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Excerpt: Dramatic changes can be reversed via epigenetics

Mysterious Epigenome, The

An excerpt from The Mysterious Epigenome . Here are the agouti mice.

Although there is still much to learn about such a tendency of succeeding generations to inherit changes engraved on their parents’ and grandparents’ epigenomes, a similar line of evidence has been found in studies of mice in the laboratory of geneticist Randy Jirtle at Duke University. These studies, which emphasized the importance of environmental factors in health and survival, focused on the epigenetic changes in expressing a section of DNA called the “agouti gene,” which causes a yellow coat to appear in mice. Unfortunately, this gene can also be over-expressed, causing the mice to activate a biochemical cascade that results in obesity and diabetes. One of the triggers that caused the epigenetic marks (methyl tags) to be removed from these genes in certain cases was an exposure to high levels of a man-made chemical pollutant in the environment, bisphenol A (BPA), which is used in some plastics. In the case of some mice, this environmental “chemical factor” appeared to activate the epigenetic switch that led to
similar kinds of unhealthy resetting of the epigenetic system that the binging behavior had caused in the children of the farmers in Sweden.

In 2007, an episode of Nova focused on Jirtle’s lab research on the epigenetics of agouti mice. After the program aired, Dr. Jirtle responded to online questions from listeners, including many about the role of BPA in triggering obesity in humans. Two of these questions were to the point: “Does the [BPA] finding suggest that fetal or environmental exposure to plastics could play a direct role in a genetic propensity toward obesity in humans? Could there be a connection between the increase in plastics in our environment and rising obesity rates?”

Jirtle replied cautiously that such a connection is possible, but has not been shown “unequivocally.” Here is his complete reply: “We have recently demonstrated that exposure of pregnant mice to bisphenol A (BPA), a building block of polycarbonate plastics and epoxy resins used to make consumer items ranging from water bottles to dental sealants, significantly reduces DNA methylation in . . . mice.

This results in the birth of more yellow offspring, mice that become obese and have a higher incidence of diabetes and cancer as adults. Thus, there could be a connection between the increase in plastics in our environment and the rising incidence of obesity in humans. However, such an association will not be able to be demonstrated unequivocally until the expression and function of genes involved in human obesity are shown to be altered by BPA.”

Fortunately, that was not the end of the research story on the epigenetics of obesity in mice. Jirtle managed to produce healthy young rats in the next generation, by changing the expression of their genes epigenetically—back to the normal, healthy setting.

What was his solution? In short, during gestation of the next generation of rats, he fed the mother rats foods that provided high levels of methyl groups—mainly B vitamins, including folic acid and vitamin B12. As we saw in previous chapters, these methyl groups normally act like molecular switches, blocking the expression of certain genes.

Jirtle’s lab results were startling. The methyl groups wound their way, bit by bit, through the mothers’ own metabolic pathways, and were attached to the agouti genes of the developing embryos. “It was a little eerie and a little scary to see how something as subtle as a nutritional change in the pregnant mother rat could have such a dramatic impact on the gene expression of the baby,” Jirtle said. “The results showed how important epigenetic changes could be. The tip of the iceberg is genomics. . . . The bottom of the iceberg is epigenetics.”

- Thomas Woodward and James Gills, The Mysterious Epigenome: What Lies Beyond DNA, pp 94-96.

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