Dec. 24, 2010 We aren't just what we eat; we are what our parents ate too. That's an emerging idea that is bolstered by a new study showing that mice sired by fathers fed on a low-protein diet show distinct and reproducible changes in the activity of key metabolic genes in their livers. Those changes occurred despite the fact that the fathers never saw their offspring and spent minimal time with their mothers, the researchers say, suggesting that the nutritional information is passed on to the next generation via the sperm not through some sort of social influence.
The new findings reported in the Dec. 23 issue of Cell, a Cell Press publication, add to evidence that epigenetic reprogramming of genes may be an important mechanism for passing information about the environment, and in this case the nutritional environment, from one generation to the next. Epigenetics refers to heritable chemical modifications to DNA that can alter the way genes are expressed without changing the underlying sequence of their As, Gs, Ts and Cs.
"The take away is that we are more than just our genes," said Oliver Rando of University of Massachusetts Medical School, "and there are many ways our parents can 'tell' us things."
Rando said the notion that what our fathers and grandfathers ate can influence our metabolism isn't new. Perhaps the best evidence in humans comes from epidemiological studies showing that if your paternal grandfather went hungry, then you will be at greater risk of developing obesity and cardiovascular disease. Earlier this year, a study in rats by another team found that fathers on a high-fat diet can pass health problems on to their daughters.
In the new study, the researchers wanted to test whether environmental conditions have transgenerational effects by screening the activity of genes in mice whose fathers were fed on a low-protein diet from the time they were weaned until they reached sexual maturity. It turned out that hundreds of genes changed in the offspring of those protein-starved males. Epigenomic profiling of the young mouse livers showed numerous differences depending on paternal diet, including chemical modification of a sequence of DNA that is thought to serve as an enhancer for the key lipid transcription factor known as Ppara. Those changes were associated with lower activity of the Ppara gene."It's consistent with the idea that when parents go hungry, it's best for offspring to hoard calories," Rando said, noting the transcription factor's role in controlling cholesterol and lipid synthesis in the liver.
However, he says it isn't yet clear whether the changes in cholesterol metabolism will prove advantageous in the context of a low-protein diet, although it's a tempting idea.
They aren't sure yet how the information is encoded and passed from father to offspring either. It isn't obvious in that the sperm don't show the same epigenetic pattern seen in the livers of the offspring.
One thing is clear. The new findings in combination with other evidence have important implications for future studies and their mice now offer a useful model for working out the mechanisms responsible for transgenerational reprogramming of metabolism.
"Together, these results suggest rethinking basic practices in epidemiological studies of complex diseases such as diabetes, heart disease, or alcoholism," the researchers wrote in conclusion. "We believe that future environmental exposure histories will need to include parental exposure histories as well as those of the patients to disentangle induced epigenetic effects from the currently sought genetic and environmental factors underlying complex diseases. Our observations provide an inbred mammalian model for transgenerational reprogramming of metabolic phenotype that will enable dissection of the exposure history necessary for reprogramming and genetic analysis of the machinery involved in reprogramming, and they suggest a number of specific pathways likely to be the direct targets of epigenetic reprogramming."
Rando is curious to see what happens in the next generation of mice. "The human studies suggest that it is grandchildren who are most affected by their grandparents' exposure histories," he says.
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- Benjamin R. Carone, Lucas Fauquier, Naomi Habib, Jeremy M. Shea, Caroline E. Hart, Ruowang Li, Christoph Bock, Chengjian Li, Hongcang Gu, Phillip D. Zamore, Alexander Meissner, Zhiping Weng, Hans A. Hofmann, Nir Friedman, Oliver J. Rando. Paternally Induced Transgenerational Environmental Reprogramming of Metabolic Gene Expression in Mammals. Cell, 2010; 143 (7): 1084-1096 DOI: 10.1016/j.cell.2010.12.008
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