[MUSIC] Welcome back. Well after that last lecture, you may be thinking, what's the big deal? What does it matter, how you turns genes off, If you turn genes off by methylation or one mutations changes in the base sequence? What does it matter? Well, it matters, the big deal is, the methylation responds to your environment. Fighting a long game of gene environment interactions, so the experience can echo in our genes across generations. The things like that can change a non-DNA inheritance with methylation. People exposed to famine in, in the Dutch Famine winter, they had less methylation of an insulin growth factor 2 gene. That's a gene involved in regulating how you use sugar, and it controls the growth of the embryo and the placenta. This was tested when the Dutch people were in their 40s and 50s. So if effect really persisted long after in utero. Well, in other words, the environment in early pregnancy, will affect you later in life through methylation changes. Now, famine is obviously an extreme case of altered nutrition. Malnutrition means that nutrients are scarce, but it does give scientists a pretty useful tool to look at how nutrition can change our epigenetics. So for example, Swedish scientists found that if your grandfather or grandmother went through a famine, you would have lower mortality risks than if they gorged. But, only if you were the same sex as the grandparent who starved or gorged. So grandfathers starving or gorging, when they were nine to 12 years old, only changed the grandsons' mortality risk. Grandmothers gorging or starving, only changed the granddaughters' mortality risk. A follow-up study in England showed that childhood smoking in fathers produced fatter sons, but not daughters. Well, these studies then, taken together, suggest that methylation is happening to the X or Y chromosome. It's not clear where or how, we're still just scraping the surface of mechanisms here. And the big problem is that it's hard to do experiments with people, and epigenetic signals are hard to detect in traditional genetic and epidemiological studies, which is probably why it's taken so long to discover them. What scientists can do then, is to turn to mice and rats. Mice are the genetic model of choice for studies on human physiology. First, what is true in mice is going to be true in you. That's why mice have something to say about the human obesity epidemic. They're just like us. Fat mice are at greater risk of heart disease, diabetes and cancer. Well here are two mice, that believe it or not, are genetically identical. They don't look genetically identical. They don't even look like the same breed of mouse, do they? But they are. They're a breed of mouse called agouti, so called because they carry a particular gene, the agouti gene, that makes the rodents ravenous and yellow. Back in 2000, Randy Jirgle, who was a professor at Duke University, and post doctoral student, Robert Waterland, set about to see if they could change the unfortunate genetic legacy of these little creatures. They found that the agouti gene can be turned off by methylation. Mice with the agouti gene turned off, are still genetically identical to their fat, yellow kin. But they're skinny and brown, because of methylation of the Agouti gene. Moreover, they did not display their parents' susceptibility to cancer and diabetes. They lived to a spry old age. The effects of the agouti gene have been virtually erased. Well, how is this possible? It's nutrition again. Typically, when fat, yellow agouti mice breed, most of the offspring are identical to the parents, just as yellow and fat as pincushions. And the fat yellow mother of the thin brown mouse, had a diet high in methyl donors for two weeks before mating. As well as through the pregnancy and lactation. Methyl donors are found in many foods, including onions, garlic, beets, and in the food supplements, such as folic acid often given to pregnant women. The implications are that, that every pregnant woman who has been taking a folic acid supplement has been engaging in an experiment in epigenetics. An experiment, because it may not be one size fits all. Our DNA sequences are different. So our methylation patterns will also be different. And maybe the potential to suppress beneficial genes, but we don't know enough to say. Now scientists use these agouti. Mice to gauge a whole wide range of diet and chemicals and other environmental conditions are going to effect epigenetic control of gene activity in animals, hopefully including humans. They're looking for conditions that tip the balance for methylation, and thus between genes that are off, and those that are on. They found that a lot of chemical, stress and other factors that interfere with methylation, shift the coat color and health of the mice, and sometimes in very unexpected ways. In 2012, Jirtle's group reported, that low level radiation signalled cells to shut down agouti activity. That's making the mice healthier. Vitamins and other antioxidants that intercepted this signal, promoted the unhealthy state. Jirtle in interviews, said that he wasn't exactly excited about the result at first. He said, nobody wants to think that low dose radiation could be advantageous, and the stuff you put in your vitamin pill would be bad. However, the results suggest that radiation may help modulate the immune, system by altering methylation of DNA and immune cells. That's interesting to know, isn't it? It may mean that certain amount of radiation may be good for some of us. Or, who'd have guessed that? But some of the other results obtained by Jirtle's group have been really disturbing. Bisphenol A. It's a chemical found in most plastics. Millions of tons are produced per year. 95% of us have detectable levels of it in our urine. Jirtle's group found that Bisphenol A blocked methylation of the agouti mice genes, so that more of their progeny developed into the yellow obese mice, than they'd expected. But with the rise of obesity in Americans coinciding with the widespread use of Bisphenol A in everything from water bottles to dental sealants, there's been speculation there might be a cause connection. There's also a majority opinion among experts, that the number of people with autism is increasing in our populations. Bisphenol A alters methylation in the mouse forebrain, making the pups more introverted. And a study on pregnant monkeys fed Bisphenol A from their babies had a condition resembling autism. More bad news. Bisphenol in the male line, effects sperm. It's passed epigenetically across at least three generations in rats. These are just the results for Bisphenol A. So far, the Jirtle group and some other researchers working on rats, have documented measurable effects from a host of environmental pollutants including pesticides, and synthetic estrogen used in some birth control pills. The base count of susceptibility in the daughters, granddaughters and great granddaughters of pregnant rats. And a variety of different fungicides of vinclozolin. That reduced male fertility even in the fifth generation. Or in the past, it was assumed that variations between people in the health risk from environmental chemicals, just depended on genetically determined variation in the proteins involved in transport and metabolism. The secretion of these chemicals. And in future, it seems, that setting standards for the safe levels of exposure to chemicals may need to take into account epigenetic effects as well. There's also a good side for our epigenetics being laid bare, and easy to order. As some consolation, the Jirtle's group found that giving the agouti mothers methyl donating substances, counteracted the reduction in DNA methylation caused by bisphenol A. They also found that a constituent of soy protein, protein called genistein, prevented an increased number of unhealthy offspring. Well, no one can yet explain exactly how epigenetic information gets passed to the next generation. The clues we have suggest a role for small RNAs called piRNAs. They direct modifier proteins to attach methyl groups. We've attached an article to the, lecture for those interested in the details, such as we know them. What is clear though, from epidemiological studies in people and molecular studies with animals, is that prenatally, and just before puberty, are key periods when the epigenome is very susceptible to disruption by external factors such as emotional stresses and smoking. These will effect you later in life. And it'll affect your children in the diseases vector. It will at least in part set your children's live's trajectories, and those of their children. What young people do today, is writing the map of illness in the world for a hundred years' time, the map has been written for us already. [NOISE]
