Paternal sperm epigenetics may help explain early pregnancy loss

When a pregnancy ends early and unexplained, the search for answers usually begins with the mother. Lacey Luense, Ph.D., wants to know what the father's sperm might have to do with it.

Lacey Luense, Ph.D., an assistant professor in the Texas A&M Department of Animal Science, is studying the male role in early pregnancy loss. (Courtney Sacco/Texas A&M AgriLife)

Luense, an assistant professor in the Texas A&M College of Agriculture and Life Sciences Department of Animal Science, studies the causes of early pregnancy loss - a problem that cuts across species and carries both personal and economic costs.

She is working with cattle, where almost 50% of pregnancies are estimated to end prematurely, to study the root causes of human infertility, where over 50% of all conceptions are estimated not to result in birth.

"We know that maternal issues can be involved," Luense said. "Sometimes it can be a chromosomal abnormality, disease or problems with the uterine environment. But we don't know the causes of many pregnancy losses. It's unexplained, and we are still trying to figure out why this happens so frequently."

Luense, who also has an appointment with Texas A&M AgriLife Research, is joining forces with Ky Pohler, Ph.D., administrator for the Texas A&M AgriLife Animal Reproductive Biotechnology Center and associate professor, Department of Animal Science, on a $1.65 million National Institutes of Health grant to look at how paternal epigenetic contributions, or non-genetic changes to DNA, are delivered to the embryo.

Determining the male factor in unsuccessful pregnancies

Luense said one potential cause for pregnancy loss could be the male's sperm and epigenetics - or everything above and around the DNA sequence - that affect how the DNA is structured or packaged.

"We are talking about nongenetic changes that can alter how those genes are turned on or off," she said. "Our research is trying to understand how dad's epigenetics or the epigenetic changes carried by the sperm can affect fertility, pregnancy and then long-term health and development."

The overall goal is to understand the nongenetic changes to DNA that are delivered to cattle embryos. The team will use sperm from bulls of high and low fertility to investigate the role of the paternal epigenome in abnormal embryo development and pregnancy loss.

Texas A&M AgriLife research is trying to understand how the male epigenetics can affect fertility and pregnancy. (Laura McKenzie/Texas A&M AgriLife)

One focus is histones, the proteins that DNA wraps around like a spool and thread. Previous studies indicate males with abnormal sperm histones are more likely to have partners who experience pregnancy loss.

"However, we don't know why that happens," Luense said. "This is something we have been learning much about over the last decade or two. We know a clinical correlation exists, but we do not understand the reasons it occurs. Determining that is our challenge."

Cattle can answer questions humans cannot

Luense is determined to help with human pregnancy loss, but experimenting with human embryos is not an option. And, while she has also worked with mouse models, cattle offer something they couldn't: early embryonic development that more closely mirrors human embryo development, particularly in cell division and timing when genes from the new embryo activate.

Where discovery meets industry

Department of Animal Science faculty are asking questions with answers that reach far beyond agriculture - into human health and everyday life.

Her team will conduct different molecular and genomic analyses on the semen samples from the high- and low-performing bulls to try to understand their biomarkers and to identify changes in the sperm to predict pregnancy loss. 

Through in vitro fertilization, IVF, they will be able to generate embryos from bulls with specific changes to the sperm epigenome. These embryos will undergo time-lapse imaging and cutting-edge genomic analyses to determine if changes to sperm histones alter development and gene regulation. Performing such experiments in humans is not possible, making the use of cattle an exciting opportunity to further our understanding of human fertility and pregnancy, Luense said.

The new Animal Reproductive Biotechnology Center, which opened in 2025, will allow them to perform gene editing, including CRISPR/CAS 9, to advance knowledge about pregnancy loss and how treatments can be developed to solve the issue.

"We are trying to identify changes in gene expression that are happening very early in pre-implantation embryo development in cattle and how that might give us information about what is happening in humans," Luense said.

The goal of the research is to find ways to achieve a higher rate of live births and calves on the ground. (Michael Miller/Texas A&M AgriLife)

Biomarkers to predict, and someday prevent, pregnancy loss

Beyond the human health question, the findings could give cattle producers new tools to address a costly problem - roughly half of cattle pregnancies do not result in live births. Better prediction could mean real savings for the industry.

"We hope that, after five years, we will be able to identify biomarkers or alterations to sperm chromatin or sperm histones that may predict pregnancy loss in humans and cattle," Luense said. "If we know what to look for, maybe it can be treated. We are trying to understand the specific gene pathways regulated by sperm epigenetics occurring in the early embryo and are necessary for a healthy pregnancy and a live birth."

The results could impact reproductive efficiency and help clinical management of human patients and livestock diagnosed with infertility, poor embryogenesis and pregnancy loss, she said.