Restraint Stress And Corticotrophin-releasing Hormone Elevation Oocyte Competence Through Activation Of The TNF-? System

With the development of society and the acceleration of life rhythm,people are under increasing psychological stress,which will cause female reproductive disorders,infertility,abortion and other diseases.Restraint stress is one of the most classic psychological stress models.While studies observed that restraint-induced corticotrophin-releasing hormone(CRH)elevation impaired oocyte competence by triggering apoptosis of mural granulosa cells,the underlying mechanisms are largely unclear.Although one study demonstrated that the CRH-elevation triggered apoptosis in mural granulosa cells and oocytes via activating Fas/FasL signaling,other studies suggested that restraint-stress might damage cells by activating other pathways as well as Fas signaling.The TNF-? system can induce apoptosis in a variety of tissues and cells.However,whether CRH also induces apoptosis of parietal granule cells through the TNF-? system,and impairing oocyte competence has not been reported.The objective of this study was to test whether RS and CRH elevation impairs oocytes by activating TNF-? signaling.This study has explored the mechanisms by which restraint stress impair oocyte competence,oocyte apoptosis,mural granulosa cells apoptosis and TNF-? activation.The results showed that compared with control,restraint stress applied during oocyte prematuration significantly increased the rate of apoptotic mural granulosa cells and denuded oocytes.The rate of blastocyst and the number of blastocysts significantly decreased,and restraint stress group significantly increased TNF-? and its receptor(TNFR1)expression in serum,ovary and mural granulosa cells(MGCs).In vitro treatment of MGCs with CRH significantly increased their apoptotic percentages and levels of TNF-? and TNFR1 expression,while significantly decreased after treatment with CRH and CRH antagonist antalarmin compared with adding CRH group.In vivo knockout of TNF-? gene or injection of TNF-alpha antagonist etanercept or in vitro knockdown of TNF-? gene by RNAisignificantly relieved the adverse effects of restraint/CRH on apoptosis of MGCs and/or developmental potential and apoptosis of oocytes.The results suggested that restraint stress/CRH-elevation in females impair oocyte competence through activating TNF-? signaling and that TNF-? antagonist might be adopted to ameliorate the adverse effect of psychological stress on oocytes.