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. Here we show 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. Insufficient demethylation by oocyte TET3 contributes to hypermethylation at the paternal alleles of several insulin secretion genes, including the glucokinase gene (Gck), that persists from zygote to adult, promoting impaired glucose homeostasis largely owing to the defect in glucose-stimulated insulin secretion. Consistent with these findings, mouse progenies derived from the oocytes of maternal heterozygous and homozygous Tet3 deletion display glucose intolerance and epigenetic abnormalities similar to those from the oocytes of HG mice. Moreover, the expression of exogenous Tet3 mRNA in oocytes from HG mice ameliorates the maternal effect in offspring. Thus, our observations suggest 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 suggests a potential benefit of pre-conception interventions in mothers to protect the health of offspring.
We thank B. Han for providing APOBEC3A deaminase, Z. Shen for anti-GCK antibody; S. Hong, C. Zhou and G. Xu for technical assistance in embryo manipulation; M. Cai for data analysis; L. Shen, Y. Pan, H. Wang, Q. Xu, L. Xu, J. Xue, Z. Zhou, X. Liu, C. Xu, J. Zhang and H. Yang for discussions; and T. Gu, L. Rui, X. Li, Y. Chen, H. Fan and S. Xuan for critical reading of the manuscript. This work is supported by the National Key R&D Program of China (2017YFC1001300 to H.H.; 2018YFA0800302 to G.-L.X.; 2017YFC1001301 to Y.-R.D.; and 2018YFC1004402 to J.S.), the National Science Foundation of China (82088102 to H.H.; 81661128010 to H.H.; 31991163 to G.-L.X.; 31671569 to J.S.; and 81971458 to G.D.), Shanghai Jiao Tong University, CAMS Innovation Fund for Medical Sciences (CIFMS) (2019-I2M-5-064 to H.H.), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01 to H.H.), Technology Innovation Action Plan Hong Kong, Macao and Taiwan Science and Technology Cooperation Project (19410760100 to H.H.), Shanghai Frontiers Science Research Base of Reproduction and Development (to H.H.) and Zhejiang Provincial Natural Science Foundation of China under Grant (LQ21H040005 to B.C.).
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
- Glucose Intolerance - genetics - metabolism
- Hyperglycemia - complications - genetics - metabolism
- Dioxygenases - metabolism
- Oocytes - metabolism
- Maternal Inheritance
- Glucose - metabolism