Scientists have discovered that tiny RNA molecules in sperm could hold the key to choosing the healthiest embryos and improving IVF outcomes, potentially transforming the future of fertility treatments.
Study: Small RNA in sperm–Paternal contributions to human embryo development. Image credit: Rohane Hamilton/Shutterstock.com
The male human gamete carries the haploid paternal genome and regulatory small RNA (sRNA) to the ovum. The involvement of sRNA in fertilization and embryonic development is unclear. A recent paper appeared in Nature Communications, exploring the contribution of sRNA to human fertility.
Introduction
With infertility rates soaring, one in six couples of reproductive age are now unable to have children without assisted reproduction technology (ART). These include procedures like in vitro fertilization (IVF), responsible for approximately 12 million births annually.
The success rate of IVF (live births per cycle) stands at about 30%, mainly because over 70% of treatment cycles result in mostly poor-quality embryos. The contribution of sperm-related genetic factors to IVF outcomes remains relatively unknown, prompting the current investigation.
Small RNAs are short molecules of RNA with lengths within a few hundred nucleotides. Subtypes of sRNA include:
- microRNA (miRNA), which regulates embryo formation
- tRNA-derived fragments (tsRNA)
- those derived from ribosomal RNA (rsRNA)
- mitochondrial-derived RNA (mitosRNA)
- those from ribonucleoprotein-associated RNA, such as Y-RNA and small nucleolar RNA.
These were independently analyzed to examine their role in IVF success.
About the study
The study included 69 couples undergoing IVF from November 2022 to June 2023 at a single ART center in Linköping, Sweden. The median age for men and women was 34 and 33 years, respectively, and the median body mass index (BMI) was 27 kg/m2 and 25 kg/m2, respectively.
Sperm concentration and progressive motility are two key parameters indicating semen quality. Here, the median for sperm concentration was 28 million sperm/mL, and progressive motility was 50%.
Sperm concentration
When comparing sperm samples with high (>16 million/mL) and low (<16 million/mL) sperm concentrations, about 1.9% of sRNAs were found to be more highly expressed in the high concentration group. In contrast, 2.1% were downregulated compared to the low concentration group.
MitosRNA made up 72% of the upregulated sRNA. In contrast, nearly half (48%) of the downregulated sRNA was ribonucleoprotein-associated sRNA, mainly Y-RNA.
Upregulated mitosRNA came from mitochondrial tRNA genes. In particular, the MT-TS1-Ser1 sRNA had an area under the curve (AUC) of 0.89, indicating its ability to differentiate high from low sperm concentration. Previous studies have associated these mitosRNA with nutrient sensing and metabolic programming, although their causal role in humans remains under investigation.
Downregulated sRNA mapped most significantly to Y-RNA with an AUC of 0.85. Both are therefore biomarkers capable of distinguishing sperm samples by high or low concentration
Progressive motility
When examining sRNA profiles in sperm samples with high vs low progressive motility ( ≥ 5 million progressively motile sperm), half of the differentially expressed sRNA overlapped with those associated with sperm concentration.
Fertilization rates
A further comparison of sRNA was made using samples that showed high and low fertilization rates (≥70% vs <70%, respectively). Here, 0.11% of sRNA was expressed at reduced levels in samples with low fertilization rates, whereas the other samples had no significant differential expression.
There were 34 sperm-associated sRNA sequences that predicted a low fertilization rate, all from a single region of the genome. However, these sequences only weakly predicted fertilization outcome (AUC 0.58), and the authors note that more data and further validation are required before these findings can be applied clinically.
Embryo quality
Finally, sperm samples were categorized as likely to produce high- vs low-quality embryos (≥20% vs <20%, respectively). The high-quality samples were associated with 60 upregulated sRNA (0.2%) vs 104 (0.4%) downregulated sRNA.
The most represented subtype was microRNA (miRNA), which predicted a higher-quality embryo. The miRNA was predicted to target multiple developmental processes involved in embryogenesis, development, or cell proliferation.
Of particular interest was hsa-let-7g expression, with an AUC of 0.8 after excluding one outlier. Preclinical studies have demonstrated that this gene family regulates growth in embryonic and postnatal life via insulin-mediated effects. The study notes, however, that a causal relationship between these miRNAs and human embryo quality is not established, and further functional studies are needed.
Conversely, higher levels of 28s rRNA in sperm were associated with the production of significantly fewer high-quality embryos.
Thus, different sRNA was increased or decreased with specific sperm sample parameters, forming unique RNA profiles linked to each parameter: sperm concentration, fertilization, and embryo quality. The miRNA carried by sperm appears to influence embryo development and predict embryo quality heavily.
In mice, sperm-borne miRNA is crucial for preimplantation embryonic development. Whether this is also true in humans remains unclear, and functional studies will be required to answer this question.
Additionally, the study briefly explores whether sperm sRNA profiles correlated with live birth, gestational age, or newborn size for gestational age. Some associations were observed, but these results were preliminary and based on small numbers, so further research is needed to confirm the clinical significance.
The authors acknowledge that separating the influence of paternal sRNA from maternal factors, such as age and BMI, is challenging, and that larger cohorts and functional studies are necessary to validate these biomarkers before they can be used in clinical settings.
Conclusions
“Sperm-borne sRNA are biomarkers for sperm concentration and embryo quality in IVF. Our work highlights the paternal role in IVF success and establishes a foundation for a new era in reproductive medicine.”
These results could help distinguish high from poor embryo quality, potentially promoting cost-effectiveness in IVF and reducing the number of cycles required to achieve the desired outcomes. However, further research and clinical validation are needed before these findings can be implemented in routine practice.
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