Scientists are learning that health is the function of genes and environment. The work of Milwaukee-based researchers suggests that this principle also applies to the health of a growing fetus and a premature infant.

Michael Laiosa, assistant professor at the University of Wisconsin-Milwaukee School of Public Health, and neonatologist Venkatesh Sampath, an assistant professor of pediatrics at the Medical College of Wisconsin, want to understand how genetics and the environment affect the health of humans during the most vulnerable stages of development.

In Milwaukee, there were 807 infant and fetal deaths between 2005 and 2008, according to the city's Fetal Infant Mortality Review. A disproportionate number were African-American. Of the 499 who were not stillborn, nearly 54% died from complications of being born too soon.

During gestation and early in life, infants reach developmental milestones at a rapid pace. But in the presence of a dysfunctional gene, toxic exposures, or a combination of both, development is prone to error.

According to Sampath, who is collaborating with colleague Ronald Hines, professor of pharmacology and toxicology at the Medical College, some premature babies may be more susceptible to necrotizing enterocolitis, or NEC, a leading cause of mortality and disability in very low birth-weight preterm infants weighing less than 3½ pounds.

What causes this disease is unknown, but doctors believe that an underdeveloped immune system or intestinal lining may leave a preterm infant's bowel vulnerable to infection or injury. What results is severe inflammation, which can lead to a deadly infection. Between 25% and 40% of babies afflicted with NEC die.

In their recent study published in the Journal of Surgical Research, Sampath and Hines detected a variant of a gene called NFKB1, differing slightly from the normal form, which is involved in mounting an immune response. Investigators said premature infants with a genetic variant may be at higher risk for developing the potentially fatal NEC.

In the study of 270 very low birth-weight preterm infants, investigators reported that of the 15 infants diagnosed with NEC, all had at least one copy of the defective gene and were disproportionately African-American.

"African-American infants run a higher risk of NEC," Sampath said of the study findings.

The defective gene turned up in 65% of infants not diagnosed with NEC, suggesting that other factors are involved in the onset of the disease. Sampath said it may be the presence of a particular bacteria, poor blood flow to the intestines, or another malfunctioning gene.

Infants with NEC experience pain, according to Sampath. "It's a nasty disease," he said.

Sampath added that those infants who survive a severe case of NEC are at greater risk for developmental delays and cerebral palsy.

Jackie Sevallius, supervisor of the newborn intensive care center at Wheaton Franciscan-St. Joseph hospital in Milwaukee, cares for infants with NEC and said signs of pain in a preterm infant are often subtle and manifest as changes in blood pressure, heart rate, breathing and color.

Very low birth-weight babies unable to muster a cry will express their pain through a facial grimace, said Sevallius.

Whether the variant gene can be used as a marker of NEC susceptibility in preterm infants is not yet clear.

"At this stage, it is preliminary, which means it needs to be addressed in a large amount of patients before we can tell for sure. It is worth further digging," Sampath said.

David Hackam, professor of surgery at the University of Pittsburgh School of Medicine, said Sampath's studies may one day offer doctors a way to screen premature infants for increased risk for NEC. Early screening could lead to earlier diagnosis and treatment, he said. Current treatments include changes in feeding, antibiotics and surgery. "These studies make a strong case for further genetic studies to understand this complex and devastating disorder," Hackam said.

Sampath said he hopes to explore whether this genetic variant can be used to predict other diseases of prematurity.

Developmental origins

How the outside world leaves its imprint on a growing fetus and potentially affects health later in life is an emerging field of research. A pregnant woman's lifestyle choices, nutrition, exposure to toxicants - and even stress - may modify when and how genes are expressed during the course of fetal development.

Laiosa said he has been intrigued by how the environment, in particular, affects health since he was a child living along the Hudson River - a place that has historically been plagued by a class of persistent pollutants called PCBs.

"I was interested in understanding how even small amounts of these chemicals might make people sick," said Laiosa. "So, you might say, I was a product of my environment."

Laiosa's work in collaboration with Calvin Williams, professor of pediatrics at the Medical College of Wisconsin, focuses on how ubiquitous environmental toxicants such as the dioxin TCDD may target the development of the fetal immune system and predispose children and adults to allergies and asthma later in life.

According to the Centers for Disease Control and Prevention, asthma disproportionately affects urban areas with high levels of poverty and large minority populations.

In Wisconsin, hospital admission rates for African-Americans suffering asthma were five times higher than for whites, based on state Department of Health Services findings between 2004 and 2009. Children exhibit the highest rate of asthma hospitalizations in the state, with 21.6 per 10,000 hospitalized in 2009, according to the state health department report.

How toxicants might disrupt development in the womb involves epigenetic programming, which Laiosa compared to the software that runs a computer.

"The genome, or DNA which you inherit from your parents, is the computer hard drive and is pretty stable for the life of the machine," he said. "Just as a computer virus messes with the software and slows some programs down, the environment can change how the DNA code is read, potentially affecting susceptibility to disease later in life."

Laiosa said that epigenetic programming provides a plausible explanation for how environmental factors such as chemicals, stress, nutrition or pathogens interact with genes during development and cause childhood or adult-onset diseases.

Laiosa uses pregnant mice as a model to understand the types of toxicants and the timing of exposures required for immune system alterations leading to diseases like asthma.

His instrument of choice is a flow cytometer, which distinguishes and then separates specific cell types from a mixed population of immune cells. Laiosa said he monitors how stem cell precursors to immune cells respond to toxicants as they mature.

Laiosa's lab is performing similar studies using stem cells from donated umbilical cord blood.

"We can measure the chemicals that moms and their babies were exposed to during pregnancy and use this information to explain differences in how the cord blood cells grow in our culture systems," he said.

Preliminary data in mice, Laiosa said, suggests that TCDD may be targeting the normal course of development of fetal immune cells. Epigenetic changes, in particular, Laiosa speculated, may explain the increased disease susceptibility he has observed in rodent offspring.

Laiosa said working with physicians at the Medical College is critical to the studies going on in his laboratory.

Like Sampath, Laiosa received funds from the Children's Environmental Health Sciences Core Center - a Milwaukee-based consortium of researchers funded by the National Institute of Environmental Health Sciences, according to David Petering, center director and professor of chemistry and biochemistry at UWM.

"High infant mortality in Milwaukee is part of a larger issue of premature and low birth-weight infants," said Petering.

"Scientists in our center focus on understanding the basis of normal and aberrant fetal and infant development in order to address these serious health issues."