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DAD'S DIET SHAPES FUTURE: THE ROLE OF SMALL NON-CODING RNAs IN SPERM AND OFFSPRING METABOLIC HEALTH

 

Mendelian inheritance is not the only route to transfer the traits from the father to the offspring, an alternative route is an intricate, vital, and environment-sensitive pool of sncRNAs (small non-coding RNAs) that are present in mature spermatozoa (sperm) which is delivered to the oocytes at the fertilization stage influencing the embryonic development and adult phenotypes. Small non-coding RNAs including miRNAs (MicroRNA), piRNAs (Piwi-interacting RNA), and siRNAs (Small interfering RNA) play a critical role in regulating gene expression, maintenance of genomic integrity, epigenetic modifications, and response to environmental stressors.


Spermatogonial stem cell, producing mature haploid spermatozoa is a two-step process including spermatogenesis in the seminiferous tubules and the maturation in the epididymis. Spermatogenesis is a convoluted process divided into 3 stages: mitosis (Spermatogonial Phase), meiosis (Spermatocyte Phase), and spermatogenesis (Spermatid Maturation). Initially, the stem cells divide through mitosis, forming two types of diploid (2n): Type A spermatogonia and Type B spermatogonia. Type A acts as the restoration stern cell, and Type B enters the next phase. Type B spermatogonia grow and differentiate into primary spermatocytes, each undergoing Meiosis I (haploid, n) and forming secondary spermatocytes that undergo Meiosis II (n) to produce two spermatids, resulting in four spermatids. These spermatids undergo morphological changes like the formation of the Acrosome, Mitochondrial Sheath, Condensation of the nucleus, and development of Flagellum to become mature spermatozoa. This process all happens in 64 to 72 days in humans. The spermatogenesis phase accounts for all the environmental susceptibility of the sperm epigenome.

The currently accepted model states that the sperm sncRNA pool is altered when entering the epididymal transit with the contribution of epididymal epithelial cells. This modification is due to the environmental factors that act on the epididymal during the maturation stage. Even the blood-testis barrier cannot stop these modifications that are targeted to spermatogenesis despite creating intergenerational, impact the next generation of offspring and transgenerational consequences which lead to stable epigenetic modifications that lead to passing down the changes to consecutive generations. However, it is not completely clear how the spermatozoa in the epididymis are directly susceptible to environmental factors.


Considering the intergenerational consequences, a study has been published with the identification of the relationship between the spermatozoa’s sncRNAs and its susceptibility to environmental factors focusing on diet in Nature titled “Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs”.


In the study, the intergenerational sequel was studied through paternal overweight and attempts were made to identify the relative contribution to testicular and epididymal exposure. The research was done on male mice and previous research has been done on mice with high fat-weight exposure. However, previous studies used various durations, 6 to 22 weeks and starting ages of 4 to 9 weeks for high-fat diet (HFD) exposure in male mice. So the previous studies overlooked the timing of spermatogenesis and only combined the effects of the testis and epididymis making it not convincing to conclude how or when environmental factors affect the sperm epigenome. 


So in this study, male mice were exposed to HFD for two weeks starting at six weeks of age, particularly the timing as the first wave of spermatogenesis completes by this and the sperm undergo maturation in the epididymis. The HFD exposure has led to partial glucose intolerance and insulin resistance in the male offspring. Notably, the exposure to HFD didn't affect the developing germ cells in the testis, so the process of spermatogenesis itself didn't contribute to the intergenerational metabolic effects. Another interesting finding is the study found that mitochondrial-encoded transfer RNAs (mt-tRNAs) and their fragments (mt-tsRNAs) levels are regulated by exposure to HFD. However, these changes in levels of mt-tRNAs were found only in the post-spermatogenesis, during sperm maturation on epididymal. 


Through research done two decades ago, researchers have discovered that certain mRNAs (protamin 2 and clusterin) have been transferred from sperm to oocytes during fertilization. However, they didn't study the direct impact of intergenerational transfer of sperm but showed that changes in these RNAs can impact the early embryos. So in this study, with the help of single-embryo transcriptomics, they found mt-tRNAs in the embryo stating that even when the composition of the RNAs changes due to exposure of HFD, the mt-tRNAs are transferred from sperm to oocytes at the fertilization. The mechanism of this accumulation has been given as the exposure to HFD causes mitochondrial dysfunction in somatic tissues and spermatozoa. This dysfunction upregulates the mtDNA transcription resulting in the accumulation of mitochondrial small non-coding RNAs (mt-sncRNAs) and their fragments (mt-tsRNAs) in the sperm which are passed on to the offspring. These inherited RNAs contribute to the alternative transcription in the early embryos in turn affecting glucose metabolism and other metabolic processes in the adult offspring.


Typically, fertilized oocytes eliminate sperm mitochondria to prevent the transmission of paternal mitochondrial DNA. The study showed that exposure to HFD-induced changes in mt-tRNAs and mt-tsRNAs in sperm which are epigenetically inherited and can modify gene expression in early embryos concluding that mt-RNAs and their fragments are diet-induced. However, the study suggests that mitochondrial signals from the father can still influence the offspring by transferring mt-tRNAs, which are not eliminated and thus can affect the embryo's development. Paternal health particularly the father's diet and metabolic status has a bigger impact on the epigenetic effects on the offspring’s health. 


REFERENCE


Tomar, A., Gomez-Velazquez, M., Gerlini, R., Comas-Armangué, G., Makharadze, L., Kolbe, T., Boersma, A., Dahlhoff, M., Burgstaller, J. P., Lassi, M., Darr, J., Toppari, J., Virtanen, H., Kühnapfel, A., Scholz, M., Landgraf, K., Kiess, W., Vogel, M., Gailus-Durner, V., . . . Teperino, R. (2024). Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs. Nature. https://doi.org/10.1038/s41586-024-07472-3


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