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

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 rec...

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Bibliographic Details
Published in:The Journal of clinical investigation 2009-12, Vol.119 (12), p.3752-3764
Main Authors: Volle, David H, Decourteix, Mélanie, Garo, Erwan, McNeilly, Judy, Fenichel, Patrick, Auwerx, Johan, McNeilly, Alan S, Schoonjans, Kristina, Benahmed, Mohamed
Format: Article
Language:English
Subjects:
Animals
Animals, Newborn
Apoptosis - drug effects
Apoptosis - physiology
Biochemistry, Molecular Biology
Biomedical research
Cancer
Development Biology
Diethylstilbestrol
Diethylstilbestrol - toxicity
Ecology, environment
Endocrinology and metabolism
Estradiol - analogs & derivatives
Estradiol - toxicity
Estrogens
Female
Fertility
Gametogenesis
Genetic aspects
Health
Histones - chemistry
Histones - metabolism
Human health and pathology
Infertility
Infertility, Male - chemically induced
Infertility, Male - physiopathology
Life Sciences
Liver
Male
Males
Methylation
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Molecular Networks
Phenols
Pregnancy
Receptors, Cytoplasmic and Nuclear - deficiency
Receptors, Cytoplasmic and Nuclear - genetics
Receptors, Cytoplasmic and Nuclear - physiology
Reproductive Biology
Retinoids - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sexual reproduction
Spermatogenesis - drug effects
Spermatogenesis - physiology
Testes
Testis - abnormalities
Testis - drug effects
Testis - physiopathology
Testosterone
Testosterone - biosynthesis
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Description
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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI38521