In what ways does lead damage the brain?

NEW YORK (Feb. 29, 2012)—Exposure to lead wreaks havoc in the brain, with consequences that include lower IQ and reduced potential for learning. But the precise mechanism by which lead alters nerve cells in the brain has largely remained unknown.

New research led by Tomás R. Guilarte, PhD, Leon Hess Professor and Chair of Environmental Health Sciences at Columbia University Mailman School of Public Health, and post-doctoral research scientist Kirstie H. Stansfield, PhD, used high-powered fluorescent microscopy and other advanced techniques to painstakingly chart the varied ways lead inflicts its damage. They focused on signaling pathways involved in the production of brain-derived neurotropic factor, or BDNF, a chemical critical to the creation of new synapses in the hippocampus, the brain's center for memory and learning.

The study appears online in the journal Toxicological Sciences.

Once BDNF is produced in the nucleus, explains Dr. Stansfield, it is transported as cargo in a railroad-car-like vesicle along a track called a microtubule toward sites of release in the axon and dendritic spines. Vesicle navigation is controlled in part through activation (phosphorylation) of the huntingtin protein, which as its name suggests, was first identified through research into Huntington's disease. By looking at huntingtin expression, the researchers found that lead exposure, even in small amounts, is likely to impede or reverse the train by altering phosphorylation at a specific amino acid.

The BDNF vesicle transport slowdown is just one of a variety of ways that lead impedes BDNF's function. The researchers also explored how lead curbs production of BDNF in the cell nucleus. One factor, they say, may be a protein called methyl CpG binding protein 2, or MeCP2, which has been linked with RETT syndrome and autism spectrum disorders and acts to "silence" BDNF gene transcription.

The paper provides the first comprehensive working model of the ways by which lead exposure impairs synapse development and function. "Lead attacks the most fundamental aspect of the brain—the synapse. But by better understanding the numerous and complex ways this happens we will be better able to develop therapies that ameliorate the damage," says Dr. Guilarte.

Study co-authors include J. Richard Pilsner from the University of Massachusetts, Amherst; and Quan Lu and Robert O. Wright of the Harvard School of Public Health.

Funding was provided by the National Institute for Environmental Health Sciences.

Founded in 1922 as one of the first three public health academies in the nation, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 300 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,000 graduate students from more than 40 nations pursuing a variety of master's and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including the International Center for AIDS Care and Treatment Programs (ICAP), the National Center for Disaster Preparedness, and the Center for Infection and Immunity. For more information, please visit www.mailman.columbia.edu.