Human Molecular Genetics Advance Access published online on March 17, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp127
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Reproductive and Epigenetic Outcomes Associated with Aging Mouse Oocytes
Montreal Children's Hospital of the McGill University Health Centre Research Institute 1 Department of Human Genetics, McGill University, Montreal, Quebec, Canada H3H 1P3. 2 Department of Pediatrics, McGill University, Montreal, Quebec, Canada H3H 1P3. 3 Department of Pharmacology and Therapeutics, and McGill University, Montreal, Quebec, Canada H3H 1P3. 4 Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada H3H 1P3.
* Corresponding author: Jacquetta M. Trasler, M.D., Ph.D., Montreal Children's Hospital of, the McGill University Health Centre Research Institute, Place Toulon, Room 222, 2300 Tupper Street, Montreal, Quebec, Canada H3H 1P3, tel. +1 (514) 412-4400 x25235, fax. +1 (514) 412-4331, email. jacquetta.trasler{at}mcgill.ca
Received January 16, 2009; Revised February 27, 2009; Accepted March 13, 2009
Female aging entails a decline in fertility in mammals, manifested by reduced oocyte reserves and poor oocyte quality accompanied by chromosomal anomalies and reduced litter size. In addition to compromised genetic integrity, recent studies suggest that epigenetic mechanisms may be altered in aging oocytes, with age affecting expression of DNA methyltransferases, which catalyze the important epigenetic modification, DNA methylation. Loss of DNA methylation patterns, most notably for imprinted genes, is lethal to mouse embryos. To investigate how maternal age affects embryonic development and underlying DNA methylation patterns, young and aged C57BL/6 females were mated with C57BL/6 or C57BL/6(CAST7) males, to allow for the identification of parental alleles; resulting blastocysts and midgestation embryos and placentas were evaluated. Although pregnancy, ovulation and implantation rates were similar between age groups, an age-related increase in resorption sites, morphological abnormalities and delayed development was found. Interestingly, placental morphology was also perturbed by aging, with elevated numbers of trophoblast giant cells in aged pregnancies. Normal monoallelic expression of the imprinted genes H19 and Snrpn was unaltered in blastocysts from aged females. We failed to observe any age-related changes in methylation of the differentially methylated regions of imprinted genes Snrpn, Kcnq1ot1, U2af1-rs1, Peg1, Igf2r and H19. Restriction Landmark Genome Scanning showed no significant differences in genome-wide DNA methylation in embryos and placentas, regardless of maternal age. Our findings demonstrate that maternal age affects post-implantation embryo and placental development, however embryos capable of developing to midgestation appear to undergo normal acquisition and maintenance of DNA methylation patterning.