacDonald
authors.affiliation: Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, 4225 Roosevelt Way N.E., Suite #100, Seattle, WA 98105, USA. Electronic address: zafshari@u.washington.edu.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Afsharinejad
authors.affiliation: Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Box: 357234, 1705 N.E. Pacific Street, Seattle, WA 98195, USA. Electronic address: tmb@uw.edu.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Burbacher
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, 1730 Minor Ave, Seattle, WA 98101, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA. Electronic address: dsiscovick@nyam.org.
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Kresge Building, 9th Floor, 677 Huntington Ave., Boston, MA 02115, USA. Electronic address: mawilliams@hsph.harvard.edu.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Williams
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, 1730 Minor Ave, Seattle, WA 98101, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA; Center for Perinatal Studies, Swedish Medical Center, 1124 Columbia Street, Suite 750, Seattle, WA 98104, USA. Electronic address: danenq@u.washington.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Enquobahrie
mesh_terms: D001724:Birth Weight / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D019175:DNA Methylation / Q000187:drug effects*; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D012737:Sex Factors
chemical_list: D004785:Environmental Pollutants; D002104:Cadmium
keywords: Cadmium; DNA Methylation; Fetal growth; Infant-Sex; Placenta