middleThere is some mystery as to whether and how parents’ lifestyles before pregnancy can affect their children’s health. Previous research on metabolic diseases such as type 2 diabetes suggests that: Paternal diet and sperm-derived small RNA It affects the disease susceptibility of offspring, but the mechanism is still unclear.1,2 “Most of these complex diseases are caused by a lack of heritability. There is a predicted genetic predisposition that does not actually match the observed heritability,” he said. Raffaele TeferinoHelmholtz, physiologist and pharmacologist at Munich, studies susceptibility to metabolic diseases. “There must be a huge component of pathogenesis that cannot be explained by genetic predisposition alone.”
Teperino explores sperm-mediated epigenetic inheritance pathways to bridge the knowledge gap between genetic predisposition and actual metabolic disease heritability. In a recent paper natureHe and his research team investigated the effects of paternal diet on the sperm transcriptome and offspring metabolism in mice and humans.3 They found that mature epididymal sperm, although not germ cells, were sensitive to diet-induced changes in mitochondrial tRNA (mt-tRNA), revealing that sperm mt-tRNA is an epigenetic regulator that influences offspring metabolism. The team also found a similar association between high paternal body weight and sperm RNA changes in humans.
Sperm harbors a complex and environmentally sensitive pool of small noncoding RNAs (sncRNAs), including mt-tRNA and its fragments (mt-tsRNA). In 2019, a small human study found that exposure to an acute high-sugar diet rapidly increased mt-tsRNA in sperm, giving Teferino a hint that these RNA species could be the 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 examining the health of their offspring. They found that an acute high-fat diet induced mitochondrial dysfunction in male mice, impairing glucose tolerance and homeostasis in male offspring that were fed normally.
“I was interested in, ‘What is the mechanism? How does all this happen?’” he said. Upasna SharmaA developmental biologist at the University of California, Santa Cruz, who studies the effects of transgenerational inheritance and environmental stress on the genetic makeup of germ cells and was not involved in the study, says: “Here they show that what changes small RNAs in sperm is mitochondrial stress or dysfunction, and that can potentially affect the next generation and phenotype. I think that’s an interesting connection.”
Teferino and his team also used hybrid two-cell embryos from genetically different maternal and paternal mouse strains to observe mt-tRNA and epigenetic regulation in the early embryo via single-embryo transcriptomes, demonstrating for the first time sperm-egg transfer of non-genetic material. “Using these two different genetic background strains, we were able to show that sperm mitochondrial tRNAs are transferred to the egg at fertilization, which further solidifies the model that we now have, that it is sperm small RNAs that change in response to the environment,” Sharma said. “These can then be transferred to the embryo and alter early embryonic gene expression and development, resulting in altered phenotypes.”
The missing piece of the puzzle was connecting 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-tRNA was the only type of small RNA that was positively associated with BMI. In a separate human data set, the researchers also confirmed an association between high paternal body weight at conception and impaired offspring metabolic health.
This study supports the influence of paternal lifestyle on offspring metabolic health, shows that mt-tRNA is a diet-induced and sperm-mediated epigenetic regulator, and demonstrates that non-genetic information is passed from father to offspring at conception. Teperino’s team also observed that sperm sncRNA levels and offspring glucose tolerance were similar after mice fed low- and high-fat diets were returned to normal diet, highlighting the importance of this modifiable mechanism. “This is a completely reversible mechanism, which leaves some hope that correcting paternal lifestyle before conception might also correct the offspring phenotype,” Teperino said. “We have found an additional risk factor, but it is a risk factor, not a determinant.”
