Placental DNA methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the art and research gaps

SUMMARY

Maternal diabetes and/or obesity in pregnancy are undoubtedly associated with later disease-risk in the offspring. The placenta, interposed between the mother and the foetus, is a potential mediator of this risk through epigenetic mechanisms, including DNA methylation. In recent years, multiple studies have identified differentially methylated CpG sites in the placental tissue DNA in pregnancies complicated by diabetes and obesity. We reviewed all published original research relevant to this topic and analysed our findings with the focus of identifying overlaps, contradictions, and gaps. Most studies focused on the association of gestational diabetes and/or hyperglycaemia in pregnancy and DNA methylation in placental tissue at term. We identified overlaps in results related to specific candidate genes, but also observed a large research gap of pregnancies affected by type 1 diabetes. Other unanswered questions relate to analysis of specific placental cell types and the timing of DNA methylation change in response to diabetes and obesity during pregnancy. Maternal metabolism is altered already in the first trimester involving structural and functional changes in the placenta, but studies into its effects on placental DNA methylation during this period are lacking and urgently needed. Foetal sex is also an important determinant of pregnancy outcome, but only few studies have taken this into account. Collectively, we provide a reference work for researchers working in this large and evolving field. Based on the results of the literature review, we formulate suggestions for future focus of placental DNA methylation studies in pregnancies complicated by diabetes and obesity.

KEYWORDS:

• Pregnancy
• placenta
• epigenetic
• DNA methylation
• gestational diabetes
• type 1 diabetes
• type 2 diabetes
• obesity
• hyperglycaemia
• hyperlipidaemia
• foetal development
• offspring

Author Contributions

LH and GD developed the ideas presented in this review, with contributions from BN, SC, RS and PD. LH, BN, SC and GD wrote the manuscript, with contributions from RS and PD. All authors critically revised the manuscript and had access to the final version.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data Availability Statement

Data is contained within the article and can be accessed from the corresponding authors on reasonable request.

Additional information

Funding

The Danish Diabetes Academy supported by the Novo Nordisk Foundation, and The Danish Diabetes Association (Diabetesforeningen). LH is partly employed at the Novo Nordisk Foundation Center for Basic Metabolic Research, which is an independent research center at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900).