Dec. 16 (UPI) -- One out of every eight American couples has trouble conceiving -- nearly 25 percent of them because of male infertility.
Now, researchers at the University of Pennsylvania may have discovered the cause of at least some of these problems and perhaps clues on how to correct it. Their findings were published Monday in the journal Developmental Cell.
"For men who have unexplained infertility, everything may look normal at the doctor: normal semen counts, normal motility. Yet they can still have problems conceiving," co-author Lacey J. Luense, a research associate at the Penn Epigenetics Institute, said in a statement.
Healthy sperm shed 90 to 95 percent of proteins called histones and replace them with protamines, or smaller proteins that allow sperm to store DNA prior to fertilization. Recently, research has linked male infertility with defective sperm that fail to "evict" these histones from DNA during development, according to Luense. However, to date, just how and why this happens has remained unclear.
"One explanation for persistent problems is histones being in the wrong location, which may affect sperm and then early development," Luense said.
For this study, the researchers, led by Shelley L. Berger, director of the Penn Epigenetics Institute, used genome-wide DNA sequencing tools and created a mouse model with a mutated version of a gene called Gcn5. The gene is involved in the histone eviction process, which allowed researchers to track defects in sperm from the early stages of development through fertilization using a technology known as ATAC-sequencing.
In the lab mice, ATAC-sequencing enabled the authors to monitor waves of histones at unique sites across the genome during the early and late stages of sperm development and identify parts of the genome that retained the sperm histones. Overall, the authors found, the mouse models created with the mutated Gcn5 gene had very low fertility.
The researchers also demonstrated that retained histones in normal mouse sperm correlated with histone positions in very young embryos, supporting the theory that paternal histones transfer epigenetic information to the next generation.
With this knowledge, future research may be able to develop treatments for male infertility that target these areas of the genome.
"Right now, the burden of IVF and other assisted-reproductive technologies fall on women. Even if it's the male factor, it's still women who have to go through hormone injections and procedures," Berger said. "Now imagine being able to apply epigenetic therapeutics to change the levels of histones and protamines in males before embryogenesis? That's one of the questions we want to explore and this model will allow us to move toward that direction."
There are already epigenetic drugs available that are used to treat cancer and other diseases, the authors said. Now, treating sperm with these drugs to increase histone eviction is one potential route to explore.
"There are a lot different factors that can alter the sperm epigenome: diet, drugs, alcohol, for example," Luense said. "We are just now starting to understand how that can affect the child and affect development. These initial, basic studies that we are doing are critical, so we can better understand what's driving these epigenetic mutations."
