A study led by the University of California, Riverside highlights that men with a poor, high-cholesterol diet can elevate the risk of cardiovascular disease (CVD) in their daughters when they become fathers.
The findings, which appeared in the journal JCI Insight, are the first to reveal this effect specifically in female offspring.
CVD, the primary cause of mortality worldwide, encompasses various disorders impacting the heart and blood vessels. High blood pressure, or hypertension, is a key risk factor for CVD. In 2022, around 703,000 individuals in the U.S. succumbed to heart disease, accounting for one in every five deaths.
“It was previously assumed that sperm only brings their genetic material during fertilization,” stated Changcheng Zhou, a biomedical sciences professor in the School of Medicine and the lead author of the study. “However, recent research, including ours, indicates that environmental factors—such as poor diet, toxins in the environment, and stress—can modify the RNA in sperm, affecting inheritance across generations.”
Ribonucleic acid, or RNA, exists in every living cell and is vital for numerous biological functions in organisms and viruses, sharing structural traits with DNA.
“Men looking to become parents should adopt a nutritious, low-cholesterol diet and work on lowering their own risk factors for CVD,” Zhou advised. “These elements seem to influence the sperm, which in turn affects the health of their female offspring. Our research implies that this information gets passed down to the next generation.”
The investigation concentrated on atherosclerosis, a long-term inflammatory condition that is the primary cause of CVD. In this condition, plaque—a thick substance composed of cholesterol, fat, and various materials in the bloodstream—accumulates within arterial walls. As the plaque hardens, it narrows the arteries, restricting blood flow and oxygen supply to essential tissues.
Sperm carries numerous small non-coding RNA molecules crucial for gene regulation as well as many cellular functions. When modified, these molecules significantly alter their roles across different biological processes. The researchers discovered that the small RNA molecules in the sperm of mice on a high-cholesterol diet exhibited changes due to dietary exposure. Additionally, these modified small RNA molecules could alter early gene expression in mouse embryonic stem cells.
Zhou noted that most research typically centers on maternal influences regarding offspring health, while the effects of paternal exposures have been largely neglected.
“Studying how parental exposures affect chronic disease development in their children is complex as these experiments are time-intensive and require meticulous planning and resources,” he mentioned.
The researchers are uncertain why only female offspring showed an increased risk of CVD. In their experiments, male genetically altered mice were given a high-cholesterol diet, leading to hyperlipidemia, a condition that can potentially lead to heart disease and stroke if untreated. These male mice were then bred with female mice consuming a standard, low-cholesterol diet, and their litter was also provided with a low-cholesterol diet. The female offspring displayed a 2-3 fold increase in atherosclerosis.
“Our study enhances the understanding of chronic disease origins from parental exposures,” Zhou commented. “We aspire that our results will inspire further research into how paternal exposures influence cardiovascular health in humans.”
Co-authors of the study include Rebecca Hernandez, Xiuchun Li, Junchao Shi, and Tejasvi R. Dave from UCR; Tong Zhou from the University of Nevada, Reno; and Qi Chen from the University of Utah, Salt Lake City.
This research received funding from grants to Zhou from the National Institutes of Health (NIH), while Hernandez benefitted from a predoctoral fellowship from the American Heart Association. Dave received support through a UCR mini-grant intended for undergraduate research and creative endeavors.
The PANDORA-seq method, developed at UCR, was utilized by the researchers to analyze sperm small RNA.
