title: Ibuprofen results in alterations of human fetal testis development.
abstract: Among pregnant women ibuprofen is one of the most frequently used pharmaceutical compounds with up to 28% reporting use. Regardless of this, it remains unknown whether ibuprofen could act as an endocrine disruptor as reported for fellow analgesics paracetamol and aspirin. To investigate this, we exposed human fetal testes (7-17 gestational weeks (GW)) to ibuprofen using ex vivo culture and xenograft systems. Ibuprofen suppressed testosterone and Leydig cell hormone INSL3 during culture of 8-9 GW fetal testes with concomitant reduction in expression of the steroidogenic enzymes CYP11A1, CYP17A1 and HSD17B3, and of INSL3. Testosterone was not suppressed in testes from fetuses younger than 8 GW, older than 10-12 GW, or in second trimester xenografted testes (14-17 GW). Ex vivo, ibuprofen also affected Sertoli cell by suppressing AMH production and mRNA expression of AMH, SOX9, DHH, and COL2A1. While PGE2 production was suppressed by ibuprofen, PGD2 production was not. Germ cell transcripts POU5F1, TFAP2C, LIN28A, ALPP and KIT were also reduced by ibuprofen. We conclude that, at concentrations relevant to human exposure and within a particular narrow 'early window' of sensitivity within first trimester, ibuprofen causes direct endocrine disturbances in the human fetal testis and alteration of the germ cell biology.
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Millissia
authors.initials: M
authors.lastname: Ben Maamar
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Laurianne
authors.initials: L
authors.lastname: Lesné
authors.affiliation: LUNAM Université, Oniris, USC INRA 1329, Laboratoire d'Etude des Résidus et Contaminants dans les Aliments (LABERCA), Nantes, F-44307, France.
authors.forename: Kristin
authors.initials: K
authors.lastname: Hennig
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Desdoits-Lethimonier
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Kilcoyne
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coiffec
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Antoine D
authors.initials: AD
authors.lastname: Rolland
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Chevrier
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.|Laboratorium of Genomic and Molecular Biomedicine, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
authors.forename: David M
authors.initials: DM
authors.lastname: Kristensen
authors.affiliation: CHU de Rennes, Service de Gynécologie, Hôpital Sud, 16, boulevard de Bulgarie, F-35700 Rennes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lavoué
authors.affiliation: LUNAM Université, Oniris, USC INRA 1329, Laboratoire d'Etude des Résidus et Contaminants dans les Aliments (LABERCA), Nantes, F-44307, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Antignac
authors.affiliation: LUNAM Université, Oniris, USC INRA 1329, Laboratoire d'Etude des Résidus et Contaminants dans les Aliments (LABERCA), Nantes, F-44307, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Le Bizec
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dejucq-Rainsford
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, Queens Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Rod T
authors.initials: RT
authors.lastname: Mitchell
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Mazaud-Guittot
authors.affiliation: Institut national de la santé et de la recherche médicale (Inserm), Institut de recherche en santé, environnement et travail (Irset - Inserm UMR 1085), Université de Rennes 1, 9 Avenue Léon Bernard, F-35000 RENNES, France.|Ecole des hautes études en santé publique (EHESP), Avenue Léon Bernard, F-35043 RENNES, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jégou
mesh_terms: D005260:Female; D005333:Fetus / Q000196:embryology* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D013737:Testis / Q000196:embryology* / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
chemical_list: D013739:Testosterone; D007052:Ibuprofen