What mom eats during pregnancy dramatically influences not only the health of her kids but future generations as well. That’s the conclusion of a new report in Science linking poor diet among pregnant mice moms to glucose intolerance and pancreatic issues in both mice offspring and grandsons. These symptoms of mouse diabetes were passed on through generations of mice, even without any apparent alterations in the letters that comprise organisms’ genetic codes—A’s, T’s, C’s and G’s.



The study is only the latest research to suggest that environmental factors, such as diet in utero, can fundamentally alter the on-off switches that control the activity of male offspring's sperm DNA, even when they do not actually cause mutations to the underlying genetic blueprints of the organism. The authors say epigenetics, or how experiences and environment affect the function of genes, are at work here. “Our findings are significant because they demonstrate that your environment when you are in the womb can not only affect your health but also can permanently alter the information that you pass on to your children when they are conceived, and that this affects their health as adults,” says study author Elizabeth Radford, who wrote the paper as an MB/PhD student at the University of Cambridge. The new research builds on earlier work and solidifies the link between epigenetics and these multigenerational health issues.



Biologists have long known that what moms-to-be eat during pregnancy can help or hurt the health of her offspring and that the nutrients they extract from food can trigger alterations in gene expression, especially during early development. But it has been less clear how, or even if, such epigenetic changes shape grandkids’ or even great-grandkids’ health. In Radford’s work a multigenerational ripple effect was apparently felt after pregnant mice were basically fed a starvation diet for six days late in pregnancy. During that time their standard mouse-chow meals were cut in half. That period of under nutrition coincided with when small collections of atoms, called methyl groups, would typically latch onto sperm DNA and lock genes in the “on” or “off” position in ways that stick with an organism throughout life.



Among male mice born to moms of the low-nutrition diet, their sperm was dotted with 10 to 30 percent fewer methyl group additions at specific locations on the DNA, perhaps resulting in less gene activity than would be normally expected. The authors say those changes in methyl group additions were likely the cause of diabetes-like symptoms in the mice. And even though the next generation of mice—the grandsons—did not have the same altered markers on their sperm, they were afflicted with the same health problems. Exactly why that happens remains a mystery. “We do not yet understand how they store this epigenetic information as they lose the [methyl group] changes that they received on fertilization,” Radford says. Her team says one explanation might be that some other form of epigenetic information is also being inherited or that perhaps these changes take place so early—when the embryo is just a few cells in size—that the effect is indelible even though the epigenetic “message” itself is lost. Other recent studies have identified on-off DNA changes influenced by parental diet across multiple generations, but some researchers say that the changes might be the result of traditional genetic inheritance rather than an epigenetic effect.



Radford’s study pinpointed 111 regions in the sperm DNA that experienced consistent losses in methyl groups across sons’ sperm. The work looked at male mice instead of female mice because it is easier to study mouse sperm and hunt for consistent markers on that DNA rather than explore the variety of ways a daughter mouse could theoretically be receiving such inheritance instructions, such as via their mitochondrial DNA.



Making the leap from how diet influences multiple generations of mice to its effect on humans is the next step. “We really have enough information now that this work needs to be taken to humans,” says Sarah Kimmins, Canada Research Chair in Epigenetics, Reproduction and Development. “What the father is exposed to, in terms of nutrition, has major ramifications for the health of his offspring—and it’s been a very understudied area,” she adds. “It’s just as critical to have a healthy father’s preconception as a healthy mother’s.”



Other factors could explain the new Science findings, cautions Timothy Bestor, professor of genetics and development at Columbia University. For one, he suggests that the researchers choice of mouse strain could have influenced the study results. Radford and colleagues did not study inbred mice because those mice had more trouble surviving the restrictive diet needed for the experiment. (Inbred mice are often studied because they are genetically homogenous across generations.) Instead, Radford studied more genetically diverse mice that could better survive the poor nutrition regime. In turn, the health issues seen in the second generation of mice (which were born free of the sperm DNA changes seen in the first generation of the mice) could be somehow genetically inherent to this mouse model, he suggests. The study authors, however, say they built in checks against that possibility, such as comparing the mice with control mice of the same breed.



For now, with limited data available, perhaps it is best for both moms and dads to hold off on unhealthy behaviors—at least until after their kids are born.



