MaWhether and how parents’ lifestyle choices before pregnancy affect their children’s health remains a mystery. Previous studies on metabolic diseases such as type 2 diabetes have shown that Father’s Meal and Small RNA from sperm It affects disease susceptibility in offspring, but the mechanism by which this occurs remains unclear.1,2 “Most of these complex diseases suffer from missing heritability, where predicted genetic predisposition doesn’t actually match observed heritability.” Raffaele TeperinoHelmholtz, a physiologist and pharmacologist at Munich who studies susceptibility to metabolic diseases, said: “There must be a significant component in the pathogenesis that cannot be explained by genetic predisposition alone.”
Teperino is studying pathways of epigenetic inheritance via sperm to bridge the knowledge gap between genetic predisposition and the actual heritability of metabolic diseases. NatureHe and his team investigated the effects of paternal diet on the sperm transcriptome and metabolism of offspring in mice and humans.3 The team found that mature epididymal sperm, but not developing germ cells, are sensitive to diet-induced changes in mitochondrial tRNA (mt-tRNA), revealing that sperm mt-tRNA is an epigenetic regulator that influences the metabolism of offspring. The team also found a similar relationship between paternal weight gain and changes in sperm RNA in humans.
Sperm harbor a complex, environmentally sensitive pool of small noncoding RNAs (sncRNAs), including mt-tRNA and its fragments (mt-tsRNAs). A small human study in 2019 showed that exposure to an acute high-carbohydrate diet rapidly increased mt-tsRNAs in sperm, prompting Teperino to look at these RNA species as first responders to metabolic stress.1 He and his team fed mice a short-term high-fat diet before profiling changes in sperm RNA expression and investigating the health of their offspring. They found that an acute high-fat diet caused mitochondrial dysfunction in male mice and impaired glucose tolerance and homeostasis in their male offspring who were fed a normally-fed diet.
“I was interested in, ‘What is the mechanism? How does this happen?'” he says. Upasna Sharma“This study shows that it’s mitochondrial stress or dysfunction that’s changing a small RNA in sperm, which could then affect the next generation and phenotype. I think that’s an intriguing connection,” said Michelle Schneider, a developmental biologist at the University of California, Santa Cruz, who studies transgenerational inheritance and the effects of environmental stress on gamete epigenomes, but was not involved in the study.
Teperino and his team also used single-embryo transcriptomics, using hybrid two-cell embryos from genetically distinct maternal and paternal mouse strains, to observe mt-tRNA and epigenetic regulation in early embryos, demonstrating for the first time the transfer of non-genetic material from sperm to oocytes. “By using strains with these two different genetic backgrounds, they were able to show that sperm mitochondrial tRNAs are delivered to the oocyte at fertilization, further strengthening the current model that sperm small RNAs change in response to the environment,” Sharma said. “They are delivered to the embryo, possibly altering gene expression and development in the early embryo, resulting in phenotypic changes.”
The missing piece of the puzzle was linking these mouse mechanisms to humans. Teperino and his team profiled sperm sncRNAs from young, healthy Finnish volunteers who were metabolically phenotyped and stratified by body mass index (BMI) and fat mass. They found that mt-tRNAs were the only type of small RNA that positively correlated with BMI. In a separate human dataset, the researchers also identified an association between higher paternal weight at conception and poorer metabolic health in their offspring.
The study confirms the influence of paternal lifestyle on the metabolic health of offspring, shows that mt-tRNA is a diet-inducible, sperm-mediated epigenetic regulator, and demonstrates that non-genetic information is transferred from fathers to offspring at the time of fertilization. Tepelino’s team also observed that sperm sncRNA levels and offspring glucose tolerance were comparable after mice fed a low-fat diet and mice fed a high-fat diet were returned to a normal diet, highlighting the importance of this modifiable mechanism. “This is a fully reversible mechanism, and in a sense, there is actually hope that if we modify the paternal lifestyle before fertilization, we can modify the phenotype of the offspring,” Tepelino said. “We found an additional risk factor, but this is a risk factor, not a determining factor.”
