The Blockade of Mineralocorticoid Hormone Signaling Provokes Dramatic Teratogenesis in Cultured Rat Embryos

• Published in: International journal of toxicology 2002-05, Vol.21 (3), p.191-199
• Main Authors: Mirshahi, M., Ayani, E., Nicolas, C., Golestaneh, N., Ferrari, P., Valamanesh, F., Agarwal, M. K.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Embryo, Mammalian - drug effects; Embryology: invertebrates and vertebrates. Teratology; Epithelial Sodium Channels; Female; Fundamental and applied biological sciences. Psychology; Immunohistochemistry; Male; Mifepristone - toxicity; Mineralocorticoid Receptor Antagonists; Mineralocorticoids - antagonists & inhibitors; Organ Culture Techniques; Polymerase Chain Reaction; Pregnancy; Rats; Receptors, Mineralocorticoid - biosynthesis; RNA, Messenger - analysis; Signal Transduction - drug effects; Sodium Channels - biosynthesis; Spironolactone - analogs & derivatives; Spironolactone - toxicity; Teratogens - toxicity; Teratology. Teratogens
• ISSN: 1091-5818; 1092-874X
• DOI: 10.1080/10915810290096324

Although the administration of adrenocortical hormones to pregnant rats provokes only limited effect on the growth and development of the fetus, the direct influence of these steroids on cultured embryos has never been studied. The disruption of cell signaling by ZK 91587, which specifically occupies the mineralocorticoid receptor, resulted within 2 days in significant and pronounced adverse effects on the total length, the somite number, the embryo curvature, the communication between vitelline and ombilical blood vessels in the allantoid, and the vascularization of the vitelline sac, in 244-hour Wistar rat embryos in culture. The average score of 16 organs declined in a dose-dependant manner, following exposure to ZK 91587, and this was totally reversed by 10 μM aldosterone which, by itself, did not at all influence the embryonic development. The organogenesis was inhibited in the order: hind limb > fore limb > optic stalk > brain > olfactory pit > otic vesicle. ZK 91587 was completely ineffective in embryos that had attained the age of 260 hours. Similar, but less dramatic, results were obtained with the mineralocorticoid antagonist RU 26752, and with the antiglu-cocorticoid RU 38486. Sprague-Dawley rat embryos responded in a manner similar to the Wistar conceptuses. Thus, steroid receptor-mediated cell signaling is of critical importance to the growth and development of cultured rat embryos, which form a new model system to unravel adrenocortical hormone action.