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Body and mind

A father’s overweight can influence his children’s risk of disease

Epigenetics plays a major role in a child’s risk of developing such diseases as obesity, type 2 diabetes, schizophrenia and autism. Danish research suggests that, if a father has an unhealthy lifestyle before a child is conceived, the epigenetics not only affects the father but may also affect the unborn child.

Obesity and unhealthy lifestyles can be passed from one generation to the next without any relation to childrearing. This concept is called epigenetics: molecular biological changes to genes that silence some genes and activate others.

Epigenetics plays a major role in conceiving and developing an embryo. For example, an egg cannot be fertilized with the cell nuclei from two females or two males, even though they are genetically compatible and could theoretically be the basis for developing an embryo. Instead, the cell nuclei from a male and a female need to be spliced to result in a fertilized egg. The reason is that epigenetics is gender specific, so even if the genes are compatible, the tiny molecular biological changes to the genes are not.

The latest research shows that epigenetics plays an alarmingly important role in developing an embryo – for both animals and humans. If a mother or father is obese, epigenetic changes can mean that their children will be predisposed to becoming obese even if they eat a normal diet. A child’s risk of developing various lifestyle-related diseases also increases, and thus a father’s unhealthy lifestyle at the time a child is conceived may affect a child for the rest of his or her life.

“Our research on the link between epigenetics and embryonic development focuses on understanding how various environmental factors, including food, exercise and obesity, influence embryonic development and a child’s subsequent health,” explains Romain Barrès, Professor, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.

Romain Barrès and his colleagues have published many scientific articles on this topic, including a review article in Ugeskrift for Læger, the journal of the Danish Medical Association.

Fat rats produce fat offspring

The researchers from the Foundation’s Center for Basic Metabolic Research carried out one study involving rats fed a high-fat diet to make them obese. The hypothesis was that such a diet would alter the epigenetics of the reproductive cells, resulting in changes to their offspring.

The researchers fed male rats a high-fat diet for 8 weeks and then mated them with female rats that had been fed a normal diet. The males and females only had contact when they mated and were otherwise separated.

After the females gave birth, the researchers examined the offspring and compared them with the offspring of male rats that had not been fed a high-fat diet. What they discovered was that the young rats with overweight fathers metabolized glucose less efficiently than did the young rats with slim fathers. Inefficient glucose utilization is associated with developing obesity and is also a marker for developing type 2 diabetes.

The researchers speculated that the high-fat diet had triggered several epigenetic changes in the sperm cells of the male rats, which was also confirmed when they examined the rats’ sperm.

“We found several epigenetic differences between the males fed a high-fat diet and those fed a normal diet. This proved that a father’s diet can alter the health of his offspring and suggested that epigenetic changes in sperm cells may cause these changes,” explains Romain Barrès.

Epigenetic changes to the genes regulating appetite and brain development

To support their findings, the researchers compared the epigenetic profiles of obese men with those of slim men. They discovered major differences in the epigenetic profile of the sperm cells.

In addition, the researchers discovered that the epigenetic changes occurred especially in the genes that regulate brain development and appetite.

“There were therefore good reasons to think that, if overweight influences the epigenetics of genes regulating appetite in sperm cells, then the children of overweight adults could have an altered regulation of appetite, for example, feeling more hungry,” says Romain Barrès.

Epigenetics of sperm cells changes after weight loss surgery

The key question for the researchers then was whether making environmental changes can also alter epigenetics.

To examine this, the researchers collected the sperm from obese men who were scheduled to undergo gastric bypass surgery, which involves making a pouch at the top of the stomach so a person cannot eat as much before they feel full. The researchers collected sperm samples before and 1 year after the operation, when the trial participants had lost an average of 40 kg.

When the researchers compared the sperm samples, they again found epigenetic changes to the genes that regulate appetite and brain development.

“Several environmental factors clearly change the epigenetics of sperm cells. So far, we have not determined whether the epigenetic risk factors inherited by the next generation result from epigenetic changes in sperm cells from diet, overweight, exercise or other factors,” explains Romain Barrès.

