Programmed for life
Scientists descend on Portland convinced that mother's diet affects future diseases
It wasn't until three weeks ago that Dr. David Barker began to feel fully validated. Seeing as how Barker, a professor of cardiology at Oregon Health and Science University, introduced an entirely new field of study 25 years ago, that may seem like a long time to wait. But pioneers have to be patient, and Barker certainly was one of those when he formulated what became known as the Barker Hypotheses.
In the '80s, Barker spent three years rummaging through old British birth records so he could compare the weight of 15,000 people at birth with what eventually caused their deaths. He found a dramatic connection - babies born lightest were suffering the most heart disease later in life.
Barker's hypothesis was that the low birth weight children hadn't received adequate nutrition during gestation. As still-forming fetuses they had been forced to divert most of the available nutrients to the brain, leaving less for the rest of the body. The rest of the body, including undernourished organs, might appear to catch up but in fact would suffer increased levels of disease during a lifetime.
Children whose mothers don't eat properly while pregnant, Barker believes, are programmed for killer diseases, from heart disease to cancer and diabetes.
The cause isn't a permanent genetic mutation but a chemical process called methylation that can turn on and off certain genes at the precise time when those changes could do the most long-term damage - while the body is being developed.
On Sunday, the 7th World Congress on Developmental Origins of Health and Disease begins four days of meetings in Portland. More than 700 physicians and scientists from around the world will gather to discuss the field Barker's ideas initiated - the fetal origins of disease.
Barker believes that while genetics and lifestyle certainly contribute to health, what passes through the placenta before people are born predetermines just as much, and possibly more. Next week's series of meetings and presentations, and a BBC documentary on his work that aired in Great Britain three weeks ago and has resulted in more than 600,000 website visits, Barker says, finally feels like public acceptance.
Tribune Photo: Christopher Onstott • Scientists at the OHSU Oregon National Primate Research Center are finding a link between obesity in pregnant monkeys and diseases in their offspring. But it may not be the mother's obesity so much as what she eats during pregnancy that dictates the diseases her offspring will suffer.
Focus on young women
Killer diseases are only part of the story. Obesity researchers believe that what a woman consumes during her pregnancy programs her children's metabolism for life - a mother's high fat diet can program offspring for a life of obesity.
Barker says developmental science explains the sharp rise in asthma cases. It's not an allergic disease, he says, but the consequence of something gone wrong in the womb affecting how the child's airways developed.
Barker is convinced that what a mother consumes during pregnancy is only part of the developmental process. In fact, he says, what she has consumed all her life could play a role in her offsprings' health. A kidney-disease causing infection suffered by the mother years before conception could have changed her metabolism and thus what she passes through the placenta.
'You've got to take the long-term view,' Barker says. 'The health of Oregonians in 100 years time is being instituted by what's happening to little girls in Oregon today.'
Portland physician Jeff Pentecost, a cardiology researcher with the OHSU Heart Research Center, says his work has been turned upside down due to his growing belief in the importance of fetal origins.
'When I was going to (medical) school we started talking to men in their 20s,' Pentecost says. 'Now we know it's important to talk to their mothers. That would have been a way to prevent this.'
In 2005, Pentecost founded Portland's Struble Foundation to educate people about heart disease and raise money for cardiovascular research. The foundation's focus for both has changed.
'It used to be males under 40, and now it's young women before they're pregnant,' Pentecost says.
On the other hand, the idea that the increase in heart disease is due to what happened during pregnancy raises a scary specter, since there aren't that many pregnancies, especially among middle- and upper-class Americans, that are hugely deficient in basic nutrients.
It may be, Pentecost says, that a good-enough pregnancy isn't good enough. He looks to the typical American high fat diet as a possible culprit.
'Something is happening in a seemingly normal pregnancy that's causing a bad outcome,' he says, of skyrocketing heart disease numbers.
Kent Thornburg, director of the heart research center, says he's concerned that even as researchers begin working to better understand developmental science, physicians need to pay heed and change the way they counsel women.
'We're not getting the word out to obstetricians,' says Thornburg, who is convinced pediatricians need to be talking with adolescent girls - the mothers of tomorrow - about their diets.
