High insulin-like growth factor 1 (IGF-1) and insulin concentrations trigger apoptosis in the mouse blastocyst via down-regulation of the IGF-1 receptor

Women with polycystic ovary syndrome have significantly higher rates of pre gnancy loss, as well as elevated insulin and IGF-1 levels. In this study, p reimplantation embryos exposed to high concentrations of IGF-1 or insulin u ndergo extensive apoptosis of the ICM nuclei. Lack of BAX expression, the c aspase inhibitor, zVAD, or the ceramide synthase inhibitor, fumonisin B1, p revents this event, suggesting involvement of programmed cell death effecto r pathways. In other systems, the IGF-1 concentration regulates IGF-1R expr ession 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 naa IGF-1. insulin-stimulated glucose uptake, an event regulated vi a the IGF-1 receptor, is decreased upon exposure to excess IGF-1, suggestin g decreased function of the receptor. The data also show that, by blocking receptor signal transduction or by decreasing receptor expression, the apop totic event can be recreated, thus strongly suggesting that the mechanism o f high IGF-1 induced apoptosis is decreased downstream IGF-1 receptor signa ling, This embryotoxic insult by high IGF-1 levels may be responsible for t he high incidence of pregnancy loss seen in women with polycystic ovary syn drome.