Male fetal germ cells are targets for androgens that physiologically inhibit their proliferation.
In adulthood, the action of androgens on seminiferous tubules is essential for full quantitatively normal spermatogenesis and fertility. In contrast, their role in the fetal testis, and particularly in fetal germ cell development, remains largely unknown. Using testicular feminized (Tfm) mice, we investigated the effects of a lack of functional androgen receptor (AR) on fetal germ cells, also named gonocytes. We demonstrated that endogenous androgens/AR physiologically control normal gonocyte proliferation. We observed an increase in the number of gonocytes at 17.5 days postconception resulting from an increase in proliferative activity in Tfm mice. In a reciprocal manner, gonocyte proliferation is decreased by the addition of DHT in fetal testis organotypic culture. Furthermore, the AR coregulator Hsp90alpha (mRNA and protein) specifically expressed in gonocytes was down-regulated in Tfm mice at 15.5 days postconception. To investigate whether these effects could result from direct action of androgens on gonocytes, we collected pure gonocyte preparations and detected AR transcripts therein. We used an original model harboring a reporter gene that specifically reflects AR activity by androgens and clearly demonstrated the presence of a functional AR protein in fetal germ cells. These data provide in vivo and in vitro evidence of a new control of endogenous androgens on gonocytes identified as direct target cells for androgens. Finally, our results focus on a new pathway in the fetal testis during the embryonic period, which is the most sensitive to antiandrogenic endocrine disruptors.
Merlet
Jorge
J
Université Denis Diderot Paris 7 and Commissariat à l'Energie Atomique, Institut de Radiobiologie Cellulaire et Moléculaire, and Institut National de la Santé et de la Recherche Médicale Unité 566, F-92265 Fontenay-aux-Roses, France.
Racine
Chrystèle
C
Moreau
Evelyne
E
Moreno
Stéphanie G
SG
Habert
René
R
D000818:Animals; D001973:Bromodeoxyuridine; D049109:Cell Proliferation; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009929:Organ Size; D011944:Receptors, Androgen / Q000172:deficiency* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000166:cytology / Q000196:embryology*
D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D011944:Receptors, Androgen; D001973:Bromodeoxyuridine