Exercise changes the epigenetics of genes regulating appetite and brain development

In a third study, the researchers examined how a 6-week training programme to improve fitness would influence the epigenetics of sperm cells of healthy young men.

The men were initially relatively unfit when they began and improved their aerobic capacity by 20%. In addition, the researchers again found epigenetic changes to the genes that regulate appetite and brain development.

“Why everything you do can change your epigenetics remains mysterious to us. Determining how manipulating epigenetics affects humans is not easy, but we are working to figure this out,” says Romain Barrès.

Too early to offer dietary and exercise advice to future fathers

Realistically, does this mean that men should exercise, live healthily and lose weight before they try to conceive a child? According to Romain Barrès, the answer is both yes and no.

Romain Barrès first explains that there is no harm in telling men that at least they should be aware that not only a woman’s health at conception influences the child’s risk of developing disease or becoming obese. Men also need to take care of themselves before they start to have children.

“The idea that men only need to deliver sperm cells no longer applies. Men also pass on epigenetics that is influenced by how they live their lives,” says Romain Barrès.

Nevertheless, the researchers cannot yet make recommendations in this field because the research still points in many different directions. For example, several animal experiments have shown that exercising before conception in males is associated with offspring predisposed with a risk of developing obesity.

“Exercise is a type of stress on the body, and the epigenetic changes may signal to the unborn embryo that it will have to store energy as much as possible to adapt to the increased needs, and this may upregulate the expression of genes that are responsible for appetite and for storing fat in the body. Too much exercise may therefore have counterproductive effects in the next generation,” explains Romain Barrès.

Parents’ overweight may be linked to a child’s risk of autism

The link between epigenetic changes to the genes that regulate brain development and a father being overweight at conception is an extremely interesting discovery in its own right.

For example, the children of obese fathers have a 73% greater risk of being autistic.

Researchers from New York have studied the of sperm cells of the fathers of autistic children and discovered epigenetic changes to the genes that regulate both appetite and brain development.

“What is interesting is that the genes the New York researchers discovered when they examined the fathers of autistic children are 80% similar to the genes we have discovered. We therefore hypothesized that an unhealthy diet may result in epigenetic changes to sperm cells that may predispose a child to having an increased appetite and a higher risk of being autistic,” says Romain Barrès.

Assisted reproduction may cause epigenetic changes

Finally, the researchers explain that these epigenetic changes that can result in various problems for children do not just apply to natural fertilization.

In assisted reproduction, the father and mother’s reproductive cells are often exposed to many media containing both nutrients and vitamins, and this may also alter the epigenetics.

In addition, children conceived by assisted reproduction technology have an increased risk of several diseases, including cardiovascular diseases.

“Although assisted reproduction technology has enabled many couples to fulfil their dreams of becoming parents, emerging research in epigenetics suggests that this assisted reproduction technology should be constantly improved to minimize the risks for the next generation,” concludes Romain Barrès.

The importance of sperm epigenetics for conception and embryology” has been published in Ugeskrift for Læger, the journal of the Danish Medical Association. The last listed author of the article, Romain Barrès, is employed at the Novo Nordisk Foundation Center for Basic Metabolic Research.

Romain Barrès
Professor
Physical traits are set by a complex interaction between genes and environment. Our cells not only contain genetic (DNA) but also an additional, epigenetic information which allows for genes to be differentially expressed in time and space. For example, although the DNA code is similar in the brain and the heart these two organs exert dramatically different shapes and function. We and others have showed that environmental factors such as diet or physical activity could remodel epigenetic information in metabolic tissues, suggesting epigenetic information to be at the interface between our genes and our environment. We have provided evidence that environmental factors could influence the predisposition to Diabetes of male offspring, suggesting epigenetic information can be also remodelled in reproductive cells. The interest of my laboratory is to investigate the mechanisms by which environmental factors induce epigenetic modifications, thus predisposing or protecting from Diabetes. We aim to address these fascinating questions: "How much our free-will alters the way our genes are expressed and do we transmit our environmentally attributes to our offspring?".