Researchers Identify Critical Link in Lead-Induced Brain Swelling
Study in major scientific journal finds that drugs can block
molecular changes and prevent brain damage in animals
For Immediate Release: March 25, 2004
Researchers at Kennedy Krieger Institute have identified a key molecule through which high doses of lead trigger brain edema, a potentially fatal swelling. According to the report published March 22, 2004, in the early on-line edition of the Annals of Neurology, drugs that interfere with the molecule can prevent edema in an animal model of lead poisoning.
"Our findings are in rodents and need to be confirmed in humans," cautioned senior author John Laterra, MD, PhD, a research scientist at Kennedy Krieger Institute and professor of Neurology, Neuroscience and Oncology at Johns Hopkins University School of Medicine.
If confirmed, however, these results would justify examining whether the same molecule plays a role in the much more prevalent cognitive deficits caused by smaller, more gradual exposures to lead in children.
For many Americans, lead toxicity was thought to be a thing of the past, abolished when the metal was removed from paint in 1977. However, lead has recently reappeared in news headlines about dangerously high concentrations in some Washington, D.C. water supplies.
For poor children living in houses with old, flaking paint, lead poisoning has never ceased to be a health issue. And indeed, recent scientific findings indicate that even very small amounts of lead can cause brain damage in children. This has triggered calls for stronger lead regulations.
Laterra, along with first author Mir A. Hossain, PhD, and their colleagues have been studying the more drastic type of lead poisoning caused by exposure to very high levels over a short period. In adults, this typically occurs in industrial settings and can lead to peripheral nerve and kidney damage, among others.
Children are more vulnerable because their brains have not yet developed adult safeguards against toxins. Small children can get quite high brain exposures if they ingest flakes of lead-based paint or inhale dust containing old lead paint, in combination with lead from other sources such as water pipes.
"Acute high-level lead toxicity, while less common now in the U.S., continues in developing countries and causes brain edema and even death," said Laterra.
Laterra and colleagues had previously found that a protein called vascular endothelial growth factor (VEGF) is elevated in nervous system cells exposed to lead. VEGF is known to be able to trigger brain edema.
In the current experiments, the researchers found that young rats that ingested high concentrations of lead accumulated the metal in their brains. This was accompanied by significant edema, as well as increases in VEGF.
VEGF is part of a so-called biochemical "pathway." Changes in the levels or activity of one molecule in a pathway affect another, which affect another, and so on down the pathway.
In an experiment that may point to improved treatment for lead toxicity, Laterra and colleagues found that a drug which blocks the ability of VEGF to effect molecular changes inside cells prevented edema in the young rats.
"It is possible that VEGF pathway inhibitors, if approved by the FDA, could be used to prevent the development of brain swelling in children acutely intoxicated with lead. It is also possible that other, more subtle, cognitive aspects of low-level lead toxicity are caused by changes in VEGF levels," said Laterra.
Even if regulatory measures manage to eliminate most sources of new lead in the environment, lead stays in the environment for a long time. There remains a pressing need to understand the mechanisms of lead toxicity, conclude the authors in their article.
The Annals of Neurology (available online via Wiley InterScience at http://www.interscience.wiley.com) is the preeminent neurological journal worldwide. It is published by the American Neurological Association, the world's oldest and most prestigious neurological association.
Article: "Vascular Endothelial Growth Factor Mediates Vasogenic Edema in Acute Lead Encephalopathy," by Mir Ahamed Hossain, PhD, Juliet C. Russell, BS, Sheila Miknyoczki, PhD, Bruce Ruggeri, PhD, Bachchu Lal, PhD, and John Laterra, PhD; Annals of Neurology online edition; March 22, 2004.
Kennedy Krieger Institute is dedicated to helping children and adolescents with disabilities resulting from disorders of the brain achieve their potential and participate as fully as possible in family, community and school life. For more information about Kennedy Krieger Institute, visit www.kennedykrieger.org.
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Allison Loritz, (443) 923-7330
Julie Lincoln, (443) 923-7334
"Our findings are in rodents and need to be confirmed in humans," cautioned senior author John Laterra, MD, PhD, a research scientist at Kennedy Krieger Institute and professor of Neurology, Neuroscience and Oncology at Johns Hopkins University School of Medicine.
If confirmed, however, these results would justify examining whether the same molecule plays a role in the much more prevalent cognitive deficits caused by smaller, more gradual exposures to lead in children.
For many Americans, lead toxicity was thought to be a thing of the past, abolished when the metal was removed from paint in 1977. However, lead has recently reappeared in news headlines about dangerously high concentrations in some Washington, D.C. water supplies.
For poor children living in houses with old, flaking paint, lead poisoning has never ceased to be a health issue. And indeed, recent scientific findings indicate that even very small amounts of lead can cause brain damage in children. This has triggered calls for stronger lead regulations.
Laterra, along with first author Mir A. Hossain, PhD, and their colleagues have been studying the more drastic type of lead poisoning caused by exposure to very high levels over a short period. In adults, this typically occurs in industrial settings and can lead to peripheral nerve and kidney damage, among others.
Children are more vulnerable because their brains have not yet developed adult safeguards against toxins. Small children can get quite high brain exposures if they ingest flakes of lead-based paint or inhale dust containing old lead paint, in combination with lead from other sources such as water pipes.
"Acute high-level lead toxicity, while less common now in the U.S., continues in developing countries and causes brain edema and even death," said Laterra.
Laterra and colleagues had previously found that a protein called vascular endothelial growth factor (VEGF) is elevated in nervous system cells exposed to lead. VEGF is known to be able to trigger brain edema.
In the current experiments, the researchers found that young rats that ingested high concentrations of lead accumulated the metal in their brains. This was accompanied by significant edema, as well as increases in VEGF.
VEGF is part of a so-called biochemical "pathway." Changes in the levels or activity of one molecule in a pathway affect another, which affect another, and so on down the pathway.
In an experiment that may point to improved treatment for lead toxicity, Laterra and colleagues found that a drug which blocks the ability of VEGF to effect molecular changes inside cells prevented edema in the young rats.
"It is possible that VEGF pathway inhibitors, if approved by the FDA, could be used to prevent the development of brain swelling in children acutely intoxicated with lead. It is also possible that other, more subtle, cognitive aspects of low-level lead toxicity are caused by changes in VEGF levels," said Laterra.
Even if regulatory measures manage to eliminate most sources of new lead in the environment, lead stays in the environment for a long time. There remains a pressing need to understand the mechanisms of lead toxicity, conclude the authors in their article.
The Annals of Neurology (available online via Wiley InterScience at http://www.interscience.wiley.com) is the preeminent neurological journal worldwide. It is published by the American Neurological Association, the world's oldest and most prestigious neurological association.
Article: "Vascular Endothelial Growth Factor Mediates Vasogenic Edema in Acute Lead Encephalopathy," by Mir Ahamed Hossain, PhD, Juliet C. Russell, BS, Sheila Miknyoczki, PhD, Bruce Ruggeri, PhD, Bachchu Lal, PhD, and John Laterra, PhD; Annals of Neurology online edition; March 22, 2004.
Kennedy Krieger Institute is dedicated to helping children and adolescents with disabilities resulting from disorders of the brain achieve their potential and participate as fully as possible in family, community and school life. For more information about Kennedy Krieger Institute, visit www.kennedykrieger.org.
Allison Loritz, (443) 923-7330
Julie Lincoln, (443) 923-7334