SB-236057: Critical window of sensitivity study and embryopathy of a potent musculoskeletal teratogen

• Published in: Birth defects research. A Clinical and molecular teratology 2004-10, Vol.70 (10), p.773-788
• Main Authors: Augustine-Rauch, Karen A., Zhang, Qin J., Posobiec, Lorraine, Mirabile, Rosanna, DeBoer, Lisa S., Solomon, Howard M., Wier, Patrick J.
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biological and medical sciences; DNA Primers; Embryology: invertebrates and vertebrates. Teratology; Female; Fundamental and applied biological sciences. Psychology; In Situ Hybridization; Indoles - toxicity; Musculoskeletal Abnormalities - chemically induced; Pregnancy; Pyridines - toxicity; Rats; Rats, Sprague-Dawley; Teratogens - toxicity; Teratology. Teratogens
• ISSN: 1542-0752; 1542-0760
• DOI: 10.1002/bdra.20079

BACKGROUND SB‐236057 is a potent skeletal teratogen in rodents and rabbits. The study objective was to identify the critical developmental window of compound sensitivity and to characterize the early onset of SB‐236057 embryopathy. METHODS SB‐236057 was orally administered to Sprague Dawley dams at 100 mg/kg/day on days 6–7, 8–11, 12–14, or 15–17 postcoitus (pc). The critical window of sensitivity was identified to occur between days 8–11 pc. Dams were then dosed on days 8–11 pc and embryos were evaluated by histochemical procedures on days 11, 13, or 15 pc. RESULTS Axial malformations were evident by day 11 pc. Analysis of the cartilaginous skeleton revealed missing posterior axial skeletal elements. However, only about one‐third of the malformed fetuses exhibited obvious rib and vertebrae abnormalities, and none of the affected fetuses exhibited abnormal appendicular skeletal elements. Expression pattern of sonic hedgehog in the notochord and floor plate was not affected, suggesting ventral midline signaling was not disrupted. Histological analysis demonstrated hypoplastic and/or missing musculature in proximity to the ribs and vertebrae. Caspase 3 analysis revealed no increases in apoptotic cells in the musculature. Confocal analysis of the limbs demonstrated truncated peripheral nerve formation and shortening of the appendicular musculature. CONCLUSIONS SB‐236057 is speculated to alter paraxial mesoderm programming. Many of the skeletal malformations may be caused secondarily from musculature abnormalities, suggesting that the myotome may be particularly sensitive to the compound. Furthermore, the finding that peripheral nerve trajectories were altered along the axis and in the limb suggests that SB‐236057 may alter early embryonic signaling pathways necessary for neuronal differentiation/axonal guidance that occur subsequently in embryo‐fetal development. Birth Defects Research (Part A), 2004. © 2004 Wiley‐Liss, Inc.