Résumés
Résumé
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.
Summary
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.
Parties annexes
Références
- 1. Auger J, Kunstmann JM, Czyglik F, Jouannet P. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med 1995 ; 332 : 281-5.
- 2. Sharpe RM, Irvine DS. How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health? Br Med J 2004 ; 328 : 447-51.
- 3. Toppari J, Larsen J, Christiansen P, et al. Male reproductive health and environmental xenoestrogens. Environ Health Perspect 1996 ; 104 : 741-803.
- 4. Toppari J, Kaleva M, Virtanen HE. Trends in the incidence of cryptorchidism and hypospadias, and methodological limitations of registry-based data.Hum Reprod Update 2001 ; 7 : 282-6.
- 5. Skakkebaek NE, Rajpert-De Meyts E, Main KM. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects.Hum Reprod 2001 ; 16 : 972-8.
- 6. Habert R, Lejeune H, Saez JM. Origin, differentiation and regulation of fetal and adult Leydig cells. Mol Cell Endocrinol 2001 ; 179 : 47-74.
- 7. Kubota Y, Temelcos C, Bathgate RA, et al. The role of insulin 3, testosterone, Mullerian inhibiting substance and relaxin in rat gubernacular growth.Mol Hum Reprod 2002 ; 8 : 900-5.
- 8. Rajpert-De Meyts E, Jorgensen N, Brondum-Nielsen K, et al. Developmental arrest of germ cells in the pathogenesis of germ cell neoplasia.Apmis 1998 ; 106 : 198-206.
- 9. Orth JM, Gunsalus GL, Lamperti AA. Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development.Endocrinology 1988 ; 122 : 787-94.
- 10. Jegou B, Auger J, Multigner L, et al. The saga of the sperm count decrease in humans and wild and farm animals. In: Gagnon C, ed. The male gamete: from basic science to clinical applications. Clearwater: Cache River Press, 1999 : 446-54.
- 11. Vos JG, Dybing E, Greim HA, et al. Health effects of endocrine-disrupting chemicals on wildlife, with special reference to the European situation.Crit Rev Toxicol 2000 ; 30 : 71-133.
- 12. Glaze GM. Diethylstilbestrol exposure in utero: review of literature.J Am Osteopath Assoc 1984 ; 83 : 435-8.
- 13. Strohsnitter WC, Noller KL, Hoover RN, et al. Cancer risk in men exposed in utero to diethylstilbestrol.J Natl Cancer Inst 2001 ; 93 : 545-51.
- 14. Wilcox AJ, Baird DD, Weinberg CR, et al. Fertility in men exposed prenatally to diethylstilbestrol.N Engl J Med 1995 ; 332 : 1411-6.
- 15. Swan SH, Main KM, Lui F, et al. Decrease in anogenital distance among male infants with prenatal phtalate exposure.Environ Health Perspect 2005 ; 113 : 1056-61.
- 16. O’Donnell L, Robertson KM, Jones ME, Simpson ER. Estrogen and spermatogenesis. Endocrinol Rev 2001 ; 22 : 289-318.
- 17. Saunders PT, Sharpe RM, Williams K, et al. Differential expression of oestrogen receptor alpha and beta proteins in the testes and male reproductive system of human and non-human primates.Mol Hum Reprod 2001 ; 7 : 227-36.
- 18. Sharpe RM. The estrogen hypothesis: where do we stand now? Int J Androl 2003 ; 26 : 2-15.
- 19. Carreau S. Estrogens: male hormones? Folia Histochem Cytobiol 2003 ; 41 : 107-11.
- 20. Delbes G, Levacher C, Pairault C, et al. Estrogen receptor beta-mediated inhibition of male germ cell line development in mice by endogenous estrogens during perinatal life.Endocrinology 2004 ; 145 : 3395-403.
- 21. Delbes G, Levacher C, Duquenne C, et al. Endogenous estrogens inhibit mouse fetal Leydig cell development via estrogen receptor alpha.Endocrinology 2005 ; 146 : 2454-61.
- 22. Habert R, Devif I, Gangnerau MN, et al. Ontogenesis of the in vitro response of rat testis to gonadotropin releasing hormone. Mol Cell Endocrinol 1991 ; 82 : 199-206.
- 23. Rouiller-Fabre V, Levacher C, Pairault C, et al. Development of the fetal and neonatal testis.Andrologia 2003 ; 35 : 79-83.
- 24. Lassurguere J, Livera G, Habert R, Jegou B. Time- and dose-related effects of estradiol and diethylstilbestrol on the morphology and function of the fetal rat testis in culture.Toxicol Sci 2003 ; 73 : 160-9.
- 25. Spearow JL, Barkley M. Reassessment of models used to test xenobiotics for estrogenic potency is overdue.Hum Reprod 2001 ; 16 : 1027-9.
- 26. Atanassova N, McKinnell C, Turner K, et al. Comparative effects of neonatal exposure of male rats to potent and weak (environmental) estrogens on spermatogenesis at puberty and the relationship to adult testis size and fertility: evidence for stimulatory effects of low estrogen levels.Endocrinology 2000 ; 141 : 3898-908.
- 27. Fielden MR, Samy SM, Chou KC, Zacharewski TR. Effect of human dietary exposure levels of genistein during gestation and lactation on long-term reproductive development and sperm quality in mice.Food Chem Toxicol 2003 ; 41 : 447-54.
- 28. Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005 ; 308 : 1466-9.