National Centers for Translational Research in Reproduction and Infertility

Understanding how Embryo Manipulation affects Implantation

University of California, San Francisco

PI:  R. Rinaudo (pilot)

The long term goal of the Rinaudo laboratory is to determine if offspring conceived by IVF have an increased incidence of adverse health effects as adults. We have found that mice generated via IVF have abnormalities in growth, fat deposition and glucose tolerance. Furthermore, we have shown that mice generated via IVF exhibit impaired placentation and fetal growth, partly due to impaired placental amino acid transport. The objective of this pilot study is to understand if the phenotype of IVF offspring is secondary to abnormalities in maternal-embryonic interactions at the time of implantation. Our central hypothesis is that decidualization is defective because of abnormal crosstalk with the IVF embryo. More specifically IVF blastocysts, because of the in vitro culture process, are intrinsically less functional and will send suboptimal signals to their surrounding decidua; as a consequence, implantation will occur later and the decidua in turn will be less functional and show defects often described as “premature senescence”. “Senescence” can be monitored by assessing the mammalian target of rapamycin complex 1 (mTORC1)-Cox2 pathway. The final result is suboptimal placentation that manifests clinically with increased preterm birth, IUGR, or preeclampsia. We plan to test our central hypothesis by assessing if IVF embryos show abnormalities in implantation (Aim1) or decidualization (Aim 2). Specifically:

AIM 1: Assess whether embryo in vitro culture triggers abnormalities in blastocyst implantation. Our working hypothesis is that IVF embryos are suboptimal because of in vitro culture, and because of in vitro culture, IVF embryos will send abnormal signals to the decidua and will show delayed implantation. The objective of this aim is to discover if IVF embryos display delayed implantation, altered spacing in the uterus and, based on preliminary data, if amount of HBEGF is different in IVF or in vivo blastocysts and their implantation sites.

AIM 2: Assess whether in vitro culture results in defective decidualization and premature endometrial senescence following blastocyst implantation. The objective of this aim is to assess if the process of decidualization is altered following transfer of in vitro generated embryos, using in vivo generated embryos as a control. Our working hypothesis is that the decidua, following transfer of IVF embryos will not develop properly. More specifically, it will show alteration of the mTORC1-Cox2 pathway.