Human Molecular Genetics Advance Access originally published online on March 17, 2009
Human Molecular Genetics 2009 18(11):2032-2044; doi:10.1093/hmg/ddp127
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Reproductive and epigenetic outcomes associated with aging mouse oocytes
1 Department of Human Genetics 2 Department of Pediatrics 3 Department of Pharmacology and Therapeutics 4 Department of Obstetrics and Gynecology, McGill University and Montreal Children's Hospital of the McGill University Health Centre Research Institute, Montreal, Quebec, Canada H3H 1P3
* To whom correspondence should be addressed at: 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 5144124400 extn 25235; Fax: +1 5144124331; 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 the 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 mid-gestation 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 mid-gestation appear to undergo normal acquisition and maintenance of DNA methylation patterning.