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Romain Lambrot,^1,2,3* Vincent Muczynski,^1,2,3* Charlotte Lécureuil,^1,2,3 Gaëlle Angenard,^1,2,3 Hervé Coffigny,^1,2,3 Catherine Pairault,^1,2,3 Delphine Moison,^1,2,3 René Frydman,^4,5 René Habert,^1,2,3 and Virginie Rouiller-Fabre^1,2,3

¹Laboratory of Differentiation and Radiobiology of the Gonads, Unit of Gametogenesis and Genotoxicity, Commissariat à l’Energie Atomique, Direction des Sciences du Vivant, Institute of Cellular and Molecular Radiation Biology, Stem Cells and Radiation Department, Fontenay aux Roses, France; ²Université Paris Diderot-Paris, Fontenay aux Roses, France; ³ Unité 566, INSERM, Fontenay aux Roses, France; ⁴Service de Gynécologie-Obstétrique, Université Paris Sud, Hôpital Antoine Béclère, Clamart, France; ⁵Unité 782, INSERM, Clamart, France

Abstract
Background: Several studies have described an increasing frequency of male reproductive disorders, which may have a common origin in fetal life and which are hypothesized to be caused by endocrine disruptors. Phthalate esters represent a class of environmental endocrine-active chemicals known to disrupt development of the male reproductive tract by decreasing testosterone production in the fetal rat.

Objectives: Using the organ culture system we developed previously, we investigated the effects on the development of human fetal testis of one phthalate—mono-2-ethylhexyl phthalate (MEHP) —an industrial chemical found in many products, which has been incriminated as a disruptor of male reproductive function.

Methods: Human fetal testes were recovered during the first trimester (7–12 weeks) of gestation, a critical period for testicular differentiation, and cultured for 3 days with or without MEHP in basal conditions or stimulated with luteinizing hormone (LH) .

Results: Whatever the dose, MEHP treatment had no eff ect on basal or LH-stimulated testosterone produced by the human fetal testis in vitro, although testosterone production can be modulated in our culture system. MEHP (10^–4 M) did not affect proliferation or apoptosis of Sertoli cells, but it reduced the mRNA expression of anti-Müllerian hormone. MEHP (10^–4 M) reduced the number of germ cells by increasing their apoptosis, measured by the detection of caspase3–positive germ cells, without modification of their proliferation.

Conclusions: This is the first experimental demonstration that phthalates alter the development of the germ cell lineage in humans. However, in contrast to results observed in the rat, phthalates did not aff ect steroidogenesis.

Key Words: human fetus, phthalates, testis development. Environ Health Perspect 117:32–37 (2009) . doi:10.1289/ehp.11146 available via http://dx.doi.org/ [Online 9 September 2008]

Address correspondence to V. Rouiller-Fabre, Unit of Gametogenesis and Genotoxicity, LDRG/SCSR/ iRCM/DSV, Centre CEA, BP6, F-92265, Fontenay aux Roses, France. Telephone: 33-1-46-54-99-23. Fax: 33-1-46-54-99-06. E-mail: virginie.rouiller-fabre@cea.fr

*These authors contributed equally to this work.

We thank the staff of the Department of Obstetrics and Gynecology of the Hôpital Antoine Béclère (Clamart, France) . We also thank N. Di Clemente (Institut National de la Santé et de la Recherche Médicale Unité 782, Clamart, France) for donating the antibody for anti-Müllerian hormone and A. Gouret for skillful secretarial assistance.

This work was supported by Université Paris Diderot-Paris 7, Commissariat à l’Energie Atomique, INSERM, and Agence Nationale pour la Recherche. V.M. holds fellowships from the Ministère de l’Education Nationale de la Recherche et de la Tehnologie. R.L. holds fellowships from the Commissariat à l’Energie Atomique and from the Association pour la Recherche sur le Cancer.

R.F. has received lecture fees from various pharmaceutical companies, which are not directly related to the material being published. The remaining authors declare they have no competing financial interests.

Received 11 December 2007 ; accepted 8 September 2008.