title: Is Hypospadias Associated with Prenatal Exposure to Endocrine Disruptors? A French Collaborative Controlled Study of a Cohort of 300 Consecutive Children Without Genetic Defect.
abstract: BACKGROUND
  Numerous studies have focused on the association between endocrine-disrupting chemicals (EDCs) and hypospadias. Phenotype variability, the absence of representative comparison groups and concomitant genetic testing prevent any definitive conclusions.
  
  
  OBJECTIVE
  To identify the role of occupational and environmental exposures to EDCs in nongenetic isolated hypospadias.
  
  
  METHODS
  A total of 408 consecutive children with isolated hypospadias and 302 normal boys were prospectively included (2009-2014) in a multi-institutional study in the south of France, the area of the country with the highest prevalence of hypospadias surgery.
  
  
  METHODS
  In patients without AR, SRD5A2, and MAMLD1 mutations, parental occupational and professional exposures to EDCs were evaluated based on European questionnaire QLK4-1999-01422 and a validated job-exposure matrix for EDCs. Environmental exposure was estimated using the zip code, the type of surrounding hazards, and distance from these hazards. Multivariate analysis was performed.
  
  
  RESULTS
  Fetal exposure to EDCs around the window of genital differentiation was more frequent in the case of hypospadias (40.00% vs 17.55%, odds ratio 3.13, 95% confidence interval 2.11-4.65). The substances were paints/solvents/adhesives (16.0%), detergents (11.0%), pesticides (9.0%), cosmetics (5.6%), and industrial chemicals (4.0%). Jobs with exposure were more frequent in mothers of hypospadiac boys (19.73% vs 10.26%, p=0.0019), especially cleaners, hairdressers, beauticians, and laboratory workers. Paternal job exposure was more frequent in the cases of hypospadias (40.13% vs 27.48%, p=0.02). Industrial areas, incinerators, and waste areas were more frequent within a 3-km radius for mothers of hypospadiac boys (13.29% vs. 6.64%, p<0.00005). Association of occupational and environmental exposures increases this risk.
  
  
  CONCLUSIONS
  This multicenter prospective controlled study with a homogeneous cohort of hypospadiac boys without genetic defects strongly suggests that EDCs are a risk factor for hypospadias through occupational and environmental exposure during fetal life. The association of various types of exposures may increase this risk.
  
  
  RESULTS
  Our multi-institutional study showed that parental professional, occupational, and environmental exposures to chemical products increase the risk of hypospadias in children.
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France; Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France. Electronic address: nicolaskalfa@gmail.com.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Kalfa
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France; Unité d'Endocrinologie et Gynécologie Pédiatriques, Service de Pédiatrie, Hôpital Arnaud de Villeneuve et Université Montpellier 1, CHU de Montpellier, Montpellier, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Paris
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Philibert
authors.affiliation: Institut Universitaire de Recherche Clinique, Laboratoire de Biostatistiques et d'Epidémiologie, Université Montpellier 1, Montpellier, France.
authors.forename: Mattea
authors.initials: M
authors.lastname: Orsini
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Broussous
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Fauconnet-Servant
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Audran
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Gaspari
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital la Timone, Marseille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Lehors
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital la Timone, Marseille, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Haddad
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital la Timone, Marseille, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Guys
authors.affiliation: Unité d'Endocrinologie et Diabétologie Pédiatriques, Hôpital la Timone, Marseille, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Reynaud
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Nord, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Alessandrini
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Nord, Marseille, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Merrot
authors.affiliation: Service de Pédiatrie, Hôpital Lenval, CHU de Nice, France.
authors.forename: Kathy
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Lenval, Nice, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Kurzenne
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Lenval, Nice, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bastiani
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Lenval, Nice, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bréaud
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Lenval, Nice, France.
authors.forename: Jean-Stéphane
authors.initials: JS
authors.lastname: Valla
authors.affiliation: Service de Chirurgie et Urologie Pédiatrique, Hôpital Saint-Joseph, Marseille, France.
authors.forename: Gérard Morisson
authors.initials: GM
authors.lastname: Lacombe
authors.affiliation: Service de Chirurgie Pédiatrique, Hôpital Pellegrin Enfants, Bordeaux, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Dobremez
authors.affiliation: Institut Universitaire de Recherche Clinique, Laboratoire de Biostatistiques et d'Epidémiologie, Université Montpellier 1, Montpellier, France.
authors.forename: Amel
authors.initials: A
authors.lastname: Zahhaf
authors.affiliation: Institut Universitaire de Recherche Clinique, Laboratoire de Biostatistiques et d'Epidémiologie, Université Montpellier 1, Montpellier, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Daures
authors.affiliation: Service d'Hormonologie, Hôpital Lapeyronie, CHU de Montpellier et Université Montpellier 1, Montpellier, France; Unité d'Endocrinologie et Gynécologie Pédiatriques, Service de Pédiatrie, Hôpital Arnaud de Villeneuve et Université Montpellier 1, CHU de Montpellier, Montpellier, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Sultan
mesh_terms: D002648:Child; D002675:Child, Preschool; D052244:Endocrine Disruptors / Q000009:adverse effects*; D004781:Environmental Exposure / Q000009:adverse effects*; D005260:Female; D005602:France; D006801:Humans; D007021:Hypospadias / Q000139:chemically induced*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D016273:Occupational Exposure / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011446:Prospective Studies
chemical_list: D052244:Endocrine Disruptors
keywords: Birth defect; Disorder of sex determination; Endocrine-disrupting chemicals; Environment; Hypospadias; Occupation; Pesticides