title: Maternal urinary phthalates and sex-specific placental mRNA levels in an urban birth cohort.
abstract: Prenatal urinary concentrations of phthalates in women participants in an urban birth cohort were associated with outcomes in their children related to neurodevelopment, autoimmune disease risk, and fat mass at 3,5,7, and 8 years of life. Placental biomarkers and outcomes at birth may offer biologic insight into these associations. This is the first study to address these associations with candidate genes from the phthalate and placenta literature, accounting for sex differences, and using absolute quantitation methods for mRNA levels.
  
  
  
  We measured candidate mRNAs in 180 placentas sampled at birth (HSD17B1, AHR, CGA, CYP19A1, SLC27A4, PTGS2, PPARG, CYP11A1) by quantitative PCR and an absolute standard curve. We estimated associations of logemRNA with quartiles of urinary phthalate monoesters using linear mixed models. Phthalate metabolites (N = 358) and mRNAs (N = 180) were transformed to a z-score and modeled as independent, correlated vectors in relation to large for gestational age (LGA) and gestational diabetes mellitus (GDM).
  
  
  
  CGA was associated with 4 out of 6 urinary phthalates. CGA was 2.0 logeunits lower at the 3rdvs. 1stquartile of mono-n-butyl phthalate (MnBP) (95% confidence interval (CI): -3.5, -0.5) in male placentas, but 0.6 logeunits higher (95% CI: -0.8, 1.9) in female placentas (sex interaction p = 0.01). There was an inverse association of MnBP with PPARG in male placentas (-1.1 logeunits at highest vs. lowest quartile, 95% CI: -2.0, -0.1). CY19A1, CYP11A1, CGA were associated with one or more of the following in a sex-specific manner: monobenzyl phthalate (MBzP), MnBP, mono-iso-butyl phthalate (MiBP). These 3 mRNAs were lower by 1.4-fold (95% CI: -2.4, -1.0) in male GDM placentas vs. female and non-GDM placentas (p-value for interaction = 0.04). The metabolites MnBP/MiBP were 16% higher (95% CI: 0, 22) in GDM pregnancies.
  
  
  
  Prenatal concentrations of certain phthalates and outcomes at birth were modestly associated with molecular changes in fetal placental tissue during pregnancy. Associations were stronger in male vs. female placentas, and associations with MnBP and MiBP were stronger than other metabolites. Placental mRNAs are being pursued further as potential mediators of exposure-induced risks to the health of the child.
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Parran Hall 5132, Pittsburgh, PA, 15261, USA. adibij@pitt.edu.|Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, USA. adibij@pitt.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Adibi
authors.affiliation: Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA.
authors.forename: Jessie P
authors.initials: JP
authors.lastname: Buckley
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Parran Hall 5132, Pittsburgh, PA, 15261, USA.
authors.forename: Myoung Keun
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Building I, Room 415, Boston, MA, 02115, USA.
authors.forename: Paige L
authors.initials: PL
authors.lastname: Williams
authors.affiliation: Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1057, New York, NY, 10029, USA.
authors.forename: Allan C
authors.initials: AC
authors.lastname: Just
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Parran Hall 5132, Pittsburgh, PA, 15261, USA.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Division of Pharmacology and Toxicology, UMKC School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, HSB 5251, Kansas City, MO, 64108, USA.
authors.forename: Hari K
authors.initials: HK
authors.lastname: Bhat
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, 722 W 168th Street, New York, NY, 10032, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Whyatt
mesh_terms: D000328:Adult; D001141:Aromatase / Q000235:genetics; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D004785:Environmental Pollutants / Q000652:urine*; D004960:Estradiol Dehydrogenases / Q000235:genetics; D050612:Fatty Acid Transport Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015292:Glycoprotein Hormones, alpha Subunit / Q000235:genetics; D006801:Humans; D008297:Male; D018811:Maternal Exposure; D047495:PPAR gamma / Q000235:genetics; D010795:Phthalic Acids / Q000652:urine*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D012727:Sex Characteristics; D014505:Urban Population; D055815:Young Adult
chemical_list: D004785:Environmental Pollutants; D050612:Fatty Acid Transport Proteins; D015292:Glycoprotein Hormones, alpha Subunit; D047495:PPAR gamma; D010795:Phthalic Acids; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C493571:SLC27A4 protein, human; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; D001141:Aromatase; C561410:CYP19A1 protein, human; D002786:Cholesterol Side-Chain Cleavage Enzyme
keywords: CGA; Correlated vector; Phthalates; Placenta; Sex difference; mRNA