A recent discovery by NIEHS researchers provides critical insights into one of the most common birth defects in males. Humphrey Yao, Ph.D., head of the institute’s Reproductive Developmental Biology Group, and his colleagues identified a previously unknown group of cells in mice that play a vital role in development of the urethra, the tube that carries urine and semen out of the body. This could help to explain the causes of hypospadias, a condition in males where the urethra does not form properly. The study was published online Dec. 6 in Science Advances.

Hypospadias affects about one in 150 boys and has been increasing over the past three decades, according to Yao. The condition can lead to serious issues later in life, including difficulty with urination and sexual intercourse. While hypospadias is typically corrected through surgery, the exact causes remain largely a mystery. Yao’s team has sought to understand how genetic and environmental factors can interact to influence this birth defect.

“We’re learning that there are unique cells essential to the process of urethral closure, and their disruption could lead to hypospadias,” he said. “This is an important insight because these cells are potentially sensitive to environmental exposures, particularly endocrine-disrupting chemicals [EDCs]. There is also some evidence that maternal heat exposure during pregnancy could negatively affect this cell population and pave the way for hypospadias.”

Migrating cells play key role

The newly identified cells, called NR5A1+ extragenital cells, are unique because they originate outside of the developing penis and migrate to it during a critical window of development. Once they arrive, these cells release chemical signals, including a molecule called neuregulin-1, that help to guide the urethra’s formation.

Using state-of-the-art tools like single-cell sequencing and genetic models, Yao’s team discovered that if these cells fail to migrate or function correctly, the urethra cannot close properly.

“This scenario can be likened to construction workers building a structure,” he said. “If some workers don’t show up or don’t perform their tasks well, the structure will be incomplete.”

Environmental influences

One takeaway from the study is that exposure to substances such as EDCs may interfere with the activity of the extragenital cells identified by the researchers, according to Yao. These chemicals can mimic or block hormones crucial for development.

“Our findings suggest that these extragenital cells are particularly vulnerable to disruptions during the early phase of pregnancy, a critical window for urethral formation,” he noted.

Preliminary data from his lab also points to maternal heat exposure as a potential risk factor. In experiments with mice, short-term exposure to elevated temperatures during pregnancy increased the likelihood of urethral defects in male offspring.

Opening door to innovation

By better understanding these extragenital cells, it may be possible for scientists to develop tools to screen for genetic mutations or exposures that increase risk of hypospadias. Also, the condition is currently treated through surgery, but Yao’s research could lead to new approaches.

“In the future, the biomedical community might be able to repair or replace damaged cells to prevent the condition altogether,” Yao said. “Our goal is to use the scientific knowledge generated from our studies to make a real difference for families.”