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

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

Ontogenesis of testicular function in humans.

The two major functions of the testis, steroidogenesis and gametogenesis, take place during fetal life. These two functions have been extensively studied in rodents and adult humans. However, their onset during fetal life is poorly documented in humans. In the first part of this work we presented both our experimental data and some data of literature concerning the development of the human fetal testis. In the second part of this article, using the organ culture system we previously developed, we have investigated the regulations or perturbations of fetal testis development both in rodent and human models. Our findings provide important insight into the potential role of exposure to environmental pollutants (physical factors, in particular ionizing radiation, cadmium and endocrine disruptors such as phthalates) during fetal testicular development and their potential deleterious effects on male fertility in adulthood. Our results highlight the specificity of the human model compared with rodent models

Membrane differentiation in the pregastrula of the teleost, Brachydanio rerio Hamilton-Buchanan (Teleostei : Cyprinidae). A scanning electron microscope study

International audienceThe pregastrula stages of the teleost, Brachydanio rerio, have been studied in intact or fractured eggs by scanning electron microscopy. The internal surface of the enveloping blastomeres was smooth, while the external surface was covered with cristae; these cristae disappeared during epiboly but reappeared when the cells were in mitosis. At the end of the morula stage, the smooth yolk cytoplasmic layer formed a ring of periblastic cristae; up to the late blastula stage that ring was attached to "star-like" complexes. Light and transmission electron microscopy images of these complexes are given and we propose hypotheses regarding their function. At first closely apposed, the deep cells seemed to be maximally dispersed during the mid-blastula stage. At the blastula stage, the yolk syncitium formed both enveloping and deep cells. This suggests a primordial role of the yolk syncitium layer in pregastrula differentiation. A new hypothesis concerning the functions of the membrane protrusions is proposed: they might play a role in the postmiotic reassociation of the blastomeres. We suggest that, during early development, the three modes of cell association, i.e. monolayer, mass aggregation, syncitium, might be correlated with the composition of the three media (perivitelline liquid, blastocoelic liquid, yolk) present at that time

Fetal testis and estrogenic endocrine disrupters

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.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

Membrane differentiation in the pregastrula of the teleost, Brachydanio rerio Hamilton-Buchanan (Teleostei : Cyprinidae). A scanning electron microscope study

International audienc

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