Nr0b2 Molecular Mechanism underlying many of the Harmful Effects of DES on Male Mice

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

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” The sexual function of male rodents can be impaired by in utero and/or neonatal exposure to external molecules that disrupt normal hormone functioning, giving rise to concerns that low-level exposure to such molecules might cause similar effects in humans. Examples of such molecules include the synthetic nonsteroidal estrogen DES, which was used as a treatment for various diseases until the mid 1990s, and BPA, which is found, among other places, in some plastic containers. “

2009 Study 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.

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