Epigenetic Synthesis

There is no surprise that food is important in all aspects of our lives—it is shared amongst families, celebrated as a major part of our culture, and crucial to our daily routine that keeps us fit, healthy, and active. Today’s western culture glorifies a skewed perspective on how food is supposed to fit into our lives. Somehow this perception has led us to believe we no longer have the time or money it takes to prepare a wholesome, healthy meal that is shared at the dinner table with family. Instead, we are trained to want a meal that is fast, cheap, and easy. This meal is usually highly processed and filled with sugars and fats. This has led us to a problem of epidemic proportions characterized by the rapid increase in obesity and diabetes.

In fact, many studies have shown a direct correlation between parental obesity and the development of obesity in their offspring.1 It has been suggested that this continuous cycle of obesity is not solely due to an individual’s nutritional choices; but, could also be due to the nutritional choices of previous generations.
Ng et al.2 was one of the first to show that the health of female offspring can be affected by the father’s diet. In this experiment, male rats were fed a high fat diet, which led to increased body weight and body fat, as well as, glucose intolerance and insulin resistance. Subsequently, the female offspring of these males were noted to have normal body weights, but developed a diabetic-like condition characterized by abnormal insulin secretion from pancreatic islet cells. On a molecular level, the paternal high fat diet altered the expression of numerous genes including the Il13ra2 gene, which showed reduced DNA methylation. Carone et al.3 further described the effects of paternal diet on metabolism. This study showed that males on low protein diets produced male and female offspring with increased hepatic expression of lipid and cholesterol synthesis genes. It was noted that there was differential methylation on the intergenic CpG Island between PPARα and Wnt7b. Another study by Ost et al.4 described a similar model of metabolic programming in offspring through Drosophila melanogaster. In this experiment, the father flies were placed on either a high sugar diet or a low sugar diet. The F1 male offspring of both groups exhibited increased triglyceride content when placed on a high sugar diet. These findings are consistent with the evidence that suboptimal nutrition profiles of fathers increase the risk of metabolic dysfunction in the offspring. Finally, G Kaati et al.5 carried out a cohort study that showed the transgenerational inheritance of these phenotypes were down the male line. Specifically, if paternal grandfathers were exposed to an abundance of food during the slow-growth period of their childhood, their grandchildren have a significantly increased risk for a diabetic related death. The rapidly progressing timeframe of this “obesity epidemic” points to the idea that there is more at play than just genetics or the environment. These studies have proposed epigenetic programming during critical growth periods as a possible explanation for how diet influences the development of metabolic dysfunction that leads to obesity, diabetes, and other chronic diseases in future generations.
The idea that obesity and other chronic diseases can be epigenetically inherited has proved to be controversial and difficult to prove mechanistically. Traditionally, it has been accepted that epigenetic modifications are marked and erased during gametogenesis or early embryogenesis, thus completely reprogramming the developing embryo to the totipotent form.1,6 This postulate would make it impossible for epigenetic inheritance to occur. However, increasing evidence has shown that epigenetic marks are not completely erased during reprogramming and that these marks are greatly influenced by environmental exposures.1,6 It is also important to note that most of the research has focused on maternal transmission of epigenetic information; however, paternal transmission of epigenetic information is proving to be equally important in the development of these phenotypes.8,9 These paternal epigenetic changes are attained during spermatogenesis commonly through DNA methylation, histone modifications, and transcription of non-coding RNA’s.9

Figure 1: Schematic overview of environmentally acquired epigenetic changes and disorders in the offspring through the paternal germ line by Soubry et al.8. Many different environmental exposures have been shown to exhibit transgenerational epigenetic inheritance, including dietary exposures. Male germ cells develop from primordial germ cells (PGC) to spermatogonia (SG) before puberty; then, further differentiate to spermatocytes (SC) and finally to spermatozoa (SZ). Epigenetic components during sperm development include DNA methylation, histone modifications, and non-coding RNA’s. DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and unbalances reactive oxygen species (ROS) provide a mechanistic link between these epigenetic changes. Ultimately, persisting changes can be beneficial, as seen in green, or they may be harmful to the organism, as seen in red.

There are many mechanisms through which the paternal diet can influence epigenetic changes during spermatogenesis.

One of the most commonly described mechanisms is altered DNA methylation, which has been noted in paternal folate deficiency7, maternal under-nourishment during pregnancy6,7, paternal high fat diets2, and paternal low protein diets3. Another mechanism is established by microRNA’s ability to regulate DNA methylation. Certain microRNA’s are known to downregulate DNA methyltransferase enzymes that function to maintain global methylation status in the genome.6 It has been proposed that environmental exposures, like nutrition, can change sperm microRNAs leading to modifications in DNA methylation.11 Histone modifications in spermatids, such as acetylation, occur in another commonly described mechanism. These diet related changes affects the structure of chromatin, which can lead to increased risk damage to DNA and thus poor sperm outcomes.6 Further influences that lead to epigenetic changes during spermatogenesis include the following: increased testicular temperature, hyperleptinemia, hyperinsulinemia, and genotoxic metabolites due to paternal fat accumulation causing increased oxidative injury to sperm cell DNA.6 These epigenetic changes are thought to influence and accelerate genetic variation that is thought to drive the evolution of a

species.7
The epigenome is highly plastic and most likely responsible for allowing us to rapidly adapt to our environment. It has been suggested that nutritional states can affect the epigenome in a way that contributes to genetic variation and the evolution of species.7 However, since these epigenetic changes are linked to the environment, they are almost always reversible.8 Changing our nutritional environment starts with an awareness of what is accepted as a healthy diet. Some healthy guidelines to follow would be to eat more fruits and vegetables, decrease carbohydrate and simple sugar intake, decrease saturated fats but increase long chain polyunsaturated fats, eat organic, wholesome foods over processed foods, and exercise daily. It is clear that obesity and diabetes are increasingly affecting our population, especially in western cultures. Recent epigenetic proof suggests the prevention of obesity and diabetes should be based on the notion that parental diet has the ability to influence health in their offspring.1,10

Works Cited
1. Wu Q, Suzuki M. Parental obesity and overweight affect the body-fat accumulation in the offspring: the possible effect of a high-fat diet through epigenetic inheritance. Obesity Reviews. 7, 201-208 (2006).
2. Ng SF, et al. Chronic high-fat diet in fathers programs β-cell dysfunction in female rat offspring. Nature. 467, 963-966 (2010).
3. Carone, B. R. et al. Paternally-induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 1084–1096 (2010).
4. Öst, A. et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell 159, 1352–1364 (2014).
5. Kaati G, et al. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. European Journal of Human Genetics. 10, 682-688 (2002).
6. Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends in Molecular Medicine. 21, 134-144 (2015).
7. Soubry A. Epigenetic inheritance and evolution: A paternal perspective on dietary influences. Progress in Biophysics and Molecular Biology. 118, 79-85 (2015)
8. Skinner MK. Fathers’ nutritional legacy. Nature. 467, 922-923 (2010).
9. Ozanne SE. Epigenetic Signatures of Obesity. New England Journal of Medicine. 372, 973-974 (2015).
10. Smith AC, et al. You Are What Your Dad Ate. Cell Metabolism. 13, 115-117 (2011).
11. Huypens P, et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nature Genetics. 48, 497-499 (2016).