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Male Fetal Germ Cells Are Targets for Androgens That Physiologically Inhibit Their Proliferation

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Male Fetal Germ Cells Are Targets for Androgens That Physiologically Inhibit Their Proliferation Male fetal germ cells are targets for androgens that physiologically inhibit their proliferation Jorge Merlet, Chryste` le Racine*, Evelyne Moreau, Ste´ phanie G. Moreno, and Rene´ Habert Laboratory of Differentiation and Radiobiology of the Gonads, Unit of Gametogenesis and Genotoxicity, Unite´Mixte de Recherche-S 566, Universite´Denis Diderot Paris 7 and Commissariat a`l’E´ nergie Atomique, Institut de Radiobiologie Cellulaire et Mole´culaire, and Institut National de la Sante´ etdela Recherche Me´dicale Unite´566, F-92265 Fontenay-aux-Roses, France Edited by Ryuzo Yanagimachi, University of Hawaii, Honolulu, HI, and approved January 8, 2007 (received for review December 21, 2006) In adulthood, the action of androgens on seminiferous tubules is Androgen actions are mediated through the androgen recep- essential for full quantitatively normal spermatogenesis and fer- tor (AR), which belongs to the steroid receptor superfamily tility. In contrast, their role in the fetal testis, and particularly in whose members function primarily as transcription factors to fetal germ cell development, remains largely unknown. Using regulate the expression of target genes by binding to specific testicular feminized (Tfm) mice, we investigated the effects of a hormone-responsive elements (19). There is nearly universal lack of functional androgen receptor (AR) on fetal germ cells, also agreement across species that AR is present in the adult testis in named gonocytes. We demonstrated that endogenous andro- Sertoli cells, peritubular cells, and Leydig cells (20). In contrast, gens/AR physiologically control normal gonocyte proliferation. We the localization of AR in the fetal testis remains more contro- observed an increase in the number of gonocytes at 17.5 days versial. It is clear that AR is expressed in peritubular cells (21). postconception resulting from an increase in proliferative activity Alternatively, the conventional view of the localization of AR in in Tfm mice. In a reciprocal manner, gonocyte proliferation is Sertoli cells is that it is present in testis only after birth (22, 23). decreased by the addition of DHT in fetal testis organotypic However, Cupp et al. detected it earlier in gestation (24). The culture. Furthermore, the AR coregulator Hsp90␣ (mRNA and localization of AR in fetal germ cells remains even more protein) specifically expressed in gonocytes was down-regulated controversial to the extent that there are reports of its presence in Tfm mice at 15.5 days postconception. To investigate whether (24, 25) and absence (21). A clear understanding of cellular these effects could result from direct action of androgens on localization of AR is necessary for an appropriate comprehen- gonocytes, we collected pure gonocyte preparations and detected sion of the cellular and molecular mechanisms of androgens and AR transcripts therein. We used an original model harboring a antiandrogens. reporter gene that specifically reflects AR activity by androgens New findings show that the male germ line is the most sensitive and clearly demonstrated the presence of a functional AR protein to antiandrogenic endocrine disruptor during the embryonic in fetal germ cells. These data provide in vivo and in vitro evidence period. Until now, the effect of androgens on gonocytes during of a new control of endogenous androgens on gonocytes identi- fetal development has never been investigated. To address these fied as direct target cells for androgens. Finally, our results focus on questions, we studied gametogenesis during fetal life in Tfm mice, which carry a naturally inactivating mutation of the a new pathway in the fetal testis during the embryonic period, androgen receptor (26, 27). We demonstrated an increase in the which is the most sensitive to antiandrogenic endocrine disruptors. proliferation of gonocytes in Tfm mice leading to an increase in germ cell number per testis. These surprising inhibitory effects androgen receptor ͉ fetal testis ͉ gonocytes ͉ Tfm of androgens on germ cell proliferation raise the following question: do androgens regulate germ cells directly or through uring mammalian development, androgens produced by the another cell type? In the present study, we detected AR tran- Dfetal testis are the most important hormones controlling the scripts in pure gonocyte extracts, showing that androgens may masculinization of the reproductive tract and the genitalia (1). act directly, and demonstrated the presence of a functional AR In the absence of production or action of androgens, genetic protein in gonocytes by using an original model harboring an males are outwardly female in appearance. In the testis, the androgen-dependent reporter gene. requirement for androgens for proper function has been dem- onstrated by