Paternal plaque attack: The hidden heart risk fathers pass to daughters

RIVERSIDE, Calif. — Recent scientific research has uncovered a surprising connection between a father’s diet and his daughter’s risk of heart disease. A study conducted by researchers at the University of California-Riverside has shown that male mice consuming a high-cholesterol diet can significantly increase the risk of cardiovascular disease in their female offspring, even when those offspring maintain a healthy diet throughout their lives.

Cardiovascular disease (CVD) is the leading cause of death globally, encompassing a range of disorders affecting the heart and blood vessels. In the United States alone, heart disease claimed the lives of nearly 703,000 people in 2022, accounting for one in every five deaths. While many factors contributing to CVD risk are well-known, this study sheds light on a previously unexplored aspect: the role of a father’s diet on their child’s health.

The research, published in the journal JCI Insight, focused on atherosclerosis, a chronic inflammatory condition that is the primary cause of CVD. Atherosclerosis occurs when plaque, composed of cholesterol, fat, and other substances, accumulates in artery walls, narrowing them and restricting blood flow to vital organs.

To investigate the impact of paternal diet on offspring heart health, the research team, led by Changcheng Zhou, a professor of biomedical sciences at UC Riverside, used mice lacking the LDL receptor (LDLR-deficient mice). These mice are prone to developing high cholesterol and atherosclerosis, making them an ideal model for studying heart disease.

Male LDLR-deficient mice were fed either a normal diet or a high-cholesterol diet for eight weeks before mating with females on a normal diet. The resulting offspring were then raised on a normal diet and examined for signs of atherosclerosis at 19 weeks of age.

The results were striking: female offspring of fathers who had consumed a high-cholesterol diet developed significantly larger arterial plaques compared to those whose fathers ate a normal diet. Surprisingly, male offspring showed no such difference, indicating that the effect is sex-specific.

To understand the mechanism behind this intergenerational effect, the researchers examined gene expression in the inner lining of the arteries (the intima) of the offspring. They discovered that female offspring of high-cholesterol diet fathers had increased expression of genes associated with inflammation and immune responses – key factors in the development of atherosclerosis.

Two proteins, CCN1 and CCN2, were found to be particularly elevated in the arterial plaques of female offspring from high-cholesterol diet fathers. These proteins can promote inflammation and the accumulation of immune cells in artery walls, potentially explaining the increased plaque formation.

The study also investigated how information about a father’s diet might be passed on to his offspring. Using an advanced sequencing technique called PANDORA-Seq, developed at UC Riverside, the researchers examined small RNA molecules in the fathers’ sperm. They found that a high-cholesterol diet altered the profile of these small RNAs, which can influence gene expression.

“It had been previously thought that sperm contribute only their genome during fertilization,” Zhou says in a media release. “However, recent studies by us and others have demonstrated that environmental exposures, including unhealthy diet, environmental toxicants, and stress, can alter the RNA in sperm to mediate intergenerational inheritance.”

This altered RNA profile could potentially carry information about the father’s diet to the embryo, influencing how genes are expressed during development and into adulthood. This represents a form of “epigenetic inheritance” – where environmental factors can influence traits passed on to offspring without changing the DNA sequence itself.

The implications of this study are significant, suggesting that a man’s diet in the months before conception could have a lasting impact on his daughters’ heart health, even if those daughters maintain a healthy lifestyle themselves.

“Men who plan to have children should consider eating a healthy, low-cholesterol diet and reducing their own CVD risk factors. These factors appear to affect their sperm in influencing the health of their female offspring,” Zhou notes.

While this research was conducted in mice, and more studies are needed to confirm whether the same effects occur in humans, it opens up new avenues for research into the prevention of heart disease. It also emphasizes the complex interplay between diet, genetics, and health across generations, highlighting the importance of preconception health for both parents.