Paternity uses multiple mechanisms to transmit information to the next generation, including a pool of small noncoding RNAs (sncRNAs) that are sensitive to environmental changes, but whether epididymal sperm are sensitive to environmental cues was unknown.
Now, the researchers are investigating the impact of fathers’ diet on their children’s health, specifically the impact of dietary habits before pregnancy. They “used two different paradigms, an acute pre-pregnancy high-fat diet, to analyze the contribution of the epididymis and testis to sperm sncRNA pools and child health.”
The researchers focused on mitochondrial tRNA (mt-tRNA) and its fragments (mt-tsRNA) and found that these RNAs play an important role in the inheritance of health traits by regulating gene expression, demonstrating that epididymal sperm are sensitive to the environment, whereas developing germ cells are not.
This mitochondrial DNA (mt-DNA) produces proteins in mitochondria via intermediate mt-RNA and is usually passed from mother to offspring. Previously, it was thought that fathers had no role in the genetic makeup of their offspring’s mitochondria. However, recent studies such as this one have shown that sperm carry a fragment of mt-RNA (mt-tsRNA) to the egg during fertilization. mt-tsRNA plays a role in epigenetics, controlling gene expression in the early embryo. By modifying the activity of certain genes in the mitochondria, they can indirectly affect the development and health of their offspring. Thus, fathers have an indirect but important influence on mitochondrial genetic imprinting and, therefore, on the energy metabolism of their children.
This work Nature The paper is titled “Diet-induced and sperm-mediated epigenetic inheritance of mitochondrial RNA.”
For their study, the researchers used data from the LIFE Child cohort, which contains information from more than 3,000 families. Their analysis showed that father’s weight influences children’s weight and susceptibility to metabolic diseases. This effect exists independently of other factors such as mother’s weight, parental genetics, and environmental conditions.
In humans, “sperm mt-tsRNA correlates with body mass index, and paternal overweight at the time of conception doubles the risk of obesity and impaired metabolic health in offspring,” the authors write.
The researchers also fed the mice a high-fat diet, which affected the animals’ reproductive organs, including the epididymis, the site of the male reproductive system where newly formed sperm mature.
“Our study shows that sperm exposed to a high-fat diet in the epididymis of mice produce offspring with an increased tendency towards metabolic diseases,” said Dr Raffaele Teperino, lead researcher in the Environmental Epigenetics Group at the Helmholtz Institute of Experimental Genetics in Munich.
Furthermore, the authors noted that sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function and metabolic phenotyping of their wild-type offspring suggested that upregulation of mt-tsRNA is downstream of mitochondrial dysfunction.
When sperm from mice fed a high-fat diet were used to create embryos through in vitro fertilization, the researchers found that mt-tsRNA from these sperm had profound effects on gene expression in early embryos, with implications for the development and health of the offspring.
More specifically, the researchers noted that “single-embryo transcriptomics of genetically hybridized two-cell embryos demonstrated that mt-tRNA is transferred from sperm to oocytes during fertilization, suggesting that it may be involved in regulating transcription in the early embryo.”
“Our hypothesis that phenotypes acquired during life, such as diabetes or obesity, can be transmitted across generations via epigenetic mechanisms has been strengthened by this study. Here, epigenetics acts as a molecular link between the environment and the genome, even across generational boundaries. This does not only occur maternalally, but also paternally, as our results show,” explained Dr. Martin Flave de Angelis, research director at Helmholtz Munich.
The findings highlight the role of paternal health before pregnancy and suggest a new approach to preventive medicine. “Our findings suggest that more attention should be paid to preventive medicine for men who want to become fathers and that programs for this purpose should be developed, especially with regard to diet,” said Teperino. “This could help reduce the risk of diseases such as obesity and diabetes in children.”
