If Hollywood has taught us anything, it’s that a road trip during our younger years can leave enduring memories that influence our adult lives. Now, a “blockbuster” study reveals that environmental pressures during maturation in the epididymis endow spermatozoa with “epigenetic” memories that influence offspring health via the intergenerational epigenetic inheritance of tRNAs.
Researchers “driven” by Raffaele Teperino (Helmholtz Zentrum München) knew that spermatozoa transfer small non-coding RNAs (sncRNAs) to oocytes to influence offspring/adult phenotypes. They sought to explore if environmental cues impacted sncRNAs in spermatozoa maturing in the epididymis and induce intergenerational effects by implementing exposure to a two-week high-fat diet (HFD) in male mice after the first wave of spermatogenesis and during sperm maturation in the epididymis. Their findings report that the intergenerational epigenetic inheritance of environmentally sensitive sperm-borne mitochondrial tRNAs and their fragments significantly impacts offspring metabolism.
Let’s hear more from Tomar, Gomez-Velazquez, Gerlini, and Colleagues on how an epididymal road trip endows spermatozoa with mitochondrial tRNAs as epigenetic memories:
- Paternal preconceptional exposure to an HFD induces glucose intolerance and insulin resistance in male offspring
- Epididymal spermatozoa (but not germ cells developing in the testis) display sensitivity to HFD through dynamic alterations to mitochondrial tRNAs and their fragments
- Of note, human spermatozoan mitochondrial tRNA fragments correlate with body mass index, while an overweight father at conception doubles obesity risk and compromises metabolic health in offspring
- Sperm sncRNA sequencing in mice carrying mutations in mitochondria-associated genes and metabolic phenotyping of wild-type offspring suggest that upregulated mitochondrial tRNA fragments lie downstream of mitochondrial dysfunction
- Single-embryo transcriptomics of two-cell embryos demonstrate the existence of sperm-to-oocyte transfer of mitochondrial tRNAs at fertilization, which may play a significant role in controlling transcription in the early-embryo
- Early two-cell embryos display significantly altered transcription of genes essential for oxidative metabolism, which can predispose to adult-onset glucose intolerance
- Overall, the data support a model in which acute HFD induces mitochondrial dysfunction in tissues and spermatozoa
- Upregulated mitochondrial DNA transcription as a compensatory mechanism prompts the accumulation of mitochondrial tRNAs and their fragments, which undergo intergenerational epigenetic inheritance and contribute to the modification of transcription in early embryos and glucose metabolism in adult offspring
Overall, this epic epigenetic road trip through the epididymis suggests that paternal health impacts the mitochondrial tRNA profiles of maturing spermatozoa, which results in intergenerational epigenetic inheritance that significantly influences offspring health following father-to-offspring transfer during fertilization.
“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,” says senior author Raffaele Teperino. “This can reduce the risk of diseases like obesity and diabetes in children.”
For more details on how mitochondrial tRNAs function as epigenetic memories of sperm’s epididymal road trip, see Nature, June 2024.