“You are what you eat.”
We’ve all heard that one. What we eat can affect our growth, life span and whether we develop disease. These days, we know that we also are what our mother eats. Or rather, what our mothers ate while we were in the womb. But are we also what our father eats? A new study shows that in mice, a dietary deficiency in dad can be a big downer for baby.
The dietary staple in the study was folic acid, or folate. Folate is one of the B vitamins and is found in dark leafy greens (eat your kale!) and has even been added to some foods like cereals. It is particularly essential to get in the diet because we cannot synthesize it on our own. And it plays roles in DNA repair and DNA synthesis, as well as methylation of DNA. It’s particularly important during development. Without adequate folate, developing fetuses are prone to neural tube disorders, such as spina bifida.
Some of the neural tube disorders caused by folate deficiency could result from breaks in the DNA itself. But folic acid is also important in the epigenome. Epigenetics is a mechanism that allows cells to change how genes are used without changing the genes themselves. Instead of altering the DNA itself, epigenetic alterations put chemical “marks” or “notes” —methyl or acetyl groups — on the DNA and the proteins associated with it. The marks can either make a gene more accessible (acetylation) or less accessible (methylation), making it more or less likely to be made into a protein. This means that each cell type can have a different epigenome, allowing a neuron to function differently than a muscle cell, even though they contain the same DNA.
Folate affects DNA synthesis, but it can also affect DNA methylation. In fact, DNA methylation requires the presence of folate. So low folate could affect whether genes are turned off or on and by how much. In a developing fetus, that could contribute to developmental problems.
Luckily, taking prenatal vitamins loaded with folic acid greatly reduces a woman’s chances that her developing baby will have these defects. But most of the time we think of folate as a “woman thing.” It turns out, though, that folate matters in men as well. And it doesn’t just matter to men, it matters to their offspring. We are what our father eats.
To look at how deficiencies in folate in fathers might affect offspring, Romain Lambrot and colleagues at McGill University in Quebec, Canada, mated a male mouse with two females. One female was on a normal diet with normal levels of folic acid (two milligrams per kilogram per day). The other was on a diet with very low folate (0.3 milligrams per kilogram per day). Both gave birth to pups, and the male pups from the low-folate female continued on a low-folate diet all the way through adulthood. Then the low-folate males were mated with a female who had normal levels of folic acid in her diet.
Lambrot and colleagues found that folate-deficient fathers themselves had delays in their first production of sperm. When the sperm caught up in growth, they looked normal and swam normally. But the sperm from low-folate fathers had a lot more DNA breaks in it. And when the folate-deficient fathers were mated, they were less fertile than their high-folate counterparts. Males raised on a normal folate diet produced pregnancies with an 85 percent success rate, while males on a low folate diet only had a 52 percent success rate. The mothers mated with low-folate dads also had increased loss of fetuses during pregnancy, the researchers report December 10 in Nature Communications.
When the pups were born, the problems continued. Low-folate fathers sired pups with a 27 percent chance of developmental abnormalities, ranging from facial abnormalities to hydrocephalus. Fathers with normal levels of folate during development only had a 3 percent rate of developmental abnormalities, most of which were more minor, like a runt in a litter.
What was the cause? The authors hypothesized that the low folate levels the fathers experienced during their lives altered the epigenome of their sperm. Studies are finding that changes to the epigenome can have big effects on development and behavior. And epigenetic changes can come from the environment, your diet and the many things going on in your daily life.
But the epigenome of sperm is a more complex phenomenon than the epigenome of other cells in the body. When sperm are being formed, many of the epigenetic marks are stripped away, only to be regained, somehow, later on. Sperm do still end up with an epigenetic pattern, but how well the epigenome is really stripped and what causes it to reform (and in what pattern) has not been established.
Lambrot and colleageus compared the sperm epigenomes of the control and folate-deficient mice. They found that 57 different regions had different methylation patterns in folate-deficient mice. Some of them had decreased methylation while others showed increased methylation. In the offspring of folate-deficient mice, two of these regions translated to changes in gene expression in the placenta of the fetus.
So daddy’s low folate diet could affect offspring, as well as whether mommy takes her folate. But does this have relevance in people in modern times? After all, because folate is in leafy greens and in many fortified foods, is any well-nourished dad going to be deficient in folate? The authors believe so. They note that increasing obesity can reduce folic acid levels. But while folate deficiency in fathers might explain some small percentage of birth defects, the levels of folic acid in humans are unlikely to be as low as it was in the mice in the study. The mice were fed a low-folate diet throughout their entire life spans, including during fetal development. In developed countries, folate levels would not remain so low for so long. And transient folic acid deficiency in your diet won’t cause too many long term problems; the body is capable of storing some amount of folic acid for use in an emergency.
It will be interesting to see what role epigenetics plays. After all, the sperm from folate-deficient mice did have a lot more DNA breaks in them. Those alone might account for some of the problems in the offspring, independent of epigenetic changes. But for now, it’s interesting to note, if this translates to humans, that dad’s diet could matter when producing kids. It’s no longer just “what mom can do” when eating right for two.