Courtesy of Dreamstime • According to scientists studying the fetal origins of disease, the fetus in this ultrasound is being programmed for diseases ranging cancer to diabetes, all before birth. Over 700 physicians and researchers are coming to Portland this week to discuss the latest findings in the burgeoning field of study.
Fat is the key
But exactly what that word should be isn't yet clear. At the Oregon National Primate Research Center in Beaverton, neuroscientist Kevin Grove is working with Thornburg and Barker on the puzzling developmental questions of obesity.
For years, researchers have known that children born to obese women have unusually high rates of heart disease, diabetes, immune disorders and even mental illness. But Grove's experiments are showing it may not be the mother's obesity that is responsible. What he's found studying pregnant monkeys in the lab is that what the mother eats during pregnancy may be more important than her own obesity.
'The good news is if a mother is obese, if she actually eats healthy, she can greatly reduce the risk that the child is going to have health problems,' Grove says.
Grove has made another discovery that could eventually shed light on one of the long-running mysteries of developmental diseases.
Barker's original hypothesis established that birth weight due to pregnant women not getting enough nourishment was tied to heart disease in their offspring. Another landmark study showed that Dutch women who were pregnant during a three-month starvation in the waning days of World War II gave birth to children who also had an increased disease rate as adults.
But Grove is feeding his pregnant lab animals high-calorie diets and producing similar results. How could high- and low-calorie diets produce the same developmental diseases? The answer, Grove theorizes, is fat.
In his lab, Grove has seen that high-fat diets cause inflammation in blood vessels so that less blood gets through the placenta. He's guessing that with mothers not getting adequate nourishment, a similar inflammation is taking place as their bodies burn stored fat to make up for their lack of food. In both cases, Grove says, it is an excess of fat circulating in their bloodstreams that might be causing the inflammation that produces offspring destined to suffer chronic diseases.
In Corvallis, David Williams, a principal investigator at the Linus Pauling Institute, is working on the theory that fetal origin research can be made to work for long-term health, rather than explain bad health such as high rates of cardiovascular disease.
Tribune Photo: Christopher Onstott • Neuroscientist Kevin Grove is finding the equivalent of a typical American high-fat diet fed to Macaque monkeys can lead to heart disease in their offspring.
Warding off cancer
If a key to health is what your mother ate while you were gestating, he reasons, it's worth searching for foods and compounds that, if eaten during pregnancy, might keep offspring healthy through adulthood.
Animal studies have shown Indole-3-Carbinol, a compound found in cruciferous vegetables such as broccoli and brussels sprouts, contains cancer-fighting properties. So, Williams gave pregnant lab rats carcinogens known to produce cancer in offspring. Most of Williams' rats developed cancer in the first few months of life; all developed cancer by middle age.
Next, Williams duplicated the experiment with one variation - he gave a new batch of pregnant rats Indole-3-Carbinol daily during pregnancy and while they were nursing their offspring. Despite the doses of carcinogens given these pregnant rats, only half of their offspring developed cancer. And those that did developed fewer and smaller tumors.
'It was amazing to me,' Williams says. 'The pups never got Indole-3-Carbinol themselves. The exposure they got in utero provided protection for them into what would be middle age as a human.'
Williams calls his work promising but cautions he still doesn't understand the mechanism behind the effect he has observed. And he says he doesn't know which would be more effective, supplements of Indole-3-Carbinol or the greater mix of compounds in the whole vegetables. Toward that end, he is repeating his experiment, giving the mice pellets made from freeze-dried broccoli and brussels sprouts rather than Indole-3-Carbinol supplements.
He's also involved with research analyzing umbilical cords after birth to see what toxins the fetuses were exposed to and how much of the cancer-fighting compounds made it through to the developing fetus.
'It's novel, and it's cutting edge,' Williams says, of his take on the new developmental science. 'Almost no one has looked at the potential for altering cancer risk by maternal diet supplementation.'
Williams sees a future where mothers can be given specific supplements that will help ward off cancer during the course of their children's lifetimes.
'I think we can get there,' he says. 'That's where it's headed.'
