Umbilical cord proteins may explain lifelong health effects of low birth weight

Researchers have long sought to discover why babies who weigh less than expected at birth, a condition known as small for gestational age, or SGA, are at higher risk for heart, lung and metabolic diseases as adults.

Now, using blood samples collected over decades, a team led by University of Arizona researchers may have identified an explanation. The scientists found that a group of proteins involved in neuronal development was overrepresented in the umbilical cord blood of about one-third of babies born SGA. The researchers also found that higher levels of these proteins were associated with poorer lung function in adulthood.

The results, reported in Nature Communications, provide new insights into the origins of chronic disease and identify promising targets for future studies examining how lower birth weight affects organ development and function.

"Low birth weight is one of the most important risk factors for the development of chronic diseases," said Dr. Fernando Martinez, director of the Asthma and Airway Disease Research Center, Regents Professor and Swift-McNear Professor of Pediatrics in the College of Medicine – Tucson, and a member of the BIO5 Institute.

"We've known about an association between lower birth weight and smaller lungs, as well as later lung dysfunction, but we don't understand the biological mechanism behind the effect," Martinez said, noting evidence from studies led by co-author Dr. Stefano Guerra, professor of medicine and The Henry E. Dahlberg Chair in Asthma Research, and colleagues. "These children frequently have underdeveloped organs and can have cardiovascular and metabolic issues. We wondered if there was a factor we could detect in the blood in early life that could explain these effects on different organs."

Martinez's team used data from the Children's Allergy and Asthma Data Repository, or CADRE, consortium, which contains information on babies from multiple studies across the United States who have been followed from birth to adulthood since the 1980s.

CADRE researchers, including Martinez, collected blood samples every five years and measured lung function. A subset of babies who were born SGA showed deficits in lung function by age 40.

The Arizona-led team analyzed stored umbilical cord blood samples from babies born SGA and compared them with samples from babies with average birth weight in five U.S. cities, representing a range of geographic environments and genetic backgrounds.

The researchers found increased levels of axon guidance proteins in approximately one-third of babies born SGA in every city studied. Axon guidance proteins help direct developing neuron protrusions called axons, which carry nerve signals, to their correct targets. The proteins also play a role in branching morphogenesis, a developmental process involved in forming the lungs and the vascular system, and possibly other organs.

It was surprising that we saw this in one-third of the babies in every cohort. We thought that this might be very different in different cohorts and environments, especially with different socioeconomic factors."

Anthony Bosco, co-author, associate professor of immunobiology, College of Medicine – Tucson

As the children aged into their 40s, the researchers found an inverse relationship between blood levels of axon guidance proteins and lung function: The higher the concentration of the proteins, the poorer the lung function.

To gather additional evidence for the proteins' role in lung development, the researchers examined genome-wide association studies, or GWAS, for genetic variants associated with axon guidance proteins. Those analyses identified variations in axon guidance genes that linked to differences in lung development and function.

In a third study using a sheep model, the scientists employed a technique called single cell sequencing to show that axon guidance genes were expressed in the brain, heart, and lung during fetal development in low- and normal-birth-weight animals.

"We have results from three studies providing a unified hypothesis to explain how low birth weight affects multiple organs through the axon guidance pathway and increases risk for multiple diseases," Bosco said.

"The mystery is, why do these chronic heart, lung and metabolic conditions often cluster together?" Martinez said. "Since the axon guidance mechanism is so important in the development of lungs and possibly all organs, we're proposing that a dysregulation in the system probably affects many body functions."

The researchers plan to study these genes and pathways in much more detail, particularly as potential therapeutic targets.

"This could be a fundamental biological system that may impact all body systems," Martinez said. "We're excited about the possibilities."

Other co-authors from the College of Medicine – Tucson include the following researchers from the Asthma and Airway Research Center: James F. Read, data analyst; Debra A. Stern, director, analytical applications; Dr. Tara F. Carr, professor of medicine and otolaryngology; Amber L. Spangenberg, research specialist, principal; and Dr. Wayne J. Morgan, professor of pediatrics.

Co-authors from the U of A School of Animal and Comparative Biomedical Sciences include: Rosa I. Luna-Ramirez, postdoctoral research associate; and Sean W. Limesand, professor, animal and comparative biomedical sciences. Meiven Yang, student worker, Department of Immunobiology, also was a co-author.