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Altérations environnementales du développement du testicule foetal: zoom sur les phtalates

Environmental effects on development of the foetal testis: phthalates under the microscope

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Résumé

L’augmentation de plusieurs anomalies de la fonction de reproduction masculine suscite de grandes inquiétudes. Au cours des quatre dernières décennies, le nombre de spermatozoïdes chez l’homme a nettement diminué, et l’incidence du cancer testiculaire a doublé. De plus, les cas de cryptorchidie et d’hypospadias sont également en augmentation. L’hypothèse la plus couramment admise est que tous ces effets néfastes sur la fonction reproductive masculine résulteraient d’anomalies survenant lors du développement du testicule pendant la vie foetale et néonatale. En outre, de nombreuses données épidémiologiques, cliniques et expérimentales suggèrent que ces troubles pourraient être dus aux effets de xénobiotiques appelés perturbateurs endocriniens qui sont de plus en plus concentrés et présents dans notre environnement. Parmi les perturbateurs endocriniens, nous avons choisi de focaliser cette revue sur les phtalates pour diverses raisons: 1) ils sont très répandus dans l’environnement; 2) leurs concentrations dans de nombreux fluides biologiques humains ont été mesurées y compris pendant la grossesse; 3) les données expérimentales utilisant le modèle rat et suggérant une reprotoxicité sont nombreuses et pertinentes; 4) les effets délétères des phtalates sur le développement et sur les fonctions du testicule foetal de rat ont largement été étudiés; 5) quelques données épidémiologiques humaines suggèrent un effet reprotoxique des phtalates aux concentrations retrouvées dans l’environnement, au moins durant la vie néonatale. Cependant, les effets directs des phtalates sur le testicule foetal humain n’avaient jamais été étudiés. Comme nous l’avions fait chez le rat dans les années 1990, nous avons récemment développé et validé un système de culture organotypique de testicule foetal humain qui permet de maintenir in vitro le développement des différents types cellulaires. Dans ce système, l’ajout de 10−4 M de MEHP (mono-2-éthylhexyl phtalate), le phtalate le plus répandu, n’a aucun effet sur la production de testostérone basale ou stimulée par l’hormone lutéinisante (LH), mais il réduit le nombre de cellules germinales en augmentant leur apoptose et sans modifier leur prolifération. Nos données constituent la première donnée expérimentale montrant que les phtalates altèrent le développement du testicule foetal humain. En outre, en utilisant le même système de culture organotypique, il est intéressant de comparer la réponse au MEHP chez l’Homme et chez les rongeurs pour analyser la pertinence des tests toxicologiques basés sur le modèle rongeur.

Abstract

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 increased 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 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 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 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 organotypic culture system, which allows maintenance of the development of the different cell types of human foetal testis. In this system, the 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 modifying their proliferation. This is the first experimental demonstration that phthalates alter the development of the foetal testis in humans. Using our organotypic culture system, it is interesting to compare these results obtained in humans with the response to MEHP in the mouse and the rat testes to analyse the relevance of toxicological tests based on rodent models.

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Correspondence to R. Habert.

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Habert, R., Muczynski, V., Lehraiki, A. et al. Altérations environnementales du développement du testicule foetal: zoom sur les phtalates. Basic Clin. Androl. 21, 24–33 (2011) doi:10.1007/s12610-011-0121-8

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Mots clés

  • Perturbateurs endocriniens
  • Testicule fœtal
  • Développement
  • Culture organotypique
  • Test de toxicologie in vitro
  • Phtalates

Keywords

  • Endocrine disruptors
  • Fetal testis
  • Development
  • Organotypic culture
  • In vitro toxicological assay
  • Phthalates