Article thumbnail
Location of Repository

Proposed Role for COUP-TFII in Regulating Fetal Leydig Cell Steroidogenesis, Perturbation of Which Leads to Masculinization Disorders in Rodents

By Sander van den Driesche, Marion Walker, Chris McKinnell, Hayley M. Scott, Sharon L. Eddie, Rod T. Mitchell, Jonathan R. Seckl, Amanda J. Drake, Lee B. Smith, Richard A. Anderson and Richard M. Sharpe


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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2012). 21: 509–516. COUP-TFII Function in Fetal Leydig Cells PLoS
  2. (2005). Abnormal Leydig Cell aggregation in the fetal testis of rats exposed to di (nbutyl) phthalate and its possible role in testicular dysgenesis.
  3. (2008). Activin signals via SMAD2/3 between germ and somatic cells in the human fetal ovary and regulates kit ligand expression.
  4. (2001). Altered gene profiles in fetal rat testes after in utero exposure to di(n-butyl) phthalate.
  5. (2010). Androgen action in the masculinization programming window and development of male reproductive organs.
  6. (2008). Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption.
  7. (2006). Cellular origins of testicular dysgenesis in rats exposed in utero to di(n-butyl) phthalate.
  8. (1997). Chick ovalbumin upstream promoter-transcription factors (COUP-TFs): coming of age.
  9. (1992). Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors.
  10. (2005). Chicken ovalbumin upstream promoter-transcription factor is a negative regulator of steroidogenesis in bovine adrenal glomerulosa cells.
  11. (2011). Coup d’Etat: an orphan takes control.
  12. (1992). COUP orphan receptors are negative regulators of retinoic acid response pathways.
  13. (2010). Critical androgen-sensitive periods of rat penis and clitoris development.
  14. (2004). Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism.
  15. (2005). Differential steroidogenic gene expression in the fetal adrenal gland versus the testis and rapid and dynamic response of the fetal testis to di(n-butyl) phthalate.
  16. (2012). Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate.
  17. (2004). Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate.
  18. (2001). EAR2 and EAR3/COUP-TFI regulate transcription of the rat LH receptor.
  19. (2003). Effect of neonatal treatment of rats with potent or weak (environmental) oestrogens, or with a GnRH antagonist, on Leydig cell development and function through puberty into adulthood.
  20. (2003). Effects of 4-tert-octylphenol, 4-tert-butylphenol, and diethylstilbestrol on prenatal testosterone surge in the rat.
  21. (2008). Essential roles of COUP-TFII in Leydig cell differentiation and male fertility.
  22. (2007). Fetal mouse phthalate exposure shows that Gonocyte multinucleation is not associated with decreased testicular testosterone.
  23. (2009). Glucocorticoids amplify dibutyl phthalate-induced disruption of testosterone production and male reproductive development.
  24. (2003). Human ‘testicular dysgenesis syndrome’: a possible model using in-utero exposure of the rat to dibutyl phthalate.
  25. (2008). Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.
  26. (1995). Immunolocalisation of androgen receptor to interstitial cells in fetal rat testes and to mesenchymal and epithelial cells of associated ducts.
  27. (2003). Immunolocalization of nuclear transcription factors, DAX-1 and COUP-TF II, in the normal human ovary: correlation with adrenal 4 binding protein/steroidogenic factor-1 immunolocalization during the menstrual cycle.
  28. (2007). In utero exposure to di(n-butyl) phthalate and testicular dysgenesis: comparison of fetal and adult end points and their dose sensitivity.
  29. (2009). New insights into the role of androgens in wolffian duct stabilization in male and female rodents.
  30. (2000). Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor.
  31. (2000). Orphan receptors COUP-TF and DAX-1 as targets in disordered CYP17 expression in adrenocortical tumors.
  32. (2009). Phthalates impair germ cell development in the human fetal testis in vitro without change in testosterone production.
  33. (2009). Phthalates impair germ cell number in the mouse fetal testis by an androgen- and estrogenindependent mechanism.
  34. (2001). Prenatal testosterone and luteinizing hormone levels in male rats exposed during pregnancy to 2,3,7,8-tetrachlorodibenzo-p-dioxin and diethylstilbestrol.
  35. (2009). Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis.
  36. (2003). Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate.
  37. (2003). Repression of the luteinizing hormone receptor gene promoter by cross talk among EAR3/COUP-TFI, Sp1/Sp3, and TFIIB.
  38. (1992). Retinoid X receptor-COUP-TF interactions modulate retinoic acid signaling.
  39. (2011). Shorter anogenital distance predicts poorer semen quality in young men in Rochester, new york.
  40. (2011). Steroidogenesis and steroidogenic gene expression in postnatal fetal rat Leydig cells.
  41. (2009). Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds.
  42. (2010). The orphan nuclear receptors COUP-TFI and COUP-TFII regulate expression of the gonadotropin LHbeta gene.
  43. (2011). The relationship between anogenital distance, fatherhood, and fertility in adult men.
  44. (2009). Time- and dose-related effects of di-(2-ethylhexyl) phthalate and its main metabolites on the function of the rat fetal testis in vitro.
  45. (2007). Timedependent and compartment-specific effects of in utero exposure to Di(n-butyl) phthalate on gene/protein expression in the fetal rat testis as revealed by transcription profiling and laser capture microdissection.
  46. (1995). Transcriptional regulation of the bovine CYP17 gene: two nuclear orphan receptors determine activity of cAMP-responsive sequence
  47. (1994). Two orphan receptors binding to a common site are involved in the regulation of the oxytocin gene in the bovine ovary.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.