RGD Reference Report - Antiandrogen exposure in utero disrupts expression of desert hedgehog and insulin-like factor 3 in the developing fetal rat testis. - Rat Genome Database

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

Authors: Brokken, LJ  Adamsson, A  Paranko, J  Toppari, J 
Citation: Brokken LJ, etal., Endocrinology. 2009 Jan;150(1):445-51. Epub 2008 Sep 4.
RGD ID: 2303053
Pubmed: PMID:18772241   (View Abstract at PubMed)
DOI: DOI:10.1210/en.2008-0230   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
male gonad development  IEP 2303053; 2303053; 2303053 RGD 
response to alkaloid  IEP 2303053; 2303053cyclopamineRGD 
response to organic cyclic compound  IEP 2303053 RGD 
response to xenobiotic stimulus  IEP 2303053flutamideRGD 
response to xenobiotic stimulus  IEP 2303053 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp11a1  (cytochrome P450, family 11, subfamily a, polypeptide 1)
Hsd3b1  (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1)
Ptch1  (patched 1)
Star  (steroidogenic acute regulatory protein)


Additional Information