EMBRYO INFILTRATION BY MATERNAL MACROPHAGES IS ASSOCIATED WITH SELECTIVE EXPRESSION OF PROTOONCOGENES IN A MURINE MODEL OF SPONTANEOUS-ABORTION

The causes and precise mechanisms leading to early embryo loss in mamm als remain largely unknown, especially from a molecular point of view, Using the CBA/J x DBA/2 murine model of early spontaneous embryo loss (25-30% embryo loss), we have previously demonstrated the involvement of infiltrating activated macrophages and their cytolytic products su ch as nitric oxide and tumor necrosis factor alpha (TNF alpha) in the etiology of early embryo loss. On the other hand, far fewer of the CBA /J x Balb/c conceptuses (5-10% embryo loss) displayed significant cell ular infiltration and nitric oxide and TNF alpha. Having used probes f or cellular activation markers, we now present evidence indicating tha t significantly increased expression of AP-1 family members, Ha-ras, K i-ras, v-erbA, v-raf, v-abl, and c-myc was present in 24.4% of the CBA /J x DBA/2 embryonic units that also harbored significant Mac-1, F4/80 , and class II major histocompatibility complex (MHC) molecule cellula r infiltration. In contrast, only 7% of the CBA/J x Balb/c conceptuses displayed increased proto-oncogene expression and increased cellular infiltration. Therefore, macrophage infiltration, cellular activation as identified by the increased expression of proto-oncogenes, and the production of cytotoxic macrophage products are closely linked to earl y embryo loss, These data add to the evidence that activated maternal macrophages may be directly responsible for spontaneous pregnancy fail ure.