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ToxSci Advance Access originally published online on July 10, 2009
Toxicological Sciences 2009 111(2):372-382; doi:10.1093/toxsci/kfp153
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
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Phthalates Impair Germ Cell Number in the Mouse Fetal Testis by an Androgen- and Estrogen-Independent Mechanism

Abdelali Lehraiki*,{dagger},{ddagger}, Chrystèle Racine*,{dagger},{ddagger}, Andrée Krust§, René Habert*,{dagger},{ddagger} and Christine Levacher*,{dagger},{ddagger},1

* Laboratory of Gonad Differentiation and Radiobiology, Stem Cells and Radiation Service, Institute of Cellular and Molecular Radiation Biology, Life Sciences Division, Commissariat à l'Energie Atomique, BP 6, 92265 Fontenay-aux-Roses, France {dagger} Université Paris Diderot-Paris 7, BP 6, 92265 Fontenay-aux-Roses, France {ddagger} Unité 967, INSERM, BP 6, 92265 Fontenay-aux-Roses, France § Institut de Génétique et de Biologie Moléculaire et Cellulaire, (CNRS, INSERM, UDS, Collège de France), BP 10142, 67404 Illkirch-Strasbourg, France

1 To whom correspondence should be addressed at Unité mixte "Cellules Souches et Radiations", Inserm U967/CEA/Université Paris-Diderot, LDRG/SCSR/IRCM/DSV, Centre CEA, BP6 18 Route du Panorama, Bat. 05A RdC, 92265 Fontenay-Aux-Roses, France. Fax: +33-1-46-54-99-06. E-mail: christine.levacher{at}cea.fr.

Received June 10, 2009; accepted July 7, 2009


  Abstract

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 (ER{alpha}KO 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.

Key Words: MEHP; phthalates; fetal testis; gonocytes; steroidogenesis; Leydig cell; development; estrogen receptor; androgen receptor.


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