Relevant Fetal Epigenetic Modifications Result From a Diabetic Intrauterine Environment
Healthy Aging Starts With a Healthy Pregnancy
See related article, p 911–920
Twenty years ago, Barker1 reported an epidemiological observation that the in utero environment can affect late-onset diseases, such as coronary heart disease, through fetal malnourishment. Subsequent molecular studies demonstrated persistent changes in metabolic parameters that could predispose an individual to diabetes mellitus, metabolic syndrome, and cardiovascular disease. In this issue of Hypertension, Golic et al2 present an interesting study that combines these 2 aspects in an animal model, showing a direct correlation between the intrauterine milieu and subsequent epigenetic modifications.
The intrauterine environment and its impact on gene expression represent one of the most interesting aspects currently under investigation for the future risk of cardiovascular and metabolic diseases. Prenatal conditions can modify regulatory gene activity and expression through epigenetic mechanisms, and this plays a fundamental role in the process of fetal programming.3 Before birth, it represents an adaptive change of the fetus to an adverse environment (lack of oxygen and nutrient supply) that, after delivery, results in altered metabolic responses to the postnatal environment. These epigenetic mechanisms, such as DNA methylation and histone modification, alter gene expression without involving a change in the nucleotide sequence. An important characteristic is that these modifications are heritable4 and are, therefore, important not only to the subject but also to future descendants.
The vast majority of data supporting the fetal programming hypothesis are based on epidemiological studies in humans and genetic observations in rodents. Different species and translational animal models for specific diseases are key sources of information. Accordingly, 2 major findings can be highlighted in the paper by Golic et al.2 The paper presents a novel translational rat model for insulin-resistant, hyperinsulinemic diabetes mellitus with hyperlipidemia (a model of type 2 diabetes mellitus) during pregnancy, which is an interesting model, especially from a clinical perspective. In fact, streptozotocin-induced diabetic rats, which are often presented as a model of type 2 diabetes mellitus, actually show a destruction of pancreatic islets (β-cell glucotoxicity) mimicking hypoinsulinemic diabetes mellitus (type 1),5 as demonstrated by the fact streptozotocin-induced diabetes mellitus can be reversed by insulin administration.6 Although it is not explicitly stated in the manuscript, this new model can also be used to study gestational diabetes mellitus as well as interventions (metformin, new drugs, response to exercise, or diet, etc) in insulin-resistant, hyperinsulinemic diabetes mellitus.
The role of epigenetic modifications that occur during fetal life can lead to a predisposition to diabetes mellitus as an early-life programming effect.7 This study demonstrates that an altered maternal phenotype during pregnancy (characterized by diabetes mellitus and hyperlipidemia) influences the fetal phenotype on a cellular and molecular levels. Although different genes have been studied to evaluate long-term epigenetic reprogramming,8 it is interesting to note that Srebf2, a gene that regulates cholesterol metabolism and is altered in adults with diabetes mellitus and metabolic syndrome,9 was chosen to demonstrate the fetal effect from maternal lipid and glucose dysmetabolism during pregnancy. Epigenetic changes in the promoter region of Srebf2 and its expression in the fetal brain and liver were altered in the offspring of diabetic pregnancies. Thus, Srebf2 seems as a potential candidate mediating intrauterine environment-driven epigenetic changes and subsequent diabetic offspring health. These findings explain important aspects of the prenatal origin of cardiovascular and metabolic disease risk in adulthood; however, they also add significant complexity to pregnancy disorders, such as alterations of fetal growth (intrauterine fetal restriction and macrosomia) secondary to abnormal nutrient supply, as occurs during diabetes mellitus and hypertension. In these cases, brain development may also be altered because epigenetic modifications can affect neuronal cholesterol metabolism.10 This aspect was not addressed by the present study; however, future research is expected to assess this important facet. The reported findings are highly interdisciplinary, addressing an important but poorly studied issue of great interest to basic scientists, obstetricians, pediatricians, cardiologists, endocrinologists, neurologists, geneticists, and molecular biologists.
- © 2018 American Heart Association, Inc.
- Golic M,
- Stojanovska V,
- Bendix I,
- et al
- Bommarito PA,
- Martin E,
- Fry RC
- Musso G,
- Cassader M,
- Bo S,
- De Michieli F,
- Gambino R