title: Experimentally induced testicular dysgenesis syndrome originates in the masculinization programming window.
abstract: The testicular dysgenesis syndrome (TDS) hypothesis, which proposes that common reproductive disorders of newborn and adult human males may have a common fetal origin, is largely untested. We tested this hypothesis using a rat model involving gestational exposure to dibutyl phthalate (DBP), which suppresses testosterone production by the fetal testis. We evaluated if induction of TDS via testosterone suppression is restricted to the "masculinization programming window" (MPW), as indicated by reduction in anogenital distance (AGD). We show that DBP suppresses fetal testosterone equally during and after the MPW, but only DBP exposure in the MPW causes reduced AGD, focal testicular dysgenesis, and TDS disorders (cryptorchidism, hypospadias, reduced adult testis size, and compensated adult Leydig cell failure). Focal testicular dysgenesis, reduced size of adult male reproductive organs, and TDS disorders and their severity were all strongly associated with reduced AGD. We related our findings to human TDS cases by demonstrating similar focal dysgenetic changes in testes of men with preinvasive germ cell neoplasia (GCNIS) and in testes of DBP-MPW animals. If our results are translatable to humans, they suggest that identification of potential causes of human TDS disorders should focus on exposures during a human MPW equivalent, especially if negatively associated with offspring AGD.
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sander
authors.initials: S
authors.lastname: van den Driesche
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Kilcoyne
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ida
authors.initials: I
authors.lastname: Wagner
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Diane
authors.initials: D
authors.lastname: Rebourcet
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Boyle
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rod
authors.initials: R
authors.lastname: Mitchell
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnell
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Sheila
authors.initials: S
authors.lastname: Macpherson
authors.affiliation: Edinburgh Urological Cancer Group, Department of Urology, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Roland
authors.initials: R
authors.lastname: Donat
authors.affiliation: Edinburgh Urological Cancer Group, Department of Urology, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Chitranjan J
authors.initials: CJ
authors.lastname: Shukla
authors.affiliation: Department of Growth & Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Jorgensen
authors.affiliation: Department of Growth & Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Ewa Rajpert-De
authors.initials: ER
authors.lastname: Meyts
authors.affiliation: Department of Growth & Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebaek
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D003993:Dibutyl Phthalate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D006059:Gonadal Dysgenesis / Q000139:chemically induced*; D006801:Humans; D008297:Male; D018811:Maternal Exposure; D010968:Plasticizers / Q000633:toxicity; D051381:Rats; D013733:Testicular Diseases / Q000139:chemically induced*
chemical_list: D010968:Plasticizers; D003993:Dibutyl Phthalate