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 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.
Volle
David H
DH
INSERM U895, Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet 2, Nice, France. david.volle@inserm.fr
Decourteix
Mélanie
M
Garo
Erwan
E
McNeilly
Judy
J
Fenichel
Patrick
P
Auwerx
Johan
J
McNeilly
Alan S
AS
Schoonjans
Kristina
K
Benahmed
Mohamed
M
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004054:Diethylstilbestrol / Q000633:toxicity*; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity; D005260:Female; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D007248:Infertility, Male / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012176:Retinoids / Q000378:metabolism; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology; D013737:Testis / Q000002:abnormalities / Q000187:drug effects* / Q000503:physiopathology; D013739:Testosterone / Q000096:biosynthesis
D006657:Histones; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012176:Retinoids; C099713:nuclear receptor subfamily 0, group B, member 2; C074283:estradiol 3-benzoate; D013739:Testosterone; D004958:Estradiol; D004054:Diethylstilbestrol