• Fathers play important role before conception
Portland cardiology researcher Dr. Jeff Pentecost sees dramatic changes in medical research as scientists learn more about the field of fetal origins. He's guessing one will be a broadening of focus away from simply looking at what mothers are giving their offspring.
There is evidence that fathers can convey lifetime maladies to their offspring through their sperm.
Twenty-five years ago researchers studying Fetal Alcohol Syndrome found that heavy drinking by mothers before and during pregnancy might not be the only factor causing birth defects in their children. They also fed male lab animals heavy doses of alcohol just prior to conception and observed birth defects in the offspring they sired, raising the possibility of what some called 'drunken sperm.'
Some researchers theorize that the alcohol was having a methylation effect similar to those causing other fetal origin diseases.
There is also evidence that a father's diet can affect the health of his children. Last year, Australian researchers discovered that male rats fed high-fat diets produce offspring prone to diabetes, regardless of the female mate's diet or body mass.
'Right now, males have almost no blame in what's going on,' Pentecost says. 'I think there's going to be interplay there that has yet to be discovered.'
• Author talks about prenatal influences
One part of the week-long international conference on the developmental origins of disease is open to the public. New Haven, Conn., author Annie Murphy Paul will deliver a talk on the science of prenatal influences.
Fascinated with the idea that so much of her child's life was being determined by what she was doing during her pregnancy, Paul researched and wrote 'Origins: How the Nine Months Before Birth Shape the Rest of Our Lives.' She based the book on her pregnancy, each month exploring a different potential influence on her unborn son, from diet to chemical exposures to stress.
Annie Murphy Paul's free public lecture is at 7 p.m., Sept. 22, at Portland State University's Lincoln Hall, 1620 S.W. Park Ave.
• OHSU study says moms who eat high-fat diet before and during pregnancy 'Program' babies to Be fatter, at risk for chronic disease later in life
New research in mice indicates that babies born to moms who eat a high-fat diet before and during pregnancy have a higher fat mass and smaller livers than babies whose moms consume low-fat fare, according to scientists at Oregon Health and Science University Doernbecher Children's Hospital.
The good news, the researchers report, is that moms who switch to a low-fat diet during pregnancy considerably reduce the risk of these negative effects. Their findings are published online in the American Journal of Physiology and Endocrinology Metabolism, a publication of the American Physiological Society.
Previous research has shown babies who receive too much or too little nutrition in the womb experience profound and permanent changes in their development - including alterations in the structure of the liver, brain and pancreas - that increase their susceptibility to developing various diseases later in life, including obesity, diabetes and cardiovascular disease.
And given that nearly half of women of childbearing age are overweight or obese in the United States, according to the Centers for Disease Control and Prevention, there is a pressing need to inform women and their health care providers of the inherent dangers maternal overeating poses to their child's future health and risk of chronic disease.
'One of the key findings here is that the offspring are born with a marked shift in body composition, away from lean mass and toward fat mass, prior to any dietary exposure in the offspring themselves,' said principal investigator Stephanie M. Krasnow, Ph.D., a scientist in the Papé Family Pediatric Research Institute at OHSU Doernbecher Children's Hospital.
Krasnow and colleagues in the Daniel Marks Lab used a mouse model to examine how consumption of a high-fat diet during pregnancy effects body composition in the newborn. Female mice were fed either a low-fat or high-fat diet for six months and were mated with male mice after 4, 12 and 23 weeks. The females who ate a high-fat diet gained more body weight and had a higher fat mass than the females who ate a low-fat diet. And on the day of birth, babies born to females who had consumed a high-fat food had more body fat, less lean mass, and smaller livers than the newborns of females that consumed low-fat food.
These changes in body composition and organ size occurred before the female mice eating a high-fat diet became obese, the researchers report. And even when the females were not obese, eating a high-fat diet prior to and during pregnancy 'programmed' their unborn babies to have increased body fat and smaller livers at birth. Fortunately, the researchers found, switching to a low-fat diet just during pregnancy prevented the infants from accumulating excess fat mass in utero and also prevented their having smaller livers.
'These findings demonstrate that changing to a low-fat diet during pregnancy minimizes the harmful effects of maternal obesity on the newborn's body composition, potentially reducing the child's risk of developing obesity and related diseases later in life,' said Krasnow.