Le testicule foetal est-il en danger ?

On assiste depuis les dernières décennies à une augmentation des anomalies de la différenciation de l’appareil génital mâle (hypospadias, cryptorchidisme) et du cancer du testicule, ainsi qu’à une diminution quantitative et qualitative de la production de spermatozoïdes. Des études épidémiologiques ont mis en relation ces altérations avec des modifications de l’environnement, et notamment avec l’exposition croissante à des molécules agonistes des oestrogènes ou antagonistes des androgènes. Des données cliniques et expérimentales laissent penser que ces xéno-oestrogènes agiraient pendant la vie foetale et néonatale en induisant des anomalies du développement testiculaire, responsables des altérations observées chez l’adulte. Nous avons effectivement démontré que les oestrogènes endogènes inhibent physiologiquement le développement du testicule foetal.Estrogens are classically known to play a major role in female reproduction, but there is now compelling evidence that they may also be involved in the regulation of male reproductive function. In humans, a decrease in sperm count and an increase in the incidences of testicular cancer, cryptorchidism and hypospadia have been observed in many countries over the last 50 years. Male reproductive alterations were also observed in wildlife. Such male reproductive disorders have been attributed to the increase in concentration of xenobiotics, and of xenoestrogens in particular, in the environment and in food. Epidemiological, clinical and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders in adulthood. Using an in vitro model, we showed that estrogens directly affected the development of the fetal testis. Lastly, we clearly demonstrated that the fetal and neonatal testis is very sensitive to estrogens since the invalidation of estrogen receptor α leads to an increase of steroidogenesis and the invalidation of estrogen receptor β enhances the development of the germ cell lineage in the male

Le testicule fœtal est-il en danger ?

On assiste depuis les dernières décennies à une augmentation des anomalies de la différenciation de l’appareil génital mâle (hypospadias, cryptorchidisme) et du cancer du testicule, ainsi qu’à une diminution quantitative et qualitative de la production de spermatozoïdes. Des études épidémiologiques ont mis en relation ces altérations avec des modifications de l’environnement, et notamment avec l’exposition croissante à des molécules agonistes des œstrogènes ou antagonistes des androgènes. Des données cliniques et expérimentales laissent penser que ces xéno-œstrogènes agiraient pendant la vie foetale et néonatale en induisant des anomalies du développement testiculaire, responsables des altérations observées chez l’adulte. Nous avons effectivement démontré que les oestrogènes endogènes inhibent physiologiquement le développement du testicule fœtal

Le testicule fœtal est-il en danger ?

Estrogens are classically known to play a major role in female reproduction, but there is now compelling evidence that they may also be involved in the regulation of male reproductive function. In humans, a decrease in sperm count and an increase in the incidences of testicular cancer, cryptorchidism and hypospadia have been observed in many countries over the last 50 years. Male reproductive alterations were also observed in wildlife. Such male reproductive disorders have been attributed to the increase in concentration of xenobiotics, and of xenoestrogens in particular, in the environment and in food. Epidemiological, clinical and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders in adulthood. Using an in vitro model, we showed that estrogens directly affected the development of the fetal testis. Lastly, we clearly demonstrated that the fetal and neonatal testis is very sensitive to estrogens since the invalidation of estrogen receptor alpha leads to an increase of steroidogenesis and the invalidation of estrogen receptor beta enhances the development of the germ cell lineage in the male

Cytoplasmic and Nuclear Phospholipase C-β1 Relocation: Role in Resumption of Meiosis in the Mouse Oocyte

The location of the phospholipase C β1-isoform (PLC-β1) in the mouse oocyte and its role in the resumption of meiosis were examined. We used specific monoclonal antibodies to monitor the in vitro dynamics of the subcellular distribution of the enzyme from the release of the oocyte from the follicle until breakdown of the germinal vesicle (GVBD) by Western blotting, electron microscope immunohistochemistry, and confocal microscope immunofluorescence. PLC-β1 became relocated to the oocyte cortex and the nucleoplasm during the G2/M transition, mainly in the hour preceding GVBD. The enzyme was a 150-kDa protein, corresponding to PLC-β1a. Its synthesis in the cytoplasm increased during this period, and it accumulated in the nucleoplasm. GVBD was dramatically inhibited by the microinjection of anti-PLC-β1 monoclonal antibody into the germinal vesicle (GV) only when this accumulation was at its maximum. In contrast, PLC-γ1 was absent from the GV from the time of release from the follicle until 1 h later, and microinjection of anti-PLC-γ1 into the GV did not affect GVBD. Our results demonstrate a relationship between the relocation of PLC-β1 and its role in the first step of meiosis.</jats:p

