Diabetes mellitus is prevalent among women of reproductive age, and many women are left undiagnosed or untreated. Gestational diabetes has profound and enduring effects on the long-term health of the offspring. However, the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated.
A recent study led by Fudan scientists has shown that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance. The expression of TET3 dioxygenase, responsible for 5-methylcytosine oxidation and DNA demethylation in the zygote, is reduced in oocytes from a mouse model of hyperglycaemia (HG mice) and humans with diabetes. The research paper entitled “Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency” was published in Nature on May 19.
The study suggests an environment-sensitive window in oocyte development that confers predisposition to glucose intolerance in the next generation through TET3 insufficiency rather than through a direct perturbation of the oocyte epigenome. This finding also reveals a potential benefit of pre-conception interventions in mothers to protect the health of offspring.
Antoine H. F. M. Peters, investigator at Friedrich Miescher Institute for Biomedical Research wrote in the review published in Nature Briefing, “It emerges that high blood sugar deregulates the enzyme TET3 in the eggs of female mice, preventing it from properly modifying sperm-derived DNA when eggs are fertilized. This leads to metabolic defects in adult progeny.”
Hefeng Huang, member of Chinese Academy of Medical Sciences and professor at Institute of Reproduction and Development, Fudan University, and Key Laboratory of Reproductive Genetics (Ministry of Education), and Guoliang Xu, member of Chinese Academy of Medical Sciences and professor at Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, and Institutes of Biomedical Sciences, Medical College of Fudan University are the correspondent authors of the paper.
Bin Chen at School of Medicine, Zhejiang University, Yarui Du at Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Hong Zhu at Institute of Reproduction and Development, Fudan University, Meiling Sun and Chao Wang at Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, share the first authorship.
Jianzhong Sheng, professor at School of Medicine, Zhejiang University and Peter R. Flatt, professor at Ulster University also contributed to this study.
Link to the paper: https://www.nature.com/articles/s41586-022-04756-4