Fathers use multiple mechanisms to pass information to the next generation, including a pool of small noncoding RNAs (sncRNAs) that are sensitive to environmental changes. However, it has been unclear whether spermatozoa in the epididymis are susceptible to environmental cues.

Now, researchers have examined the impact of paternal diet on children’s health—specifically, the influence of diet before conception. They used “two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health.”

The researchers focused on mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) and found that these RNAs play a key role in the inheritance of health traits by regulating gene expression. In doing so, they showed that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment.

This mitochondrial DNA (mt-DNA) produces proteins in the mitochondria via the intermediate mt-RNA and is typically inherited from mothers to offspring. Previously, it was assumed that fathers had no part in the genetic makeup of their offspring’s mitochondria. However, recent studies like this one show that sperm carry fragments of mt-RNA (mt-tsRNA) into the egg during fertilization. The mt-tsRNAs play a role in epigenetics, regulating gene expression in the early embryo: they can indirectly influence the development and health of the offspring by modifying the activity of certain genes in the mitochondria. Thus, fathers have an important, albeit indirect, influence on the genetic imprinting of mitochondria and thereby on the energy metabolism of their children.

This work is published in Nature in the paper, “Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

For their study, the researchers used data from the LIFE Child cohort, which includes information from over 3,000 families. The analyses showed that the father’s body weight influences the weight of the children and their susceptibility to metabolic diseases. This influence exists independently from other factors such as the mother’s weight, parental genetics, or environmental conditions.

In humans, the authors wrote, “mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health.”

The researchers also fed mice a high-fat diet. This had effects on the reproductive organs of the animals, including the epididymis—the area in the male reproductive system where freshly formed sperm mature.

“Our study shows that sperm exposed to a high-fat diet in the mouse epididymis led to offspring with an increased tendency to metabolic diseases,” said Raffaele Teperino, PhD, principal investigator in the Environmental Epigenetics Group at the Institute of Experimental Genetics at Helmholtz Munich.

Further, the authors noted that sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction.

When sperm from mice that had been exposed to a high-fat diet was used to create embryos through in vitro fertilization, they found mt-tsRNAs from these sperm in early embryos, significantly influencing gene expression. This, in turn, affects the development and health of the offspring.

More specifically, they noted that “single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription.”

“Our hypothesis that acquired phenotypes over the course of life, such as diabetes and obesity, are transmitted via epigenetic mechanisms across generations, is reinforced by this study. Here, epigenetics serves as a molecular link between the environment and the genome, even across generational boundaries. This occurs not only through the maternal line but, as our research results indicate, also through the paternal line,” explained Martin Hrabě de Angelis, PhD, research director at Helmholtz Munich.

The findings underline the role of paternal health before conception—and offer new approaches to preventive health care: “Our results suggest that preventive health care for men wishing to become fathers should receive more attention and that programs should be developed for this purpose, especially with regard to diet,” said Teperino. “This can reduce the risk of diseases like obesity and diabetes in children.”

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