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

Fetal testis and estrogenic endocrine disrupters

Des de fa ja molt temps, se sap que els estrògens tenen un paper molt important en la reproducció femenina, i hi ha ja també una forta evidència que poden també estar implicats en la regulació reproductiva masculina. En els humans, en diversos països i durant els darrers cinquanta anys, s'ha observat una disminució considerable en el recompte d'espermatozoides i un augment en la incidència de càncers testiculars, criptorquídies i hipospàdies. En les espècies salvatges, també s'han observat canvis semblants en la vida reproductiva dels mascles. Aquests desordres reproductius han estat atribuïts als xenobiòtics i, particularment, als xenoestrògens que, darrerament, han augmentat progressivament en diversitat i concentració en l'entorn i en el menjar. Estudis epidemiològics, clínics i experimentals han suggerit que l'exposició excessiva als estrògens i als xenoestrògens durant la vida fetal i neonatal podrien conduir a desordres reproductius en la vida adulta. En aquesta revisió presentem, en un model in vitro, que els estrògens afecten directament el desenvolupament del testicle fetal. També demostrem clarament que els testicles fetals i neonatals són molt sensibles als estrògens, ja que el silenciament del receptor d'estrògens alfa comporta un augment de l'esteroïdogènesi, i el silenciament del receptor d'estrògens beta facilita el desenvolupament de la línia cell. ular germinal en el mascle.Estrogens play a major role in female reproduction, but there is now compelling evidence that they may also be involved in the regulation of the male reproductive function. In humans, a decrease in sperm count and an increase in the incidences of testicular cancer, cryptorchidism and hypospadias, have been observed in many countries in the last fifty years. Changes in the male reproductive function have also been observed in wildlife. These male reproductive disorders have been attributed to xenobiotics, and particularly to xenoestrogens, which have steadily increased in diversity and concentration in the environment and in food. Epidemiological, clinical and experimental studies have suggested that excessive exposure to estrogens and xenoestrogen during fetal/neonatal life can lead to reproductive disorders in adulthood.We showed, in an in vitro model, that estrogens directly affected the development of the fetal testis. We also clearly demonstrated that fetal and neonatal testes were very sensitive to estrogens, as the invalidation of the estrogen receptor alpha led to an increase in steroidogenesis, and the invalidation of the estrogen receptor beta enhanced development of the germ cell lineage in the male

Phthalates Impair Germ Cell Number in the Mouse Fetal Testis by an Androgen- and Estrogen-Independent Mechanism

Data from experiments conducted almost exclusively in the rat have established that some phthalates have deleterious effects on the fetal testis probably due to their antiandrogenic and/or estrogenic effects, but their mechanisms of action remain unknown. A recent study reported that phthalates also have deleterious effects on human fetal testis with germ cell number, but not steroidogenesis altered. Therefore, we used organ culture of fetal testes at different stages of development to analyze the direct effects of phthalates on both steroidogenesis and gonocyte development and to determine if the effects of MEHP on these functions reported in the rat can be extended to other mammalian species. We defined specific periods of sensitivity of the fetal mouse testis to MEHP for these two functions and showed that the effects of phthalates on steroidogenesis vary with the developmental stage. Conversely, the strong deleterious effects of phthalates on germ cells were constantly present during the active phases of gonocyte development and thus share no relationship with the steroidogenic status. Moreover, all the effects of phthalates were unchanged in testes from mice deficient for estrogen (ERαKO or ERβKO) or androgen (Tfm) receptors. In conclusion, our results demonstrate that phthalates impair mouse fetal germ cell number similarly to other mammalian species, but are neither estrogenic nor antiandrogenic molecules because their effects do not involve, directly or indirectly, ER or AR

Adverse effects of endocrine disruptors on the foetal testis development: focus on the phthalates.

There are great concerns about the increasing incidence of abnormalities in male reproductive function. Human sperm counts have markedly dropped and the rate of testicular cancer has clearly augmented over the past four decades. Moreover, the prevalence rates of cryptorchidism and hypospadias are also probably increasing. It has been hypothesized that all these adverse trends in male reproduction result from abnormalities in the development of the testis during foetal and neonatal life. Furthermore, many recent epidemiological, clinical and experimental data suggest that these male reproductive disorders could be due to the effects of xenobiotics termed endocrine disruptors, which are becoming more and more concentrated and prevalent in our environment. Among these endocrine disruptors, we chose to focus this review on the phthalates for different reasons: 1) they are widespread in the environment; 2) their concentrations in many human biological fluids have been measured; 3) the experimental data using rodent models suggesting a reprotoxicity are numerous and are the most convincing; 4) their deleterious effects on the in vivo and in vitro development and function of the rat foetal testis have been largely studied; 5) some epidemiological data in humans suggest a reprotoxic effect at environmental concentrations at least during neonatal life. However, the direct effects of phthalates on human foetal testis have never been explored. Thus, as we did for the rat in the 1990s, we recently developed and validated an organ culture system which allows maintenance of the development of the different cell types of human foetal testis. In this system, addition of 10-4 M MEHP (mono-2-ethylhexyl phthalate), the most produced phthalate, had no effect on basal or LH-stimulated production of testosterone, but it reduced the number of germ cells by increasing their apoptosis, without modification of their proliferation. This is the first experimental demonstration that phthalates alter the development of the foetal testis in humans. Using our organotypic culture system, we and others are currently investigating the effect of MEHP in the mouse and the rat, and it will be interesting to compare the results between these species to analyse the relevance of toxicological tests based on rodent models

Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors.

International audienceFetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk

CONTROLE DE LA GAMETOGENESE PENDANT LA VIE FTALE ET NEONATALE CHEZ LE RAT. ETUDE DE L'EFFET DES RETINOIDES DANS UN MODELE DE CULTURE DE CELLULES TESTICULAIRES DISPERSEES

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Effets et mécanismes d'action du Mono (2-ethylhexyl) phtalate (MEHP) sur le développement du testicule foetal et neonatal de souris in vitro

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Lipogenesis as related to endocrine control of adipose cellularity in the rat

International audienc

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