There's more and more evidence that men's lifestyle and environment long before they have kids can affect their future children's health. Now, a Canadian-led study has shed some light on how and why that effect occurs.
It's another critical piece of information that says we really need to start looking at fathers' pre-conception health - Sarah Kimmins, McGill University
When the researchers changed signals on proteins called histones in the sperm of male mice, their offspring and even their grandchildren had increased birth defects, mortality and stunted growth, they reported in the journal Science. The signals that were changed are the type of signals that are affected by environmental factors such as food, drugs and stress in both mice and humans.
"We didn't expect these lasting effects across generations from changing a protein in one generation," said Sarah Kimmins, an associate professor of reproductive biology at Montreal's McGill University, the senior author of the study.
"It's a completely non-DNA based transmission of this abnormal development."
While efforts to prevent birth defects are mainly focused on mothers and their health before conception and during pregnancy, Kimmins says the new discovery emphasizes that what's transmitted in the father's sperm is also essential to the health and development of the offspring.
"It's another critical piece of information that says we really need to start looking at fathers' pre-conception health," she said. "And that's a message that's really missed in society."
Kimmins said there are two main kinds of evidence that have shown that men's (and other male mammals') environment before conception affects their offsprings' health:
- Epidemiological studies that link things such as a father's smoking and diet with their children's and grandchildren's health, growth and risk of health problems such as cardiovascular disease.
- Lab studies in animals making a direct link between a father's diet, stress and exposure to drugs or toxic substances with their offsprings' health.
"What we don't understand is how that information is transmitted from the father across generations," Kimmins added.
It's well-known that fathers pass on DNA and genes to their offspring, but those genes and DNA don't change much except for rare mutations.
More recently, scientists have started looking at signals called methylation that attach to the DNA to turn genes up or down. Those signals are part of the "epigenome" – a system that affects the way genes are expressed.
Kimmins and her team decided to look at histones because they're also part of the epigenome and they're found in sperm in tiny amounts. They act like spools that DNA wraps around, and they organize the DNA, opening it up to make genes available to make proteins, or closing the DNA to stop genes from working. They also help direct other proteins involved in gene regulation.
Most interestingly, new research had shown that histones are associated with DNA involved in development of both mice and humans during pregnancy.
Kimmins and her team created transgenic mice with a faulty gene that caused unusual methylation in the histone proteins in their sperm.
They found that the offspring of those mice were far more likely to die shortly after birth or have birth defects such as limb, skeletal and facial deformities. Many others also had skin problems or stunted growth.
The problems even extended to the grandchildren of the transgenic mice, even if they and their parents didn't inherit the faulty gene, showing this wasn't a genetic effect involving DNA, but could still be passed down through generations.
While a gene was originally responsible for changes to the epigenome in this case, the same kinds of changes are known to be caused by environmental factors such as stress and diet.
Kimmins is confident the same effects would be seen in humans as mice because humans have very similar histone proteins in their sperm that interact with the same genes in the same places.
Kimmins and her colleagues are now trying to determine whether they can observe epigenetic changes in the sperm of humans – a group of men in Toronto and a group of men in Africa – linked with their diet and their exposure to substances such as alcohol.