Compromised oocyte quality and assisted reproduction contribute to sex-specific effects on offspring outcomes and epigenetic patterning.
Clinical studies have revealed an increased incidence of growth and genomic imprinting disorders in children conceived using assisted reproductive technologies (ARTs), and aberrant DNA methylation has been implicated. We propose that compromised oocyte quality associated with female infertility may make embryos more susceptible to the induction of epigenetic defects by ART. DNA methylation patterns in the preimplantation embryo are dependent on the oocyte-specific DNA methyltransferase 1o (DNMT1o), levels of which are decreased in mature oocytes of aging females. Here, we assessed the effects of maternal deficiency in DNMT1o (Dnmt1Δ1o/+) in combination with superovulation and embryo transfer on offspring DNA methylation and development. We demonstrated a significant increase in the rates of morphological abnormalities in offspring collected from Dnmt1Δ1o/+  females only when combined with ART. Together, maternal oocyte DNMT1o deficiency and ART resulted in an accentuation of placental imprinting defects and the induction of genome-wide DNA methylation alterations, which were exacerbated in the placenta compared to the embryo. Significant sex-specific trends were also apparent, with a preponderance of DNA hypomethylation in females. Among genic regions affected, a significant enrichment for neurodevelopmental pathways was observed. Taken together, our results demonstrate that oocyte DNMT1o-deficiency exacerbates genome-wide DNA methylation abnormalities induced by ART in a sex-specific manner and plays a role in mediating poor embryonic outcome.
Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
Laura
L
Whidden
Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Josée
J
Martel
Department of Human Genetics, McGill University, Montreal, QC, Canada
Sophia
S
Rahimi
Department of OB/GYN and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
J Richard
JR
Chaillet
Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Donovan
D
Chan
Montreal Children's Hospital and Research Institute of the McGill University Health Centre, Montreal, QC, Canada.|Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada|Department of Human Genetics, McGill University, Montreal, QC, Canada|Department of Pediatrics, McGill University, Montreal, QC, Canada
Jacquetta M
JM
Trasler
D000367:Age Factors; D000818:Animals; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D007247:Infertility, Female / Q000503:physiopathology; D051379:Mice; D023421:Models, Animal; D009865:Oocytes / Q000473:pathology / Q000502:physiology*; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D012099:Reproductive Techniques / Q000009:adverse effects*; D013480:Superovulation / Q000235:genetics / Q000502:physiology
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619381:Dnmt1 protein, mouse