Prenatal plus postnatal exposure to Di(n-Butyl) phthalate and/or flutamide markedly reduces final sertoli cell number in the rat

Endocrinology. 2010 Jun;151(6):2868-75. doi: 10.1210/en.2010-0108. Epub 2010 Apr 14.


Androgens may be important regulators of Sertoli cell (SC) proliferation perinatally, with implications for the testicular dysgenesis syndrome (TDS) hypothesis. Fetal exposure of rats to 500 mg/kg . d di(n-butyl) phthalate (DBP) reduces fetal testosterone production and SC number at birth, but SC number recovers to normal by postnatal d (Pnd)25. It is unclear when and how SC proliferation is affected prenatally by DBP exposure or when and how postnatal compensation occurs. This study addressed these questions and investigated whether continued maternal exposure to DBP or to flutamide from Pnd1-Pnd15 could prevent SC number compensation, because this would have implications for how sperm counts might be lowered in TDS. DBP exposure attenuated SC proliferation by 7-18% throughout embryonic d (e)15.5-e21.5 (P < 0.05 at e21.5). After birth, SC proliferation increased significantly (>1.5-fold) between Pnd6 and Pnd10 in prenatally DBP-exposed animals, explaining the compensation. Continued maternal administration of DBP after birth attenuated (19% reduction) SC number compensation at Pnd25 and maternal administration of flutamide (100 mg/kg . d) to prenatally DBP-exposed animals was even more effective (42% reduction), suggesting the postnatal compensatory increase in SC proliferation after prenatal DBP exposure is androgen dependent. SC maturation (Pnd25) was unaffected, based on analysis of expression of key proteins, but lumen formation/expansion was attenuated in parallel with treatment-induced reduction in SC number. Our results provide further evidence that perinatal SC proliferation is androgen dependent and, importantly, show that similar exposure of mothers to antiandrogenic chemicals before birth and during lactation reduces final SC number, with implications for the origin of low sperm counts in TDS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dibutyl Phthalate / pharmacology*
  • Female
  • Fetus / drug effects
  • Fetus / physiology
  • Flutamide / pharmacology*
  • Immunohistochemistry
  • Male
  • Organ Size / drug effects
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Rats
  • Rats, Wistar
  • SOX9 Transcription Factor / metabolism
  • Sertoli Cells / cytology*
  • Sertoli Cells / drug effects*
  • Sertoli Cells / metabolism
  • Testis / cytology
  • Testis / drug effects
  • Testis / metabolism
  • Testis / physiology


  • SOX9 Transcription Factor
  • Dibutyl Phthalate
  • Flutamide