Male reproductive health and intergenerational metabolic responses from a small RNA perspective

Abstract

The world has recently experienced a decline in male reproductive (e.g. sperm counts and motility) and metabolic (e.g. obesity and diabetes) health. Accumulated evidence from animal models also shows that the metabolic health of the father may influence the metabolic health in his offspring. Vectors for such paternal intergenerational metabolic responses (IGMRs) involve small noncoding RNAs (sncRNAs) that often increase in spermatozoa during the last days of maturation in the epididymis. We and others have shown that the metabolic state – depending on factors such as diet, obesity and physical exercise – may affect sperm quality and sperm sncRNA. Together, this suggests that there are overlapping aetiologies between the male metabolic syndrome, male factor infertility and intergenerational responses. In this review, we present a theoretical framework for an overlap of these aetiologies by exploring the advances in our understanding of the roles of sncRNA in spermatogenesis and offspring development. A special focus will lie on novel findings about tRNA‐derived small RNA (tsRNA), rRNA‐derived small RNA (rsRNA) and small mitochondrial RNA (mitoRNA), and their emerging roles in intergenerational metabolic and reproductive health.

5’XP sRNA-seq: Efficient Identification of Transcripts With and Without 5’ Phosphorylation Reveals Evolutionary Conserved Small RNA

“…Like rRFs, tRNA derived sRNA (tRFs) can also originate from the 5’ or 3’ terminal. In addition, internal (i’) fragments, which neither start nor end in the terminals of full-length tRNA have been described [26, 27]. We used these classifications as an independent confirmation of the differences in 5’ and 3’ affinities between the 5P- and 5X-type libraries that we observed in sRNA derived from rRNA.…”

tRNA Biology in the Pathogenesis of Diabetes: Role of Genetic and Environmental Factors

“…The impact of nutrients or other environmental insults on the function of the tRNA-modifying enzymes TRMT10A or CDK5RAP1 remains to be investigated [73,97]. The deleterious effect of 5 -tRNA Gln fragments generated in TRMT10A-deficient pancreatic β-cells [53], as well as the high fat feeding-induced tRHs that contribute to the nongenetic inheritance of metabolic traits [30,55,213,215] highlight the importance of tRNA fragmentation on cell functionality. The molecular mechanisms associating these tRNA fragments with insulin resistance and β-cell dysfunction are still largely unknown.…”

“…Intergenerational inheritance in humans is difficult to study experimentally. There is increasing evidence, however, that diet affects both male fertility and offspring predisposition to metabolic diseases (reviewed and summarized in Natt et al [213]). RNA sequencing showed that tRHs are the most frequent type of small RNA in human sperm [206,214].…”

Aging Induces Profound Changes in sncRNA in Rat Sperm and these Changes are Modified by Perinatal Exposure to Environmental Flame Retardant

“…The role of sncRNA in spermatogenesis was reviewed in a recent paper (Natt, Ost, 2020). Composition of different sncRNAs changes dynamically throughout spermatogenesis cycle (74 days in humans, 56 days in rat (Creasy, 1997)) (Sharma, U. et al, 2016.…”