Altered metabolism in embryo generated by in vitro fertilization

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Project Summary/Abstract We propose studies to evaluate the direct impact of preimplantation embryo manipulation on the metabolism of embryos and tissues. Because embryo manipulation is routinely used in the context of Assisted Reproductive Technologies (ART) to treat patients with infertility, these goals have wide clinical implications. In fact, more than 8 million children have been conceived by the technologies and more than 2.5 million in vitro fertilization (IVF) cycles occur every year. Hence, there is great need to know if preimplantation embryo manipulation induces subtle, but possibly long-lasting effects on the health of ART offspring. The focus of this application is at the core of the PI’s expertise, as he has devoted most of his career to understanding how ex-vivo embryo manipulation is associated with changes in the embryo (altered gene expression, development, mitochondria function) and long-term maladaptive changes in the offspring (defects in placentation, altered postnatal growth and ultimately altered glucose homeostasis). While these results are important, multiple key questions remain unanswered. In particular, the molecular mechanisms responsible to alter growth and metabolism in adults are unknown. For example, it is unclear if metabolism is altered in embryos generated in vitro and if these metabolic alterations are maintained in adults and responsible to cause abnormal glucose handling in adults generated by IVF. Importantly, the President's Council on Bioethics and Congress urged the NICHD to determine whether these adverse outcomes are specifically related to ART procedures. Exciting novel preliminary data suggest that alteration of glycolysis and lactate metabolism are present in embryos and possibly in adult generated by IVF. Based on preliminary data, objectives of this application are to: 1) understand if alteration of glycolytic pathways exist in embryo who have undergone different degrees of manipulation; discover the mechanisms leading to 2) metabolic alterations and 3) if specific epigenetic changes exist; finally, 4) study if these alterations are maintained in adult mice conceived by IVF. Our central hypothesis is that the ex vivo embryonic environment, deviating profoundly from the in vivo conditions (different oxygen concentrations, altered energetic sources) cause increase in reactive oxygen species. Reparative mechanisms will induce metabolic alterations and epigenetic changes. These molecular alterations will be maintained in adult offspring resulting in altered glucose and lactate metabolism. Regarding expected outcomes, we will: 1) determine what culture conditions produce greater or smaller change in glycolysis in embryos, 2) discover the pathways responsible for these changes, 3) describe the specific epigenetic changes induced by these alterations and finally 4) discover what metabolic pathways are altered in IVF offspring. These datasets are expected to have an important impact because of the translational value to the fields of developmental reprogramming, diabetes, obesity and for patients affected with infertility.