ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2018) 15 2.17 | DOI: 10.1530/ey.15.2.17


To read the full abstract: Nat Genet. 2018 Mar;50(3):432-442

Maternal obesity is associated with poor outcomes across the reproductive spectrum including infertility, increased time to pregnancy, early pregnancy loss, congenital abnormalities and neonatal complications. Adverse effects are detectable as early as the oocyte and preimplantation embryo stage, and that these early effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception. The impacts of abnormal maternal metabolic environment on oocyte quality and pregnancy outcomes have been studied in diabetic mouse models. Female mice with models of type 1 diabetes produce oocytes that are smaller, show impaired maturation and increased granulosa cell apoptosis and display poor reproductive outcomes including growth restriction and congenital anomalies. The growth restriction and congenital abnormalities result from a maternal oocyte effect rather than a diabetic uterine environmental effect, as transfer of one-cell zygotes derived from diabetic mothers to control non-diabetic mothers failed to rescue the developmental defects. Likewise, high fat diet mouse models of obesity display similar negative impacts on the oocyte, the embryo, and pregnancy outcomes. Oocytes from obese mice are smaller, show delayed meiotic maturation, have increased follicular apoptosis and their offspring exhibit embryonic developmental defects and growth retardation.

In this study the authors report an important role of DPPA3 (developmental pluripotency associated 3, also known as Stella or PGC7) in mediating the phenotypic effects of maternal obesity in embryos and offspring. Dppa3 has been described in mice as an important maternal factor produced by the oocyte that participates in protecting the maternal genome from oxidation of methylated cytosines (5mC) to hydroxymethylated cytosines (5hmC). Dppa3 is also required for normal mouse preimplantation development. The study identified substantial reductions of Stella protein in mature oocytes from obese mice. Zygotes derived from obese mothers are disrupted in the normal maternal–paternal pronuclear asymmetry in CpG methylation, consistent with the demonstrated role of Stella in inhibiting demethylation of 5-methycytosine (5mC). Notably, overexpression of Stella in oocytes suppressed the developmental defects of embryos produced from oocytes derived from obese mothers. The high fat diet in mice not only reduced DAPP3, but also led to global hypomethylation across the genome. Interestingly when DPPA3 was overexpressed in the oocytes of high fat diet fed mice this restored the epigenetic remodeling in zygotes. These findings indicate that Stella insufficiency in the oocyte may represent a key connection between maternal metabolic syndrome, embryo development and, potentially, alterations in offspring physiology. The molecular mechanism/s by which maternal high fat diet modulates Stella protein levels in mouse oocytes is still unclear and futher studies on will shed light on Stella.