title: Human Chorionic Gonadotropin Partially Mediates Phthalate Association With Male and Female Anogenital Distance.
abstract: BACKGROUND
  Prenatal exposure to phthalates disrupts male sex development in rodents. In humans, the placental glycoprotein hormone human chorionic gonadotropin (hCG) is required for male development, and may be a target of phthalate exposure.
  
  
  OBJECTIVE
  This study aimed to test the hypothesis that phthalates disrupt placental hCG differentially in males and females with consequences for sexually dimorphic genital development.
  
  
  METHODS
  The Infant Development and Environment Study (TIDES) is a prospective birth cohort. Pregnant women were enrolled from 2010-2012 at four university hospitals.
  
  
  METHODS
  Participants were TIDES subjects (n = 541) for whom genital and phthalate measurements were available and who underwent prenatal serum screening in the first or second trimester.
  
  
  METHODS
  Outcomes included hCG levels in maternal serum in the first and second trimesters and anogenital distance (AGD), which is the distance from the anus to the genitals in male and female neonates.
  
  
  RESULTS
  Higher first-trimester urinary mono-n-butyl phthalate (MnBP; P = .01), monobenzyl phthalate (MBzP; P = .03), and mono-carboxy-isooctyl phthalate (P < .01) were associated with higher first-trimester hCG in women carrying female fetuses, and lower hCG in women carrying males. First-trimester hCG was positively correlated with the AGD z score in female neonates, and inversely correlated in males (P = 0.01). We measured significant associations of MnBP (P < .01), MBzP (P = .02), and mono-2-ethylhexyl phthalate (MEHP; P < .01) with AGD, after adjusting for sex differences. Approximately 52% (MnBP) and 25% (MEHP) of this association in males, and 78% in females (MBzP), could be attributed to the phthalate association with hCG.
  
  
  CONCLUSIONS
  First-trimester hCG levels, normalized by fetal sex, may reflect sexually dimorphic action of phthalates on placental function and on genital development.
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Adibi
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Myoung Keun
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Naimi
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Emily
authors.initials: E
authors.lastname: Barrett
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Ruby H
authors.initials: RH
authors.lastname: Nguyen
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Sheela
authors.initials: S
authors.lastname: Sathyanarayana
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Mari-Paule
authors.initials: MP
authors.lastname: Thiet
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: J Bruce
authors.initials: JB
authors.lastname: Redmon
authors.affiliation: Department of Epidemiology, Graduate School of Public Health (J.J.A., Y.Z.), and Department of Obstetrics, Gynecology and Reproductive Sciences (J.J.A.), University of Pittsburgh. Pittsburgh, Pennsylvania 15261; Department Obstetrics and Gynecology (A.I.N.), McGill University, Montréal, H3A 0G4, Canada; Department of Obstetrics and Gynecology (E.B.), School of Medicine and Dentistry, University of Rochester, Rochester, New York 14604; Division of Epidemiology & Community Health (R.H.N.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pediatrics (S.S.), Seattle Children's Research Institute, University of Washington, Seattle, Washington 98105; Department of Obstetrics, Gynecology and Reproductive Sciences (M.-P.T.), University of California, San Francisco, Francisco, California 94143; Department of Medicine (J.B.R.), University of Minnesota, Minneapolis, Minnesota 55455; and Department of Preventive Medicine (S.H.S.), Icahn School of Medicine at Mt Sinai, New York, New York 10029.
authors.forename: Shanna H
authors.initials: SH
authors.lastname: Swan
mesh_terms: D000328:Adult; D002657:Child Development / Q000187:drug effects*; D006063:Chorionic Gonadotropin / Q000097:blood*; D004781:Environmental Exposure; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects*; D005837:Genitalia, Male / Q000187:drug effects*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010795:Phthalic Acids / Q000633:toxicity*; D011247:Pregnancy; D012733:Sex Differentiation / Q000187:drug effects*; D055815:Young Adult
chemical_list: D006063:Chorionic Gonadotropin; D010795:Phthalic Acids; C032279:phthalic acid