The Epigenetics Revolution

A major metabolic disturbance during early pregnancy, such as the dramatically decreased availability of food during the Dutch Hunger Winter, would significantly alter the epigenetic processes occurring in the foetal cells. The cells would change metabolically, in an attempt to keep the foetus growing as healthily as possible despite the decreased nutrient supply. The cells would change their gene expression to compensate for the poor nutrition, and the patterns of expression would be set for the future because of epigenetic modifications to the genes. It’s probably no surprise that it was the children whose mothers had been malnourished during the very early stages of pregnancy, when developmental programming is at its peak, who went on to be at higher risk of adult obesity. Their cells had become epigenetically programmed to make the most of limited food supply. This programming remained in place even when the environmental condition that had prompted it – famine – was long over.

Recent studies examining DNA methylation patterns in the Dutch Hunger Winter survivors have shown changes at key genes involved in metabolism. Although a correlation like this doesn’t prove cause-and-effect, the data are consistent with under-nutrition during the early developmental period changing the epigenomic profile of key metabolic genes[37].

It’s important to recognise that even in the Dutch Hunger Winter cohort, the effects that we see are not all-or-nothing. Not every individual whose mother had been malnourished early in pregnancy became obese. When scientists studied the population they found an increased likelihood of adult obesity. This is again consistent with a model where random epigenetic variability, the genotypes of the individuals and early environmental events, and the responses of the genes and cells to the environment combine in one great big complicated – and as yet not easily decipherable – equation.

Severe malnutrition is not the only factor that has effects on a foetus that can last a lifetime. Excessive alcohol consumption during pregnancy is a leading preventable cause of birth defects and mental retardation (foetal alcohol syndrome) in the Western world[38]. Emma Whitelaw used the agouti mouse to investigate if alcohol can alter the epigenetic modifications in a mouse model of foetal alcohol syndrome. As we have seen, expression of the Avy gene is epigenetically controlled via DNA methylation of a retrotransposon. Any stimulus that alters DNA methylation of the retrotransposon would change expression of the Avy gene. This would affect the colour of the fur. In this model, fur colour becomes a ‘read-out’ that indicates changes in epigenetic modifications.

Pregnant mice were given free access to alcohol. The coat colour in the pups from the alcohol-drinking mothers was compared with the coat colour of the pups from pregnant mice that didn’t have access to booze. The distribution of coat colours was different between the two groups. So were the levels of DNA methylation of the retrotransposon, as predicted. This showed that the alcohol had led to a change in the epigenetic modifications in the mice. Disruption of epigenetic developmental programming may lead to at least some of the debilitating and lifelong symptoms of foetal alcohol syndrome in children of mothers who over-use alcohol during pregnancy.

Bisphenol A is a compound used in the manufacture of polycarbonate plastics. Feeding bisphenol A to agouti mice results in a change in the distribution of coat colour, suggesting this chemical has effects on developmental programming through epigenetic mechanisms. In 2011 the European Union outlawed bisphenol A in drinking bottles for babies.

Early programming may also be one of the reasons that it’s been very difficult to identify the environmental effects that lead to some chronic human conditions. If we study pairs of MZ twins who are discordant for a specific phenotype, for example multiple sclerosis, it may be well nigh impossible to identify an environmental cause. It may simply be that one of the pair was exceptionally unlucky in the random epigenetic fluctuations that established certain key patterns of gene expression early in life. Scientists are now mapping the distribution of epigenetic changes in concordant and discordant MZ twins for a number of disorders, to try to identify histone or DNA modifications that correlate with the presence or absence of disease.