The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice
David H. Volle, … , Kristina Schoonjans, Mohamed Benahmed
David H. Volle, … , Kristina Schoonjans, Mohamed Benahmed
Published November 2, 2009
Citation Information: J Clin Invest. 2009;119(12):3752-3764. https://doi.org/10.1172/JCI38521.
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Research Article Endocrinology

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

Abstract

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.

Authors

David H. Volle, Mélanie Decourteix, Erwan Garo, Judy McNeilly, Patrick Fenichel, Johan Auwerx, Alan S. McNeilly, Kristina Schoonjans, Mohamed Benahmed

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Figure 9

Proposed model for the role of Nr0b2 in DES-induced testicular abnormalities.

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Proposed model for the role of Nr0b2 in DES-induced testicular abnormali...
Our results indicate that Nr0b2 is a major actor in DES-induced testicular pathophysiology. Nr0b2 deficiency counteracts the negative effects of DES. In P10 mice, DES induces a blockage in meiosis entry and/or progression, which is characterized by the higher expression of genes of undifferentiated spermatogonia (Nanos3) and a decrease of meiotic genes (Stra8). The effect is stronger in DES-treated males compared with males with 1 EB treatment, which could be explained, at least in part, by the specific induction of Oct3/4 expression by DES. EB and DES treatment alters H3K9me1 and H3K9me2, which are essential for meiosis progression (29). The impact on histones is driven by the lower accumulation of G9a mRNA after DES exposure. This effect on meiosis is explained, at least in part, by the lack of the repressive activity of Nr0b2 on Rar and retinoid signaling. Finally, in adults, Nr0b2 inhibits testicular steroidogenesis, on the one hand by inhibiting the expression of Nr5a2, which controls the expression of the steroidogenic genes, and on the other hand by repressing the transcriptional activity of Nr5a2 and/or Nr5a1. All these data explain how Nr0b2 plays a major role in the subfertility induced by DES exposure.