Symptomatic treatment was a common approach for chronic diseases in the past. For example, diabetes is treated by controlling excess glucose and relieving various complications caused by diabetes with insulin. However, how to prevent diabetes has remained elusive in the scientific and medical community, and has become a hotspot for global research to discover the origin of the disease to allow early intervention.
Recently, the team led by Professor Huang Hefeng from Women’s Hospital of Zhejiang University College of Medicine and the team led by Professor Xu Juuliang from the Center of Excellence in Molecular Cell Sciences at the Chinese Academy of Sciences discovered a new mechanism for the transmission of diabetes from one generation to the next. Their research indicated an environmentally sensitive window in developing eggs that confers susceptibility to glucose intolerance in the next generation. These search results were published in the May 18 issue of temper nature.
Professor Huang Hefeng, a well-known obstetrician and gynecologist, was intrigued by a mother’s potential impact on her offspring. To this end, she led her team to conduct research on diseases of adult sons caused by harmful environmental factors of the mother. The team found that exposure to elevated glucose/androgens can lead to intergenerational or transgenerational heritability of chronic diseases by altering the DNA methylation profile in utero/embryo fetuses or by affecting epigenetic modifications of sperm/oocytes. Professor Huang has concluded from clinical investigations and animal models that chronic diseases such as diabetes and hypertension can be of developmental origin, and is thus a pioneer in reporting the ‘epigenetic inheritance across gametes’ hypothesis. However, this hypothesis remained unconfirmed.
To confirm this hypothesis, Professor Huang’s team began to focus on the following questions: Do maternal environmental factors prior to conception affect the health of the offspring? Does high blood sugar in mothers increase the risk of chronic disease via oocytes?
To answer these questions, the team built a female model of hyperglycemic mice. To rule out persistent effects of hyperglycemia on embryonic and embryonic development, they ingeniously removed infected eggs for in vitro fertilization and transferred embryos into healthy brood mice to produce offspring. Metabolic measurements showed that their offspring showed impaired glucose tolerance, indicating that oocytes, affected by the hyperglycemic environment, had increased susceptibility to chronic disease. So the result supports Professor Huang’s hypothesis.
Faced with this important discovery, the team began to question the very “culprit” that increases the offspring’s susceptibility to diabetes. After a complex series of experiments, they found the key – TET methylcytosine dioxygenase 3 (TET3) – and suggested the regulatory pathways for chronic diseases in offspring through TET3 deficiency.
The joint research by Professor Huang Hefeng and Professor Xu Guoliang confirmed that the elevated glucose environment in glycemic female mice resulted in an insufficient dose of TET3 protein in the oocytes, which contributed to the poor ability of TET3 to reprogram in the fertilized egg and ultimately “demethylation.” insufficient” or “excessive methyl.”
How does TET3 increase offspring’s susceptibility to diabetes? The glucokinase (GCK) gene is one of the most important proteins that regulate insulin secretion. During the process of reproduction and division of the fertilized egg, hypermethylation of relevant genes related to insulin secretion, including GCK, leads to impaired exploitation of TET3. TET3 deficiency persists into adulthood in the offspring. Hypermethylation and decreased expression of such genes as GCK lead to insufficient insulin secretion, lower blood glucose, and increased susceptibility to diabetes as they age.
This study was also confirmed in pregnant women with diabetes clinically. Immature oocytes and discarded baluster sacs from clinically diabetic patients received in several hospitals in Hangzhou and Shanghai also showed low TET3 expressions and excessive methylation in the GCK promoter region, respectively. This further indicates the clinical significance of this study.
“These research findings provide revolutionary insights into the prevention and control of chronic diseases at their origin, which will help reduce birth defects and improve the health of our population,” said Professor Huang. “Now that diabetes and high blood pressure, too often, run in families, special attention must be paid to the transgenerational inheritance caused by the reproductive environment. While caring for our health, we must also protect our next generation.”
You are what your parents eat
Bin Chen et al, Maternal inheritance of glucose intolerance via TET3 hypocholesterolemia, temper nature (2022). DOI: 10.1038 / s41586-022-04756-4
Provided by Zhejiang University
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