A father’s way of life before conception could shape his future children in ways that researchers are only starting to uncover.
A recent study reports that obesity in men may alter minute sperm molecules known as microRNAs. These changes could affect the way their sons handle sugar and accumulate fat in later life.
Scientists at the University of Southern Denmark, working with international partners, found indications that a father’s weight and diet before having children may have lasting effects on the metabolism of those children.
Fathers may transmit obesity risks
Scientists have long recognised that obesity frequently occurs within families, although genetics alone cannot account for the pattern.
Previous research, including studies of the Dutch Hunger Winter and Sweden’s Överkalix area, has indicated that diet could influence later generations through mechanisms beyond genes.
The researchers set out to establish how a father’s pre-conception diet might affect his child. Sperm cells, and the tiny molecules they contain, may provide the explanation.
Testing fathers’ diets
The researchers examined this theory in mice. One set of male mice was fed a healthy, low-fat diet, whereas a second set received a high-fat diet and became obese.
A third set of mice was made obese, then moved onto a healthy diet and lost weight before mating.
Each male mouse was subsequently mated with a healthy female, while every offspring was brought up in identical healthy conditions. This enabled the researchers to isolate the effects of the father’s health history.
Initially, every offspring appeared healthy.
Healthy sons show hidden problems
The first generation of offspring had roughly the same body weight, irrespective of their father. More detailed assessments, however, identified substantial differences.
Male offspring of obese fathers had poorer glucose regulation and lower insulin sensitivity. They also had larger fat cells in their adipose tissue and sharply elevated leptin levels, all of which are associated with metabolic dysfunction.
“We monitored the development of the offspring [of obese males] for six months and noticed that, although the animals showed no changes in weight, their metabolism was compromised as if they were obese,” said Jan Wilhelm Kornfeld, who coordinated the study.
Milder effects in females
The effects in female offspring were less severe.
“In the case of females, we also noticed a tendency [toward metabolic dysfunction], but it wasn’t as pronounced as in males,” said Kornfeld.
“It’s like in humans: women are metabolically more resilient.”
One finding was especially striking. Offspring whose fathers had lost weight before conception had much healthier metabolic profiles. This indicated that the harmful signal could be reversed.
Fat tissue shows damage
The researchers then investigated the processes occurring within the offspring’s cells.
They used mass spectrometry to analyse proteins in fat tissue. Their findings suggested extensive disruption to mitochondria, the cell structures that generate energy.
Proteins associated with oxidative phosphorylation, ATP production and the electron transport chain were lower in both obese fathers and their sons.
Notably, the inherited effects seemed most pronounced in fat tissue. Although liver tissue from obese fathers displayed obesity-related alterations, these changes were not passed to offspring in the same manner.
This pointed to fat tissue as a key site of inherited metabolic disruption.
Tiny sperm molecules carry signals
The team next looked for the molecular mechanism responsible for these effects.
They concentrated on microRNAs: small strands of genetic material that help control protein production within cells.
Certain microRNAs promote mitochondrial health, but these useful molecules were reduced in obese mice and in their offspring.
Meanwhile, a different microRNA family, called let 7, increased markedly. Let 7d and let 7e levels rose in the fat tissue of obese fathers, were detected in their sperm cells, and subsequently appeared in the fat tissue of their sons.
The same molecular pattern was passed from father to child.
Recreating the disease
To determine whether let 7 itself caused the inherited effects, the researchers carried out a decisive experiment.
They injected fertilised eggs from healthy mice with very small quantities of let 7d or let 7e. A separate group was given an inactive control molecule.
The embryos developed as normal and produced pups that looked healthy. In adulthood, however, these mice developed the same metabolic problems observed in offspring of obese fathers.
They had difficulty controlling glucose, developed insulin resistance and had reduced mitochondrial function in fat tissue.
Let 7 molecules alone could reproduce the inherited condition.
Changes begin after fertilisation
The team also investigated when these effects first emerged during development.
They allowed the injected embryos to divide to the eight-cell stage before examining their RNA activity.
At this exceptionally early stage, embryos exposed to let 7 already had altered gene activity connected with mitochondrial energy production.
The inherited signal therefore started to affect development almost as soon as fertilisation occurred.
A clear biological pathway
Additional experiments revealed another significant part of the process.
Let 7 molecules directly suppressed a protein called DICER1, an enzyme that processes other microRNAs.
As DICER1 levels fell, mitochondrial regulation became weaker and energy production decreased.
The researchers confirmed that lowering DICER1 on its own reduced oxygen consumption in fat cells.
The biological sequence was then clearer: obesity raised let-7 levels, which lowered DICER1 expression. Reduced DICER1 subsequently impaired mitochondrial function.
Scientists still seek answers
One important mystery nevertheless remains.
Marcelo Mori, a collaborator on the study, is a researcher at the State University of Campinas in Brazil.
“Something we still need to discover is how these microRNAs [let-7] also increase in sperm and where they come from,” said Mori.
“It’s possible that they’re transferred from adipose tissue to the reproductive cell, as suggestive evidence indicates, but that remains an open question.”
Earlier work by Mori found that exercise and other healthy lifestyle measures can raise DICER expression, with the potential to improve metabolic health.
Human sperm shows same pattern
Research in mice often prompts questions about whether the same biology operates in humans. To explore this, the scientists partnered with a Danish fertility clinic that followed obese men taking part in weight-loss programmes.
They measured let 7 levels in semen samples collected before and after weight loss.
The results mirrored the mouse findings. As the men lost weight, their levels of let 7d and let 7e declined.
“The results show that the more weight the individual lost, the lower their let-7 levels in semen,” Mori said.
These findings indicate that human sperm may carry comparable obesity-related metabolic signals.
Weight loss may reverse risks
The study’s most encouraging result may be that these effects do not appear to be permanent.
In both mice and humans, the harmful molecular signals fell after weight loss.
A father’s health before conception may therefore affect his future children, but these biological messages may also be altered.
Parents’ health shapes future children
“Everything indicates that it’s less advantageous to have children when stressed or infected, when too many or too few calories are being eaten, or when facing any other health issue,” Kornfeld said.
“Children conceived under unbalanced conditions tend to be less healthy.”
The study describes a form of inheritance that is considerably more dynamic than scientists once believed. Tiny molecules within sperm seem able to transfer information about a father’s lifestyle to the next generation.
Unlike DNA mutations, however, these signals may still be rewritten before conception takes place.
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