studies of the murine testicular feminization (Tfm) Results mutation, androgen receptor-null mutants, and human testos- Tfm Mice Study. Morphometric studies. At 17.5 days postconception terone insensitive syndrome (2–5). It is also established that from (dpc), testicular histology and volume were similar in Tfm mice puberty onward, germ cells are the targets of androgens (sper- and control littermates (respective volumes: 0.19 Ϯ 0.02 vs. matogenic arrest at the late spermatocyte/spermatid stage) with 0.18 Ϯ 0.02 mm3, n ϭ 5; Fig. 1 A and B). Tfm mice had 40% more evidence pointing to an effect mediated by Sertoli cells (2, 6–8). gonocytes than control littermates (8,080 Ϯ 558 in Tfm vs. There are various lines of evidence that point to a role for 5,756 Ϯ 493 in control, n ϭ 5, P Ͻ 0.05; Fig. 1C), but the mean androgens in fetal germ cell development. First, cases of andro- nuclear diameter was not significantly different (8.86 Ϯ 0.47 vs. gen insensitivity and low androgen levels are associated with a 7.94 Ϯ 0.35 ␮m). high risk of testicular cancer (9–11), which may result from altered development of gonocytes. Second, there is general agreement that the decrease in sperm count (12, 13) and the Author contributions: J.M., C.R., and R.H. designed research; J.M., C.R., E.M., and S.G.M. performed research; J.M., C.R., E.M., and S.G.M. contributed new reagents/analytic tools; increase in the incidence of testicular cancer (9, 14) observed in J.M., C.R., E.M., and R.H. analyzed data; and J.M., C.R., E.M., and R.H. wrote the paper. many countries result from endocrine disruptor (particularly The authors declare no conflict of interest. antiandrogens) exposure during the fetal testis development This article is a PNAS direct submission. (15). Recent investigations show that in utero exposure to an Abbreviations: AMH, anti-mullerian hormone; AR, androgen receptor; DHT, dihydrotest- antiandrogenic disruptor (Vinclozolin) can influence develop- osterone; dpc, days postconception; ER␤, estrogen receptor ␤; Hsp90, heat shock protein; ment and induce reprogramming in the epigenetic imprinting of Tfm, testicular feminized. the fetal male germ line that promotes transgenerational disease *To whom correspondence should be addressed. E-mail: [email protected]. PHYSIOLOGY states (16–18). © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0611421104 PNAS ͉ February 27, 2007 ͉ vol. 104 ͉ no. 9 ͉ 3615–3620 Downloaded by guest on September 24, 2021 Fig. 3. Effect of androgen receptor deficiency on heat shock protein 90␣ (Hsp90␣) and mRNA levels in 15.5-dpc testes. (A) immunohistochemical stain- Fig. 1. Morphometric analysis of 17.5 dpc fetal testes. (A) Histologic appear- ing of Hsp90␣ in control and testicular feminized (Tfm) testes. (Scale bars, 10 ance of the testis in control and testicular feminized (Tfm) fetuses. Sertoli cells ␮m.) (B and C) Oct-4 (B) and Hsp90␣ (C) mRNA expression in 15.5-dpc testis (arrows) were immunostained with anti-mullerian hormone and located at from control and Tfm fetuses was measured by Q-PCR using ␤-actin or Oct-4, the periphery of the seminiferous cord, whereas gonocytes (arrowheads) were respectively, as reference. Results are expressed in relative units with the the large unstained cells in the center of the cord. (Scale bars, 10 ␮m.) (B and control animals having a value of 1. n ϭ 5; , P Ͻ 0.05; , P Ͻ 0.01 in Student’s C) Testicular volume (B) and number of gonocytes per testis (C)inTfm mice and * ** t test. their normal littermates. All results are shown as the mean Ϯ SEM; n ϭ 5. *, P Ͻ 0.05 in Student’s t test. 17.5 (data not shown). In a reciprocal manner, gonocyte prolif- eration was analyzed in explanted 13.5 dpc testis (Fig. 2C), which Gonocyte proliferation. During fetal life, gonocytes develop in two was treated, or not, for 30 h with dihydrotestosterone (DHT). successive phases: proliferation until 15.5 to 16.5 dpc and a The number of BrdU-positive gonocytes in the DHT-treated quiescent phase until day 0 to 1 postpartum (28). To determine testis was the mirror image of the situation in Tfm mice with a the cause of the increase of gonocyte number at 17.5 dpc in Tfm Ј 27% decrease in their proliferation compared with paired con- mice, 5-bromo-2 -deoxyuridine (BrdU) incorporation in gono- trols (P Ͻ 0.05). cytes (Fig. 2A) and the mitotic figures (Fig. 2B) were analyzed Hsp90␣ expression in fetal Tfm gonocytes. The AR signaling pathway from 15.5 to 17.5 dpc. Androgen receptor deficiency resulted in comprises a multimeric cytosolic complex, including the chap- Ͻ a significant increase (P 0.05) in the percentage of BrdU- erone protein Hsp90 (heat shock protein 90) (29). Two Hsp90- positive gonocytes at 15.5 dpc, but there was no significant related proteins (Hsp90␣ and Hsp90␤) have been identified in difference at 16.5 dpc. Likewise, the percentage of gonocytes mouse testis. One of them, Hsp90␣, is specifically expressed in with mitotic figures was significantly higher (P Ͻ 0.05) in Tfm gonocytes during fetal and neonatal life (30).
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