The Epigenetics Revolution

The data from the Dutch Hunger Winter and other famines support the idea that poor nutrition during pregnancy has effects on offspring, and that these consequences can be transmitted to subsequent generations as well. In other words, poor nutrition can have epigenetic effects on later generations. The data from the Överkalix cohort, although more difficult to interpret, suggested that excess consumption at key points in a boy’s life can have adverse consequences for later generations. Is it possible that the obesity epidemic in the human population will have knock-on effects for children and grandchildren? As we don’t really want to wait 40 years to work this out, scientists are again turning to animal models to try to gain some useful insights.

The first animal data suggested that nutrition might not have much effect transgenerationally. The change in coat pattern of pups when pregnant agouti mice were given diets high in methyl donors didn’t transmit to the next generation[48]. But perhaps this is too specialised a model. In 2010, two papers were published that should at least give us pause for thought. They were published in two of the best journals in the world – Nature and Cell. In both cases, the researchers overfed male animals and then monitored the effects on their offspring. By restricting their experiments to males, they didn’t need to worry about the intra-uterine and cytoplasmic complications that cause such (metaphorical) headaches if studying females.

One of the studies used a breed of rat called Sprague-Dawley. This is an albino rat, with a chilled-out temperament that makes it easy to keep and handle. In the experiments male Sprague-Dawleys were given a high-fat diet, and allowed to mate with females who had been fed an ordinary diet. The over-fed males were overweight (hardly a surprise), had a high percentage of fat to muscle and had many of the symptoms found in type 2 diabetes in humans. Offspring were normal weight but they too had the diabetes-type abnormalities[49]. Many of the genes that control metabolism and how mammals burn fuel were mis-regulated in these offspring. For reasons that aren’t understood, it was particularly the daughters that showed this effect.

A completely independent group studied the effects of diet in an inbred mouse strain. Male mice were fed a diet that was abnormally low in protein. The diet had an increased percentage of sugar to make up for this. The males were mated to females on a normal diet. The researchers examined the expression of genes in the liver (the body’s major organ when it comes to metabolism) in three-week-old pups from these matings. Analysing large numbers of mouse pups, they found that the regulation of many of the genes involved in metabolism was abnormal in the offspring of the males that had been fed the modified diet[50]. They also found changes in the epigenetic modifications in the livers of these pups.

So, both these studies show us that, at least in rodents, a father’s diet can directly influence the epigenetic modifications, gene expression and health of his offspring. And not because of environment – this isn’t like the human example of a child getting fat because their Dad only ever feeds them super-sized portions of burgers and chips. It’s a direct effect and it occurred so frequently in the rats and mice that it can’t have been due to diet-induced mutations, they just don’t happen at that sort of rate. So the most likely explanation is that diet induces epigenetic effects that can be transmitted from father to child. Although the data are quite preliminary, the results from the mouse study in particular support this.

If you look at all the data in its entirety – from humans to rodents, from famine to feast – a quite worrying pattern emerges. Maybe the old saw of ‘we are what we eat’ doesn’t go far enough. Maybe we’re also what our parents ate and what their parents ate before them.