Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents

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, Richard M Sharpe

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)e37064
JournalPloS one
Volume7
Issue number5
DOIs
Publication statusPublished - 2012

Fingerprint

COUP Transcription Factor II
masculinization
steroidogenesis
Leydig cells
Leydig Cells
ovalbumin
Rodentia
rodents
transcription factors
promoter regions
chickens
Testosterone
testosterone
Steroidogenic Factor 1
Rats
Dibutyl Phthalate
dibutyl phthalate
Diethylstilbestrol
rats
diethylstilbestrol

Keywords

  • Animals
  • Binding Sites
  • COUP Transcription Factor II
  • Cell Nucleus
  • DNA-Binding Proteins
  • Dibutyl Phthalate
  • Female
  • Fetus
  • Leydig Cells
  • Male
  • Male Urogenital Diseases
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Pregnancy Complications
  • RNA, Messenger
  • Rats
  • Rats, Wistar
  • Rodentia
  • Steroidogenic Factor 1
  • Testosterone

Cite this

van den Driesche, Sander ; Walker, Marion ; McKinnell, Chris ; Scott, Hayley M ; Eddie, Sharon L ; Mitchell, Rod T ; Seckl, Jonathan R ; Drake, Amanda J ; Smith, Lee B ; Anderson, Richard A ; Sharpe, Richard M. / Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents. In: PloS one. 2012 ; Vol. 7, No. 5. pp. e37064.
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van den Driesche, S, Walker, M, McKinnell, C, Scott, HM, Eddie, SL, Mitchell, RT, Seckl, JR, Drake, AJ, Smith, LB, Anderson, RA & Sharpe, RM 2012, 'Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents', PloS one, vol. 7, no. 5, pp. e37064. https://doi.org/10.1371/journal.pone.0037064

Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents. / van den Driesche, Sander; Walker, Marion; McKinnell, Chris; Scott, Hayley M; Eddie, Sharon L; Mitchell, Rod T; Seckl, Jonathan R; Drake, Amanda J; Smith, Lee B; Anderson, Richard A; Sharpe, Richard M.

In: PloS one, Vol. 7, No. 5, 2012, p. e37064.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents

AU - van den Driesche, Sander

AU - Walker, Marion

AU - McKinnell, Chris

AU - Scott, Hayley M

AU - Eddie, Sharon L

AU - Mitchell, Rod T

AU - Seckl, Jonathan R

AU - Drake, Amanda J

AU - Smith, Lee B

AU - Anderson, Richard A

AU - Sharpe, Richard M

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Animals

KW - Binding Sites

KW - COUP Transcription Factor II

KW - Cell Nucleus

KW - DNA-Binding Proteins

KW - Dibutyl Phthalate

KW - Female

KW - Fetus

KW - Leydig Cells

KW - Male

KW - Male Urogenital Diseases

KW - Mice

KW - Mice, Inbred C57BL

KW - Pregnancy

KW - Pregnancy Complications

KW - RNA, Messenger

KW - Rats

KW - Rats, Wistar

KW - Rodentia

KW - Steroidogenic Factor 1

KW - Testosterone

U2 - 10.1371/journal.pone.0037064

DO - 10.1371/journal.pone.0037064

M3 - Article

C2 - 22615892

VL - 7

SP - e37064

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

ER -