The Effects of Iron

Babies who lack iron early in life score poorly on developmental tests. "And the damage appears not to be reversible," says professor of nutrition John Beard.

Plus, in a weird metabolic twist, as they grow old such children may become at higher risk for multiple sclerosis, Alzheimer's, and Parkinson's—diseases linked to too much iron in the brain.

Through Penn State's Life Sciences Consortium, Beard, neuroscientist James Connor, and pharmacogeneticist Byron Jones are investigating the uptake, metabolism, regulation, and toxicity of iron throughout the lifespan. Beard concentrates on infant development. "It would be unethical to withhold iron from severely anemic children," he notes, so much of his work is done with animal studies. In a rat model Beard and his students developed, for example, some expectant moms are iron deficient, some receive iron supplementation, and some are controls. Beard switches the pups four days after they are born. ("Rats don't care which babies are whose," he explains.) Some of the pups with normal iron levels are made iron deficient in the last third of the lactation period—which is what happens in humans. Beard and his students can then evaluate the time-dependence of iron-related development.

micrograph of Astrocytes

Astrocytes (the brown cells with filaments) express the gene for transferrin, a protein that moves iron. "A decrease in the ability to move iron out of the brain," says neuroscientist James Connor, "could lead to Alzheimer's disease."

"Iron requirements are high for normal infant growth rates," he explains, "but breast milk has very little iron." Nature might have designed such a system—in which the iron supply does not meet the infant's physiological demands—because the lack of free iron is actually beneficial: It prevents bacterial infections. "Bacteria require large amounts of iron to proliferate," Beard explains. "The iron that breast-milk does have is bound in a protein called lactoferrin. Iron is bioavailable to the infant, but not to the bacteria."

"Because of the high demand for iron," Beard continues, "weaning foods, which children typically begin to eat after eight months, are important sources of iron." But more refined and purified foods have entered the food supply, Beard explains, and these have fewer impurities (i.e. dirt) and therefore less accidental iron than they used to. For this reason, food producers began adding iron to foods in the 1970s. "You see the same thing in pig farming," Beard says. "When you keep the piglets in pens, you need to give them an iron injection shortly after birth. But if you permit them to root in the dirt, they don't need iron supplements."

Three hypotheses explain how iron-deficiency delays development in humans. First, iron may be needed to organize the physical structure of the brain. During development, brain cells migrate; if an infant is iron deficient, fewer neural connections may be made. The second theory (one focus of Connor's research) is that oligodendrocytes—the cells that produce the nerve cell-protect-ing material myelin—don't make as much myelin during an iron shortage. Without myelin, people are less mentally and physically coordinated. Connor's lab has recently uncovered evidence of a relationship between iron and multiple sclerosis, a de-myelinating disease. The third theory (the focus of collaborative studies between Beard and Jones) is based on the observation that the cells of iron-deficient individuals carry a different number of dopamine receptors. "Genetically different strains of inbred mice tolerate iron deficiency differently," Jones says, "and so do people. Iron deficiency affects several different genes. Some of the possible results are schizophrenia, Parkinson's disease, and obsessive-compulsive disorder." It may also result in drug misuse: The reduction in dopamine receptors alters an animal's response to cocaine, and behavioral studies have shown that iron-deficient mice need twice as much cocaine to show the same drug-induced symptoms as control animals. "Up to now," Jones says, "no one ever thought that early dietary problems could have an effect on drug usage."

Symptoms of Alzheimer's and Parkinson's disease may also be iron-related. With the consumption of oxygen, iron donates electrons that are necessary for energy production and biosynthesis. "Some say life wouldn't exist without iron," says Connor, "and I agree with that." But when iron is out of balance, it's toxic. The same interactions that produce energy can produce highly reactive molecules called radicals. These radicals, which damage cell membranes and DNA, are believed to cause the tissue damage that ultimately results in the memory loss of Alzheimer's and the loss of motor control in Parkinson's disease.

Recently, scientists discovered that vitamin E given to animals before a stroke can limit brain damage. Strokes are caused when blood vessels are clogged or get holes in them, and damage may occur from the release of oxygen and iron from the blood into the surrounding tissue. Scientists now that anti-oxidants like vitamin E scavenge oxygen radicals. But Connor believes that a more direct therapeutic approach would be to eliminate the extra iron.

Five years ago, Beard and Connor proposed a startling new idea: that iron is mobile in the brain. Previously, scientists held that once acquired, iron was held tightly in place. "But if you radiolabel iron," says Connor, "you can see it in the brain in about an hour. You clearly couldn't continue to accumulate iron at that rate throughout your life." Iron deficiency during the first half of lactation may cause sequestering mechanisms to develop in the brain, causing over-accumulation of iron in certain regions. Says Connor, "This explains why children who are iron deficient at critical periods during development may end up with an over-accumulation of iron when they are adults —thus increasing the risk of Alzheimer's and Parkinson's disease." Connor and Beard have proposed experiments to test this hypothesis.

According to Connor, men and post-menopausal women have the highest risk for developing neurodegenerative diseases because they are more likely to accumulate iron. Women of child-bearing age are protected from the excess by their menses. For this reason, he says, it is important that people in the high-risk groups (with their physicians' approval) give blood two to three times per year. "I sometimes say I'm going to go give iron when I mean blood,"he says.

James Connor, Ph.D., is professor and vice chair of neuroscience and anatomy and director of the George M. Leader Laboratory for Alzheimer's Disease Research in the College of Medicine, 500 University Dr., Box 850, Hershey PA 17033; 717-531-8650; jrc3@psu.edu. John Beard, Ph.D., is acting director of the graduate nutrition program, co-director of the LSC option in nutrition, and professor of nutrition in the College of Health and Human Development, 126 Henderson Bldg., University Park, PA 16802; 814-863-2917; its@psu.edu. Byron Jones, Ph.D., is professor of biobehavioral health and pharmacology in the College of Health and Human Development, 210 Henderson Bldg., 863-0167; bcj1@psu.edu.This research is supported by the Penn State Life Sciences Consortium and the National Institutes of Health. Writer Heather L. Fletcher is a graduate student in chemistry at Penn State.

Last Updated May 01, 2010