Developmental changes in testicular sensitivity to estrogens throughout fetal and neonatal life

There is now compelling evidence that inappropriate exposure to estrogen during fetal or neonatal life could affect adult reproductive functions because the testis is sensitive to estrogens during specific periods of its development. Therefore, we investigated the effects of exogenous estrogens on gametogenesis and steroidogenesis during fetal and neonatal testicular development in the rat. We used in vitro systems, organ cultures, and dispersed testicular cell cultures, which allow the development of fetal and neonatal germ cells (gonocytes) and Leydig cells. Exogenous estrogens inhibited testosterone production in dispersed testicular cell cultures throughout fetal life, but this inhibition was observed only in the early fetal stages in organ culture. By using an aromatase inhibitor (letrozole, Novartis Pharma AG), we showed that the inhibitory effect of exogenous estrogens on testosterone production is masked in the whole testis at later stages (20.5 days postconception) due essentially to local production of estrogens. In both systems, additions of high concentrations (10(-6) M) of 17beta-estradiol or diethylstilbestrol decreased the number of gonocytes during the first fetal proliferative period but not during the neonatal period. Letrozole was without effect, suggesting that the aging-related loss of responsiveness of gonocytes is not due to any aromatase activity in the gonocytes.</br

Endogenous estrogens inhibit mouse fetal Leydig cell development via estrogen receptor alpha

It is now accepted that estrogens play a role in male fertility and that exposure to exogenous estrogens during fetal/neonatal life can lead to reproductive disorders in the male. However, the estrogen receptor (ER)-mediated processes involved in the regulation of male reproduction during fetal and neonatal development are still largely unclear. We previously reported that ER beta deficiency affects gametogenesis in mice but changes neither the number nor the differentiated functions of fetal Leydig cells. We show here that ER alpha-deficient mice (ER alpha-/-) display higher levels of testicular testosterone secretion than wild-type mice from fetal d 13.5 onwards. This results from higher levels of steroidogenic activity per fetal Leydig cell, as indicated by the hypertrophy of these cells and the higher levels of mRNA for StAR, P450c17 and P450scc in the testis, for a similar number of Leydig cells. Because LH is not produced on fetal d 13.5 and because no change in plasma LH concentration was observed in 2-d-old ER alpha-deficient mice, LH is probably not involved in the effects of estrogens on testicular steroidogenesis in fetal and early neonatal Leydig cells. Furthermore, inactivation of ER beta did not change the effect of ER alpha inactivation on steroidogenesis. Lastly, in an organ culture system, 1 mum diethylstilbestrol decreased the testosterone secretion of wild-type fetal and neonatal testes but not of ER alpha-/- testes. Thus, this study shows that endogenous estrogens physiologically inhibit steroidogenesis via ER alpha by acting directly on the testis early in fetal and neonatal development.</br

Estrogen receptor beta-mediated inhibition of male germ cell line development in mice by endogenous estrogens during perinatal life

Epidemiological, clinical, and experimental studies have suggested that excessive exposure to estrogens during fetal/neonatal life can lead to reproductive disorders and sperm abnormalities in adulthood. However, it is unknown whether endogenous concentrations of estrogens affect the establishment of the male fetal germ cell lineage. We addressed this question by studying the testicular development of mice in which the estrogen receptor (ER) beta or the ERalpha gene was inactivated. The homozygous inactivation of ERbeta (ERbeta-/-) increased the number of gonocytes by 50% in 2- and 6-d-old neonates. The numbers of Sertoli and Leydig cells and the level of testicular testosterone production were unaffected, suggesting that estrogens act directly on the gonocytes. The increase in the number of gonocytes did not occur during fetal life but instead occurred just after birth, when gonocytes resumed mitosis and apoptosis. It seems to result from a decrease in the apoptosis rate evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method and cleaved caspase-3 immunohistochemical detection. Last, mice heterozygous for the ERbeta gene inactivation behaved similarly to their ERbeta-/- littermates in terms of the number of gonocytes, apoptosis, and mitosis, suggesting that these cells are highly sensitive to the binding of estrogens to ERbeta. ERalpha inactivation had no effect on the number of neonatal gonocytes and Sertoli cells. In conclusion, this study provides the first demonstration that endogenous estrogens can physiologically inhibit germ cell growth in the male. This finding may have important implications concerning the potential action of environmental estrogens.</br