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Antiandrogen exposure in utero disrupts expression of desert hedgehog and insulin-like factor 3 in the developing fetal rat testis

Brokken, Leon LU ; Adamsson, Annika; Paranko, Jorma and Toppari, Jorma (2009) In Endocrinology 150(1). p.51-445
Abstract
Testicular development is an androgen-dependent process, and fetal exposure to antiandrogens disrupts male sexual differentiation. A variety of testicular disorders may result from impaired development of fetal Leydig and Sertoli cells. We hypothesized that antiandrogenic exposure during fetal development interferes with desert hedgehog (Dhh) signaling in the testis and results in impaired Leydig cell differentiation. Fetal rats were exposed in utero to the antiandrogen flutamide from 10.5 d post conception (dpc) until they were killed or delivery. Fetal testes were isolated at different time points during gestation and gene expression levels of Dhh, patched-1 (Ptc1), steroidogenic factor 1 (Sf1), cytochrome P450 side-chain cleavage... (More)
Testicular development is an androgen-dependent process, and fetal exposure to antiandrogens disrupts male sexual differentiation. A variety of testicular disorders may result from impaired development of fetal Leydig and Sertoli cells. We hypothesized that antiandrogenic exposure during fetal development interferes with desert hedgehog (Dhh) signaling in the testis and results in impaired Leydig cell differentiation. Fetal rats were exposed in utero to the antiandrogen flutamide from 10.5 d post conception (dpc) until they were killed or delivery. Fetal testes were isolated at different time points during gestation and gene expression levels of Dhh, patched-1 (Ptc1), steroidogenic factor 1 (Sf1), cytochrome P450 side-chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase type 1 (Hsd3b1), and insulin-like factor 3 (Insl3) were analyzed. To study direct effects of hedgehog signaling on testicular development, testes from 14.5 dpc fetuses were cultured for 3 d in the presence of cyclopamine, sonic hedgehog, or vehicle, and gene expression levels and testosterone secretion were analyzed. Organ cultures were also analyzed histologically, and cleaved-caspase 3 immunohistochemistry was performed to assess apoptosis. In utero exposure to flutamide decreased expression levels of Dhh, Ptc1, Sf1, P450scc, Hsd3b1, and Insl3, particularly from 17.5 dpc onward. Inhibition of hedgehog signaling in testis cultures resulted in similar effects on gene expression levels. Apoptosis in Wolffian ducts was increased by cyclopamine compared with sonic hedgehog- or vehicle-treated cultures. We conclude that exposure to the antiandrogen flutamide interferes with Dhh signaling resulting in an impaired differentiation of the fetal Leydig cells and subsequently leading to abnormal testicular development and sexual differentiation. (Less)
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author
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Contribution to journal
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published
subject
keywords
Cell Surface/genetics, Receptors, Luteinizing Hormone/metabolism, Male, Polymerase Chain Reaction, Organ Culture Techniques, Testis/*embryology, Testosterone/metabolism, Insulin/*genetics, Hedgehog Proteins/*genetics, Flutamide/*pharmacology, Fetal Development/*drug effects, Female, DNA Primers, Cholesterol Side-Chain Cleavage Enzyme/genetics, Androgen Antagonists/*pharmacology, Progesterone/metabolism, Animals, Pregnancy, Rats, Proteins/*genetics, Androgen/metabolism
in
Endocrinology
volume
150
issue
1
pages
51 - 445
publisher
Endocrine Society
external identifiers
  • scopus:58149473438
ISSN
0013-7227
DOI
10.1210/en.2008-0230
language
English
LU publication?
no
id
5fa32959-358f-4e58-88d2-23e097bd4c36 (old id 1500984)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18772241
http://endo.endojournals.org/content/150/1/445.long
date added to LUP
2013-05-14 14:42:16
date last changed
2017-12-10 03:50:29
@article{5fa32959-358f-4e58-88d2-23e097bd4c36,
  abstract     = {Testicular development is an androgen-dependent process, and fetal exposure to antiandrogens disrupts male sexual differentiation. A variety of testicular disorders may result from impaired development of fetal Leydig and Sertoli cells. We hypothesized that antiandrogenic exposure during fetal development interferes with desert hedgehog (Dhh) signaling in the testis and results in impaired Leydig cell differentiation. Fetal rats were exposed in utero to the antiandrogen flutamide from 10.5 d post conception (dpc) until they were killed or delivery. Fetal testes were isolated at different time points during gestation and gene expression levels of Dhh, patched-1 (Ptc1), steroidogenic factor 1 (Sf1), cytochrome P450 side-chain cleavage (P450scc), 3beta-hydroxysteroid dehydrogenase type 1 (Hsd3b1), and insulin-like factor 3 (Insl3) were analyzed. To study direct effects of hedgehog signaling on testicular development, testes from 14.5 dpc fetuses were cultured for 3 d in the presence of cyclopamine, sonic hedgehog, or vehicle, and gene expression levels and testosterone secretion were analyzed. Organ cultures were also analyzed histologically, and cleaved-caspase 3 immunohistochemistry was performed to assess apoptosis. In utero exposure to flutamide decreased expression levels of Dhh, Ptc1, Sf1, P450scc, Hsd3b1, and Insl3, particularly from 17.5 dpc onward. Inhibition of hedgehog signaling in testis cultures resulted in similar effects on gene expression levels. Apoptosis in Wolffian ducts was increased by cyclopamine compared with sonic hedgehog- or vehicle-treated cultures. We conclude that exposure to the antiandrogen flutamide interferes with Dhh signaling resulting in an impaired differentiation of the fetal Leydig cells and subsequently leading to abnormal testicular development and sexual differentiation.},
  author       = {Brokken, Leon and Adamsson, Annika and Paranko, Jorma and Toppari, Jorma},
  issn         = {0013-7227},
  keyword      = {Cell Surface/genetics,Receptors,Luteinizing Hormone/metabolism,Male,Polymerase Chain Reaction,Organ Culture Techniques,Testis/*embryology,Testosterone/metabolism,Insulin/*genetics,Hedgehog Proteins/*genetics,Flutamide/*pharmacology,Fetal Development/*drug effects,Female,DNA Primers,Cholesterol Side-Chain Cleavage Enzyme/genetics,Androgen Antagonists/*pharmacology,Progesterone/metabolism,Animals,Pregnancy,Rats,Proteins/*genetics,Androgen/metabolism},
  language     = {eng},
  number       = {1},
  pages        = {51--445},
  publisher    = {Endocrine Society},
  series       = {Endocrinology},
  title        = {Antiandrogen exposure in utero disrupts expression of desert hedgehog and insulin-like factor 3 in the developing fetal rat testis},
  url          = {http://dx.doi.org/10.1210/en.2008-0230},
  volume       = {150},
  year         = {2009},
}