Studies On The Mechanisms By Which Glucocorticoids Impair Oocyte Developmental Potential And Preimplantation Maternal Restraint Stress Increases Offspring's Anxiety

Previous studies indicate that stress damages oocytes with increased secretion of glucorticoids.However,although injection of female mice with cortisol decreased oocyte competence,exposure of mouse oocytes directly to physiological or stress-induced concentrations of glucorticoids did not affect oocyte maturation and embryo development.This study has explored the mechanisms by which glucocorticoids impair oocyte competence by observing the effects of injecting female mice with cortisol on oocyte competence,ovarian cell apoptosis and Fas/FasL activation.The results showed that cortisol injection of female mice decreased(a)oocyte developmental potential,(b)the E2/P4 ratio in serum and ovaries,and(c)expression of insulin-like growth factor 1,brain-derived neurotrophic factor and glucocorticoid receptor in mural granulosa cells(MGCs),while increasing levels of(a)cortisol in serum and ovaries,(b)apoptosis in MGCs and cumulus cells(CCs),(c)Fas L secretion in ovaries and during oocyte maturation in vitro,and(d)Fas in MGCs,CCs and oocytes.The detrimental effects of cortisol-injection on oocyte competence and apoptosis of MGCs and CCs were significantly relieved when gld mice harboring Fas L mutations were observed.Together,the results suggested that glucocorticoids impair oocyte competence by triggering apoptosis of ovarian cells via activating the Fas system.The data have the first time up-to-date established the pathways by which glucorticoids diminishes oocyte developmental potential and are important for our understanding the role of glucocorticoids in a broad spectrum of stress-related diseases.Epidemiological studies in human suggest that prenatal stress may impair the emotional development,leading to increased incidence of depression,anxiety,schizophrenia,and autism in offspring.However,the mechanisms by which prenatal stress affects offspring behavioral and neuroendocrine systems are largely unknown.Furthermore,most studies on this issue were conducted during late pregnancy;studies on the effect of preimplantation stress are limited and in vitro studies are lacking.This study has tested whether preimplantation restraint stress(PIRS)affects offspring behavior,and whether it occurs by increasing secretion of glucocorticoids,using both in vivo and in vitro models.Results showed that both PIRS and embryo culture with corticosterone increased anxiety and glucorticoid secretion while decreasing glucorticoid receptor(GR)and brain-derived neurotrophic factor(BDNF)expression in the hippocampus of offspring.Culture with corticosterone also decreased GR expression in embryos.It was concluded that PIRS of pregnant mice increased offspring's anxiety by facilitating secretion of glucorticoids,which acted directly on the embryo by downregulating GR expression.This is the first report that PIRS and embryo culture with glucorticoids increased offspring's anxiety and the data are of great importance to our understanding of the mechanisms by which prenatal stress affects offspring.