Sperm bring more than DNA to the party. They also pick up RNA on their way through the epididymis, a duct situated between the testis and the vas deferens. This RNA, it turns out, influences gene regulation in developing embryos, helping them implant in the uterus more efficiently.

These findings, which emerged from a pair of studies appearing in the journal Developmental Cell, add to our knowledge about the paternal environment’s effects on fertility and reproduction. To date, most studies have focused on contributions of mammalian females to their offspring, both genetic and epigenetic. Male contributions beyond DNA have received less attention.

The current studies come from a research team led by Oliver J. Rando, M.D., Ph.D., professor, biochemistry and molecular pharmacology at the University of Massachusetts Medical School. With these studies, Dr. Rando and colleagues hope to improve our understanding of how a man's lifestyle and exposure to potentially hazardous elements—such as stress and toxins—can affect the levels and types of small RNA in the sperm.

“It's vital to look at the differences between sperm removed directly from the testicles and ejaculated sperm,” notes Dr. Rando, “to investigate whether these differences may have an impact on the long-term health of the offspring.”

In the first of the two studies (“Small RNAs Are Trafficked from the Epididymis to Developing Mammalian Sperm”), Dr. Rando’s team looked at what happens to small RNAs when sperm mature in the epididymis, a process that takes about two weeks. Researchers found that the sperm underwent dramatic changes to their RNA “payload” during this time.

“By characterizing small RNA dynamics during germ cell maturation in mice, we confirm and extend prior observations that sperm undergo a dramatic switch in the RNA payload from piRNAs to tRNA fragments (tRFs) upon exiting the testis and entering the epididymis,” the article’s authors wrote. “Tissue-specific metabolic labeling of RNAs in intact mice definitively shows that mature sperm carry RNAs that were originally synthesized in the epididymal epithelium.”

In the second study (“Small RNAs Gained during Epididymal Transit of Sperm Are Essential for Embryonic Development in Mice”), the investigators looked at the functional implications of small RNAs in sperm and whether these small RNAs have any effect on sperm or the fertilized egg. They found that small RNAs in sperm are essential for normal pre-implantation development.

“We generated zygotes via intracytoplasmic sperm injection (ICSI) using sperm obtained from the proximal (caput) versus distal (cauda) epididymis and then characterized the development of the resulting embryos,” the article indicated. “Embryos generated using caput sperm significantly overexpress multiple regulatory factors throughout preimplantation development, subsequently implant inefficiently, and fail soon after implantation.”

The investigators found that they could reverse the defects in gene regulation by injecting small RNAs from the end of the epidydimal pathway into the newly formed embryo.

“Remarkably, microinjection of purified cauda-specific small RNAs into caput-derived embryos not only completely rescued preimplantation molecular defects but also suppressed the post-implantation embryonic lethality phenotype,” the authors detailed. “These findings reveal an essential role for small RNA remodeling during post-testicular maturation of mammalian sperm and identify a specific preimplantation gene expression program responsive to sperm-delivered microRNAs.”

Commenting on the studies, Dr. Rando points out that the study of paternal contributions to development, including environmental contributions to the health of sperm, is a burgeoning field of research. “In addition,” he continues, “because of the rise in the use of assisted reproduction, it's also vital to look at the differences between sperm removed directly from the testicles and ejaculated sperm, to investigate whether these differences may have an impact on the long-term health of the offspring.”

The researchers plan to continue studying the role of small RNAs in reproduction and development. “A substantial subset of embryos are created using fertilization with testicular sperm, which have subtly different RNA contents from ejaculated sperm,” emphasizes Dr. Rando. “Since we now show that even relatively subtle RNA differences between sperm from the beginning versus the end of the epididymis can impact offspring it will be interesting to explore these effects of sperm used in assisted reproduction.”

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