title: Association between In Utero arsenic exposure, placental gene expression, and infant birth weight: a US birth cohort study.
abstract: BACKGROUND
  Epidemiologic studies and animal models suggest that in utero arsenic exposure affects fetal health, with a negative association between maternal arsenic ingestion and infant birth weight often observed. However, the molecular mechanisms for this association remain elusive. In the present study, we aimed to increase our understanding of the impact of low-dose arsenic exposure on fetal health by identifying possible arsenic-associated fetal tissue biomarkers in a cohort of pregnant women exposed to arsenic at low levels.
  
  
  METHODS
  Arsenic concentrations were determined from the urine samples of a cohort of 133 pregnant women from New Hampshire. Placental tissue samples collected from enrollees were homogenized and profiled for gene expression across a panel of candidate genes, including known arsenic regulated targets and genes involved in arsenic transport, metabolism, or disease susceptibility. Multivariable adjusted linear regression models were used to examine the relationship of candidate gene expression with arsenic exposure or with birth weight of the baby.
  
  
  RESULTS
  Placental expression of the arsenic transporter AQP9 was positively associated with maternal urinary arsenic levels during pregnancy (coefficient estimate: 0.25; 95% confidence interval: 0.05 - 0.45). Placental expression of AQP9 related to expression of the phospholipase ENPP2 which was positively associated with infant birth weight (coefficient estimate: 0.28; 95% CI: 0.09 - 0.47). A structural equation model indicated that these genes may mediate arsenic's effect on infant birth weight (coefficient estimate: -0.009; 95% confidence interval: -0.032 - -0.001; 10,000 replications for bootstrapping).
  
  
  CONCLUSIONS
  We identified the expression of AQP9 as a potential fetal biomarker for arsenic exposure. Further, we identified a positive association between the placental expression of phospholipase ENPP2 and infant birth weight. These findings suggest a path by which arsenic may affect birth outcomes.
authors.affiliation: Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Dennis Liang
authors.initials: DL
authors.lastname: Fei
authors.forename: Devin C
authors.initials: DC
authors.lastname: Koestler
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.forename: Camilla
authors.initials: C
authors.lastname: Giambelli
authors.forename: Avencia
authors.initials: A
authors.lastname: Sanchez-Mejias
authors.forename: Julie A
authors.initials: JA
authors.lastname: Gosse
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
mesh_terms: D000328:Adult; D020346:Aquaporins / Q000235:genetics* / Q000378:metabolism; D001151:Arsenic / Q000652:urine*; D015415:Biomarkers / Q000378:metabolism; D001724:Birth Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D018811:Maternal Exposure; D015999:Multivariate Analysis; D009513:New Hampshire; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D014874:Water Pollutants, Chemical / Q000652:urine*; D000099189:Lysophospholipase D
chemical_list: D020346:Aquaporins; D001151:Arsenic; D015415:Biomarkers; D010727:Phosphoric Diester Hydrolases; D014874:Water Pollutants, Chemical; D000099189:Lysophospholipase D; C109669:AQP9 protein, human