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Phthalates impair germ cell number in the mouse fetal testis by an androgen- and estrogen-independent mechanism.

Lehraiki A, Racine C, Krust A, Habert R, Levacher C - Toxicol. Sci. (2009)

Bottom Line: 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 (ERalphaKO or ERbetaKO) 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 (ERalphaKO or ERbetaKO) 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.

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Related in: MedlinePlus

Schematic representation of the development of gonocytes during mouse fetal and neonatal life in relation to the timing and duration of the organ cultures as described in “Material and Methods.”
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fig1: Schematic representation of the development of gonocytes during mouse fetal and neonatal life in relation to the timing and duration of the organ cultures as described in “Material and Methods.”

Mentions: During fetal and neonatal development of the testis (Jost and Magre, 1993; Olaso and Habert, 2000), after migration of the primordial germ cells (PGCs) from extra-embryonic mesoderm to the genital ridge at embryonic day 11.5 (E11.5) in the mouse (Yoshimizu et al., 2001), the differentiating Sertoli cells (Wilhelm et al., 2007) surround the germ cells, therefore called gonocytes, to form the seminiferous cords from E12.5. The gonocytes divide actively, many of them undergoing apoptosis by E12.5-14.5 (Wang et al., 1998) and then enter a quiescent period (Nagano et al., 2000; Vergouwen et al., 1991). After birth, they resume mitosis while a second wave of apoptosis occurs (Boulogne et al., 2003; Wang et al., 1998) (Fig. 1) and start to differentiate into spermatogonia. The interstitial region contains mesenchymal cells and steroid-secreting Leydig cells from E12.5 (Livera et al., 2006; O'Shaughnessy et al., 2005). Interactions between the different cell lineages occur early in morphogenesis of the testis and are crucial for its normal development. Androgens mediate a wide range of developmental and physiological responses that are critical for the male reproductive and nonreproductive system (Sharpe, 2006; Welsh et al., 2008). During fetal life, testis development is physiologically modulated by, among other factors (Olaso and Habert, 2000), estrogen and androgen because estrogen receptor beta (ERβ) and androgen receptor (AR) inactivation lead to an increase in germ cell number (Delbes et al., 2004; Merlet et al., 2007), whereas testosterone production is enhanced by ERα inactivation (Delbes et al., 2005).


Phthalates impair germ cell number in the mouse fetal testis by an androgen- and estrogen-independent mechanism.

Lehraiki A, Racine C, Krust A, Habert R, Levacher C - Toxicol. Sci. (2009)

Schematic representation of the development of gonocytes during mouse fetal and neonatal life in relation to the timing and duration of the organ cultures as described in “Material and Methods.”
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2742583&req=5

fig1: Schematic representation of the development of gonocytes during mouse fetal and neonatal life in relation to the timing and duration of the organ cultures as described in “Material and Methods.”
Mentions: During fetal and neonatal development of the testis (Jost and Magre, 1993; Olaso and Habert, 2000), after migration of the primordial germ cells (PGCs) from extra-embryonic mesoderm to the genital ridge at embryonic day 11.5 (E11.5) in the mouse (Yoshimizu et al., 2001), the differentiating Sertoli cells (Wilhelm et al., 2007) surround the germ cells, therefore called gonocytes, to form the seminiferous cords from E12.5. The gonocytes divide actively, many of them undergoing apoptosis by E12.5-14.5 (Wang et al., 1998) and then enter a quiescent period (Nagano et al., 2000; Vergouwen et al., 1991). After birth, they resume mitosis while a second wave of apoptosis occurs (Boulogne et al., 2003; Wang et al., 1998) (Fig. 1) and start to differentiate into spermatogonia. The interstitial region contains mesenchymal cells and steroid-secreting Leydig cells from E12.5 (Livera et al., 2006; O'Shaughnessy et al., 2005). Interactions between the different cell lineages occur early in morphogenesis of the testis and are crucial for its normal development. Androgens mediate a wide range of developmental and physiological responses that are critical for the male reproductive and nonreproductive system (Sharpe, 2006; Welsh et al., 2008). During fetal life, testis development is physiologically modulated by, among other factors (Olaso and Habert, 2000), estrogen and androgen because estrogen receptor beta (ERβ) and androgen receptor (AR) inactivation lead to an increase in germ cell number (Delbes et al., 2004; Merlet et al., 2007), whereas testosterone production is enhanced by ERα inactivation (Delbes et al., 2005).

Bottom Line: 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 (ERalphaKO or ERbetaKO) 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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 (ERalphaKO or ERbetaKO) 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.

Show MeSH
Related in: MedlinePlus