2009 Study Summary
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.
Our results demonstrated that Nr0b2 plays a major role in the DES signaling pathway, which affects the development and function of the male reproductive system. We showed that Nr0b2L male mice were protected against the deleterious effects of DES, as they were still able to reproduce even when exposed to high doses of DES. This is caused by the multiple actions of Nr0b2 during testicular development. First, in neonatal animals, Nr0b2 controls germ cell differentiation through inhibition of the retinoid pathway. Nr0b2 regulates the expression of genes involved in the entry and progression of meiosis, such as Stra8 and Nanos3. It also affects meiosis through regulation of the expression of the histone methyltransferase G9a and the subsequent modification of H3K9 methylation marks. These alterations in methylation upon DES exposure induce abnormal chromosomal complexes favoring germ cell apoptosis and could affect the meiosis process. Next to these effects, which appear to be mediated through the estrogenic pathway, DES seems to inhibit germ cell differentiation at P10 through estrogen-independent pathways, as shown by Oct3/4 deregulation specifically in DES-treated mice. Second, in adult animals, the effect of Nr0b2 was dependent on the inhibition of testosterone production, leading to germ cell death. Together, our present data define Nr0b2 as one of the major actors in the molecular events leading to DES-mediated male infertility.
Sources and Full Study
- The orphan nuclear receptor small heterodimer partner mediates male infertility induced by diethylstilbestrol in mice, NCBI, PMID: 19884658, 2009 Dec.
- Full study The Journal of Clinical Investigation. 2009;119(12):3752-3764. doi:10.1172/JCI38521. PMC2786790. 2009 Dec.
More DES DiEthylStilbestrol Resources
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- DES studies on in-utero exposure to DES and side-effects.
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- Papers on DES lawsuits.
- DES videos and posts tagged DES, the DES-exposed, DES victims.