The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice

INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet 2, Nice, France.
The Journal of clinical investigation (Impact Factor: 13.22). 11/2009; 119(12):3752-64. DOI: 10.1172/JCI38521
Source: PubMed


Studies in rodents have shown that male sexual function can be disrupted by fetal or neonatal administration of compounds that alter endocrine homeostasis, such as the synthetic nonsteroidal estrogen diethylstilbestrol (DES). Although the molecular basis for this effect remains unknown, estrogen receptors likely play a critical role in mediating DES-induced infertility. Recently, we showed that the orphan nuclear receptor small heterodimer partner (Nr0b2), which is both a target gene and a transcriptional repressor of estrogen receptors, controls testicular function by regulating germ cell entry into meiosis and testosterone synthesis. We therefore hypothesized that some of the harmful effects of DES on testes could be mediated through Nr0b2. Here, we present data demonstrating that Nr0b2 deficiency protected mice against the negative effects of DES on testis development and function. During postnatal development, Nr0b2-null mice were resistant to DES-mediated inhibition of germ cell differentiation, which may be the result of interference by Nr0b2 with retinoid signals that control meiosis. Adult Nr0b2-null male mice were also protected against the effects of DES; however, we suggest that this phenomenon was due to the removal of the repressive effects of Nr0b2 on steroidogenesis. Together, these data demonstrate that Nr0b2 plays a critical role in the pathophysiological changes induced by DES in the mouse testis.

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    • "Quantitative real-time PCR was performed using the StepOnePlus Real-Time PCR System (Applied Biosystems, Carlsbad, CA) and the SensiMixPlus SYBR Kit (Quantace, London, UK) according to the manufacturer’s procedure. The primer sequences for the genes were as follows: P450c17-F: 5′-CCAGGACCCAAGTGTGTTCT-3′; P450c17-R: 5′-CCTGATACGAAGCACTTCTCG-3′; StAR-F: 5′-TGTCAAGGAGATCAAGGTCCTG-3′; StAR-R: 5′-CGATAGGACCTGGTTGATGAT-3′; 3β-HSD-F: 5′-ATGGTCTGCCTGGGAATGAC-3′; 3β-HSD-R: 5′-ACTGCAGGAGGTCAGAGCT-3′ [32]; Tgfbr2-F: 5′-TGCAATGCTGTGGGAGAA-3′; Tgfbr2-R: 5′-GATCTGGATGCCCTGGTG-3′; Tgfbr1-F: 5′-CACCGTGTGCCAAATGAA-3′; Tgfbr1-R: 5′-TGCCTCGCCAAACTTCTC-3′. Finally, mRNA levels were normalized to β-actin (actin-F: 5′-GAGACCTTCAACACCCCAGCC-3′; actin-R: 5′-CCGTCAGGCAGCTCATAGCTC-3′). "
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    PLoS ONE 08/2014; 9(8):e104812. DOI:10.1371/journal.pone.0104812 · 3.23 Impact Factor
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    • "Studies have shown that EDCs exert their effects by interfering with endogenous hormone action and can affect male and female reproduction (Gore et al., 2013; Zoeller et al., 2012). Feminization of animals derived from areas polluted by EDCs has been observed in all classes of vertebrates including fish, amphibians, reptiles, birds and mammals (Baldigo et al., 2006; Giesy et al., 2003; Hayes et al., 2002; Kö rner et al., 2005; Volle et al., 2009; Willingham, 2005). Impacts of EDCs have become a widespread problem, especially well known to affect freshwater fishes all over the world. "
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    Environmental Research 06/2014; 133. DOI:10.1016/j.envres.2014.05.018 · 4.37 Impact Factor
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    • "Concerning the development of the urogenital sinus and particularly the testis, the impacts of endocrine disruptors have been fairly well described on human and experimental models (33–35). This is especially true for hypospadia, cryptorchidism, and infertility; but the link with TGCC has to be explained. "
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    Frontiers in Endocrinology 05/2014; 5:63. DOI:10.3389/fendo.2014.00063
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