Infertile couples are increasingly turning to Assisted Reproductive Technologies (ART) to treat their infertility. Of growing concern is that ART-conceived children are at increased risk for specific loss-of-imprinting disorders, as well as congenital malformations, intrauterine growth restriction, and preeclampsia. Given the difficulty of conducting studies using human embryos, a mouse model system, which anticipated some risks associated with ART, will be used to assess effects of ART procedures on gene expression, DNA methylation in embryos and extra-embryonic tissues, and physiological and behavioral outcomes in the offspring.
Specific Aim 1 will test the hypothesis that (a) expression and epigenetic modification of imprinted genes in embryonic and extra-embryonic tissues are differentially sensitive following ART manipulations, and (b) global patterns in gene expression and promoter DNA methylation are differentially perturbed in extra-embryonic and embryonic tissues. The outcomes of ART procedures will be pursued in Specific Aim 2, which will test the hypothesis that epigenetic changes occurring in response to ART manipulations are linked with adverse outcomes in the offspring as assessed by physiological and behavioral assays. The experimental design will enable us to correlate such changes for a given offspring with molecular changes in that offspring's placenta that are in turn linked to ART manipulations prior to implantation. One-carbon metabolism is central to DNA methylation. Accordingly, Specific Aim 3 will test the hypothesis that folate supplementation of the diet of donor and recipient mothers from which the embryos are derived will alleviate, to some degree, the perturbations in DNA methylation and gene expression observed in Specific Aim 1, as well as restore a more normal physiological profile and behavioral response for those assays conducted in Specific Aim 2. The results will provide a plethora of information regarding molecular mechanisms underlying the linkage between epigenetic changes and gene expression, and whether such changes directly become manifest in offspring. Moreover, our findings may suggest experimental modifications to ART procedures that will minimize the effect of ART manipulations on epigenetic gene regulation.

Public Health Relevance

The proposed studies will provide new information regarding molecular mechanisms that underlie epigenetic changes that result from manipulations associated with Assisted Reproductive Technologies. The results of these studies will likely impact on the treatment of human infertility and Assisted Reproductive Technologies.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHD1-DSR-L)
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University of Pennsylvania
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