Changes to sperm's small RNA in the epididymis may help ensure mouse embryos implant

This week, Louise Brown, the first person born after conception by in vitro fertilization (IVF), celebrates her 40th birthday. Thanks to assisted reproductive technologies like IVF and intracytoplasmic sperm injection and to new techniques developed in laboratory animals, researchers are able to uncover new details about the processes of fertilization and reproduction in mammals. This research is providing insight into inheritance and the genetic and epigenetic contributions to offspring from both mother and father.

Two studies published in the journal Developmental Cell on July 26 provide new information about the contribution of males to their offspring. Both looked at small RNAs to determine how these molecules contribute to epigenetic changes in sperm in mice. Contributions of the mammalian females to their offspring are apparent -- starting from both nuclear and mitochondrial DNA as well as exposure to various factors during gestation, for example -- but much less is known about male contributions beyond the DNA found in sperm.

"The study of paternal contributions to development, including environmental contributions to the health of sperm, is a burgeoning field of research," says Oliver J. Rando, an investigator in biochemistry and molecular pharmacology at the University of Massachusetts Medical School and senior author of both papers. "In addition, 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."

In one study, led by postdoctoral fellow Upasna Sharma, the investigators looked at the small RNA dynamics that occur as sperm leave the testis and travel through the epididymis toward the vas deferens, a process that takes about two weeks. They found that the sperm underwent dramatic changes to their RNA payload during this time. They also confirmed that some of the RNA found in sperm originates in the paternal epididymis and is later transferred to sperm cells, a finding that provides evidence for soma-to-germline information transfer in mammals.

The second study looked at the functional implications of small RNAs in sperm -- that is, whether these small RNAs have any effect on sperm or the zygote. The team, led by first author Colin C. Conine, found that small RNAs in sperm are essential for normal preimplantation development. Specifically, they showed that sperm taken from early in the epididymis exhibited dramatic misregulation in a variety of RNA and other epigenetic regulators. When this sperm was used to fertilize eggs, the result was the embryo's failure to implant in the uterus efficiently. They also showed that these defects can be corrected by microinjecting small RNAs from the end of the epididymal pathway into the newly formed embryo.

Earlier studies from Rando's lab and others suggested that paternal environmental conditions can affect the health of their offspring and that 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.

The researchers plan to continue studying the role of small RNAs in reproduction and development. "This research is vitally important because of the increasing use of assisted reproduction," Rando says. "A substantial subset of embryos are created using fertilization with testicular sperm, which have dramatically different RNA contents from ejaculated sperm. Since we now show that even relatively subtle RNA differences between sperm from the beginning versus the end of the epididymis can seriously affect offspring, it's crucial to understand whether children born from testicular sperm will have any increased disease risks as they grow into the age of complex adult-onset disease."

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