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High Insulin-Like Growth Factor 1 (IGF-1) and Insulin Concentrations Trigger Apoptosis in the Mouse Blastocyst via Down-Regulation of the IGF-1 Receptor¹

Department of Obstetrics and Gynecology (M.M.C., A.L.S., K.H.M.), Department of Cell Biology and Physiology (K.H.M.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Dr. Kelle H. Moley, Departments of OB/GYN and Cell Biology and Physiology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, St. Louis, Missouri 63110. E-mail: moleyk{at}msnotes.wustl.edu

Women with polycystic ovary syndrome have significantly higher rates of pregnancy loss, as well as elevated insulin and IGF-1 levels. In this study, preimplantation embryos exposed to high concentrations of IGF-1 or insulin undergo extensive apoptosis of the ICM nuclei. Lack of BAX expression, the caspase inhibitor, zVAD, or the ceramide synthase inhibitor, fumonisin B1, prevents this event, suggesting involvement of programmed cell death effector pathways. In other systems, the IGF-1 concentration regulates IGF-1R expression and thus high concentrations lead to down-regulation of the receptor. Here, data show a decrease in IGF-1 receptor protein expression, both by confocal immunofluorescent microscopy and by Western analysis upon exposure to 130 nM IGF-1. Insulin-stimulated glucose uptake, an event regulated via the IGF-1 receptor, is decreased upon exposure to excess IGF-1, suggesting decreased function of the receptor. The data also show that, by blocking receptor signal transduction or by decreasing receptor expression, the apoptotic event can be recreated, thus strongly suggesting that the mechanism of high IGF-1 induced apoptosis is decreased downstream IGF-1 receptor signaling. This embryotoxic insult by high IGF-1 levels may be responsible for the high incidence of pregnancy loss seen in women with polycystic ovary syndrome.

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