title: Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents.
abstract: Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3β-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.
authors.affiliation: MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom. S.vandenDriesche@ed.ac.uk
authors.forename: Sander
authors.initials: S
authors.lastname: van den Driesche
authors.forename: Marion
authors.initials: M
authors.lastname: Walker
authors.forename: Chris
authors.initials: C
authors.lastname: McKinnell
authors.forename: Hayley M
authors.initials: HM
authors.lastname: Scott
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Eddie
authors.forename: Rod T
authors.initials: RT
authors.lastname: Mitchell
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Drake
authors.forename: Lee B
authors.initials: LB
authors.lastname: Smith
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D051837:COUP Transcription Factor II / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003993:Dibutyl Phthalate / Q000009:adverse effects; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D052801:Male Urogenital Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012377:Rodentia; D054339:Steroidogenic Factor 1 / Q000235:genetics / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D051837:COUP Transcription Factor II; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D054339:Steroidogenic Factor 1; D003993:Dibutyl Phthalate; D013739:Testosterone