New Light on Fetal Origins of Adult Disease
ASHG session focuses on epidemiological and experimental evidence
Ricki Lewis / The Scientist 14[21]:1 30oct00

Human prenatal development can be viewed as a program of genetic switches that turn on, in a highly regulated manner, at specific places and times. But a body of evidence is emerging that paints a less hardwired picture, one of responses to environmental challenges fostering changes early on that reverberate decades later, in the guise of cardiovascular disease and diabetes. A symposium at the American Society of Human Genetics annual meeting, held in Philadelphia Oct. 3-7, addressed the fetal origin of adult diseases.

"Most people have Brave New World all wrong. The book that supposedly says that we are the products of our genes really means we are the products of the environment," said Peter Nathanielsz, the J. Law professor of physiology at Cornell University College of Veterinary Medicine. He was referring to the "epsilon" class of fetuses in Aldous Huxley's famed novel who were treated with ethanol to dampen their intelligence. "That's the story we are addressing now. Certain features of the intrauterine environment can lead to long-term throwing of switches," he added.

All of the speakers emphasized that the vulnerable fetus is one that is starved in utero, a condition technically termed intrauterine growth retardation (IUGR). Such an infant is born roughly on time, but is severely underweight. That is, the individual is "small for gestational age" rather than premature. The adaptations that enabled the fetus to continue to grow despite near-starvation later in life became risk factors for certain common illnesses. "These adaptations permanently change the developing body's structure and physiology," said David J.P. Barker, of the MRC Environmental Epidemiology Unit in Southampton, U.K. The ultimate result can be coronary artery disease, stroke, hypertension, and/or type II diabetes mellitus.

The mounting evidence that events in the fetus can set the stage for adult disease is both epidemiological and experimental.

Epidemiological Evidence

More than 100 studies clearly correlate low birth weight due to IUGR with increased incidence of the classic cardiovascular disease risk factors, and of the diseases themselves. The links between then and now indeed make sense. "The undernourished fetus redistributes blood flow to protect key organs, such as the brain. Endocrine function and body composition change. These babies lack muscle, and that is the site of insulin action. Thinness at birth, and accelerated weight gain in childhood, sets the stage for coronary heart disease and type II diabetes. Some people with chronic adult diseases grew differently before birth and during infancy and early childhood," Barker explained. Changes in insulin resistance may lead to diabetes; abnormal stress hormone levels, stiffer arteries, and too few kidney tubules can contribute to hypertension.

Interesting epidemiological clues come from health records dating from World War II. One analysis of individuals who were fetuses during a seven-month famine in the Netherlands in 1943 is particularly telling. "That prenatal exposure led to inability to maintain glucose homeostasis 50 years later," Barker said.

Paul McKeigue, a reader in epidemiology at the London School of Hygiene and Tropical Medicine, reported on the Uppsala Birth Cohort Study, which has followed 14,611 men and women born between 1915 and 1929. The records include birth weight, morbidity, and mortality statistics, and are linked to census data. Interestingly, low birth weight due to IUGR predicts mortality in early childhood but has no apparent link to disease or death between the ages of 15 and 64. It is only after age 65 that nutrient-deprived beginnings are echoed as heightened cardiovascular disease as the primary cause of death. And the specific underpinnings of the disease are different from the common elevated serum cholesterol route. "This so-called small baby syndrome doesn't produce lipid abnormalities, but increased blood pressure and glucose intolerance," McKeigue said.

Experimental Evidence

Anecdotal, case report, and epidemiological studies provide the impetus for experiments that directly test the hypothesis that starvation in utero translates later into diabetes and cardiovascular disease. Nathanielsz works with fetal sheep, exposing the head while the ewe is anesthetized. He inserts a catheter in the fetal carotid artery to monitor blood pressure, and a flow probe around various vessels to measure circulation rates. He also removes sections of blood vessels and measures peripheral resistance using a myograph, and tracks key hormone levels in ewe and offspring.

The sheep work so far has identified some key differences in physiology before and after birth. "The fetus and the adult have opposite responses to glucocorticoids. We can accept nothing that goes on postnatally as also happening prenatally. There is a completely different set of rules in the uterus," he explained. For example, glucocorticoid exposure to a fetus increases thyroid function; the same exposure after birth decreases thyroid function. Normally, increased glucocorticoid production in a fetus helps it cope with the pressures of a contracting uterus, and the rigors of birth and beyond--remove a fetus' adrenal glands, and blood pressure doesn't rise. "Endogenous production of glucocorticoids in a fetus may play a profound role in changes in the cardiovascular system. The first environment in the womb plays as much a role in how the cardiovascular system reacts as the genotype," Nathanielsz concludes.

Marisa Bartolomei, a Howard Hughes Medical Institute assistant investigator and associate professor of cell and developmental biology at the University of Pennsylvania, takes another approach to monitoring effects of differing in utero environments. She looks at the expression of imprinted genes in cultured cells from mouse blastocysts, the early prenatal stage in which the cells destined to develop into the embryo are set aside along an interior surface of a hollow ball. Imprinted genes are those that are expressed differently, depending on the parent of origin. Bartolomei exposed such cells to either of two media--a standard one called Whitten's, and another called KSOM plus amino acids that is more similar to in vivo conditions. She then examined RNAs and DNA methylation patterns to determine which gene variants are active under which conditions--and she found distinctions. The results, she reported, could sound a cautionary note: "an embryo may look fine but have subtle changes."

Rat Model, Too

In the molecular biology laboratory in the department of clinical chemistry at Vrije University Hospital in Amsterdam, Cees B.M. Oudejans is taking yet another experimental approach to fetal origins of adult disease. He has developed a rat model of placental dysfunction by ligating the artery that controls blood flow to the embryo, resulting in intrauterine growth retardation. He finds that the deprived rats maintain a persistent excess of the hormone somatostatin well into adulthood--an effect not seen in rats that were undernourished as pups. Somatostatin is a pancreatic hormone that affects the rate of nutrient absorption into the bloodstream. "Therefore, malnutrition before birth is different than after," he said.

Oudejan's work clearly shows that the maternal- offspring connection plays a role in predisposing the animal to hormonal imbalances. "The placenta mobilizes nutrients from the mother. The prenatal placental control of embryonic growth is similar to the hypothalamic control of growth after birth," he added.

The idea that stresses to the embryo and fetus can cause adult disease is well along the path from hypothesis to theory. And that means a host of new experiments and ultimately new ways to think about preventing these common diseases. "That cardiovascular disease, for example, can arise from adverse intrauterine conditions is no longer a matter of contention. We need to find out what the stimuli are," said Nathanielsz. And Oudejans concurred. "The growth-retarded embryo dramatically, but selectively and permanently, affects the expression of a subset of genes. We need studies of the functioning of the placenta in ongoing pregnancies."

In a broader sense, the fetal-adult health connection argues against genetic determinism--the functioning of an adult animal body cannot be explained by gene sequences alone. 

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