By Marisa Sanchez, Genetics ’15
Most people know that poor diet, lack of exercise, and smoking as an adult can increase the risk of developing cardiovascular disease (CVD) and Type II diabetes. However, research over the past couple of decades has shown that risk for CVD and type II diabetes could begin as early as prenatally through adverse exposures, such as overnutrition and placental insufficiency. Some mechanisms involved in determining risk for CVD and Type II diabetes are oxidative stress, inflammation, lipotoxicity, and epigenetics.
Oxidative stress is associated with increased production of oxidizing species or a decrease in the effectiveness of antioxidant defenses. Inflammation is associated with elevated C-Reactive protein levels. Lipotoxicity is associated with an imbalance of the amount of lipids produced and the amount that is used. Epigenetics is represented by modifications in gene expression and epigenetics plays a key-role in understanding how the environment and genes interact with one another. One important gene modification associated with CVD and type II diabetes is DNA methylation.
One study that links oxidative stress and higher risk for CVD and/or type II diabetes was with sheep hearts. This study showed that hearts of obese pregnant sheep, that consumed a high-fat diet, showed oxidative stress. Increased oxidative stress was also shown to be present in the hearts of the offspring of the obese sheep that ate a high-fat diet during pregnancy. Studies in sheep have shown that elevated levels of oxidative stress in the heart along with activation of p38, JNK, and AMPK in offspring correspond with maternal obesity. P38 and JNK are mitogen–activated protein kinases in the heart that are activated by numerous pathologic stresses, including oxidative stress. Activation of p38 in human hearts has been linked with advance heart failure. JNK activation diminishes mitochondrial gene expression involved in oxidative phosphorylation chain reaction and fatty acid metabolism, which both have a major impact on the energetic status of the heart. A lower energetic status is associated with an increased risk for CVD. AMPK is a AMP-activated protein kinase. It is activated in response to alterations in cellular energy levels. Metabolic activators of AMPK include oxidative stress and glucose deprivation. The activation of AMPK results in fatty acid oxidation, acceleration of glycolysis, promotion of glucose transport, and inhibition of protein synthesis and triglycerides. Activation of AMPK has been linked to an increase risk for CVD and type II diabetes.
Another study that showed oxidative damage definitely played a role in the development of CVD and type II diabetes was with mice. Pregnant mice were fed a high-fat diet, but some were also administered antioxidants. In the offspring whose mothers were fed antioxidants, hypertension was prevented from developing and blood glucose levels were normal. By preventing the development of CVD and type II diabetes, this shows that oxidative stress caused by maternal diet definitely plays a role in their development.
In human placentas of obese pregnancies there were signs of inflammation and mitochondrial dysfunction, which are both associated with having negative impacts on fetal growth. Inflammation during pregnancy has been linked to a decrease in the intrinsic ability of the heart to contract. In a study with female mice, one group of mice had a high-fat diet during pregnancy, lactation, and postnatally and another group ate a high-fat diet only postnatally. Both groups showed elevated levels of C-Reactive Protein (CRP). However, the only offspring with elevated levels of CRP were in the group where the mothers consumed a high-fat diet during pregnancy. CRP is a protein that is found in the blood, and CRP levels rise in response to inflammation. Elevated levels of CRP are associated with an increase risk of CVD and type II diabetes.
Lipotoxicity has been associated in offspring whose mothers consumed a high-fat diet during pregnancy. Lipotoxicity is a metabolic syndrome that results in accumulation of lipid intermediates in non-adipose tissues, like heart tissue, which can lead to cellular dysfunction and death. Lipotoxicity in the heart is associated with excess saturated fatty acids. In a study with mice where mouse offspring were exposed to a maternal high-fat diet prenatally and postnatally, during lactation, the offspring had lipid accumulation within the heart indicating Lipotoxicity. Lipotoxicity is associated with development of CVD and type II diabetes.
DNA methylation can silence the expression of specific genes This is done through transcriptional repression, which is caused by blocking the binding of transcription factors. This is done by altering recognition sites for transcription factors and/or promoting the binding of the methyl CpG binding protein-2. This results in the reduction of accessibility of DNA for transcription, which results in a lower expression of the proteins encoded by that DNA. Many times methylation patterns are established prenatally or in early developmental stages due to the fact that DNA methylation plays a key role in cell differentiation. Silencing the expression of particular genes during development allows for cell differentiation.
In a study where different rats were fed a different amount of protein during pregnancy, it was found that the rats that were fed a low protein diet during pregnancy had offspring with high blood pressure, which is common in people who develop CVD and/or type II diabetes. It was also found that the offspring had insulin resistance, which is associated with diabetes. Decreasing protein in the maternal diet led to hypomethylation of the PPARa and GR promoter. PPARa is a transcription factor and major regulator of lipid metabolism in the liver. The GR is expressed in most cells in the body and regulates most genes that control development, metabolism, and immune response. This suggests that epigenetic change can modify the activity associated with metabolic pathways, which then can lead to the development of CVD and/or Type II diabetes.
There is consistent evidence that adverse exposures prenatally can lead to the development of CVD and type II diabetes later in life. Many studies show that overnutrition and placental insufficiency are the main prenatal causes of the development of these diseases. Further studies still need to be done to confirm these findings, but so far the evidence is promising. It is important that those expecting are aware of their nutritional intake for not only their own sake, but for their child’s sake as well. A well balanced diet and moderate exercise are some the most important factors in having a healthy pregnancy and baby.
Blackmore, H. L. “Maternal Diet-Induced Obesity and Offspring Cardiovascular Health.”Comp. S. E. Ozanne. Journal of Developmental Origins of Health and Disease 4.5(2013): 338-47. Print.
Jackson, Alan A. “Diet, Nutrition and Modulation of Genomic Expression in Fetal Origins ofAdult Disease.” Comp. Graham C. Burdge and Karen A. Lillycrop. Journal of Nutrigenetics and Nutrigenomics 101 (2011): 192-208. Print.