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Imaging the Effects of Childhood Lead Exposure on Neuronal Circuitry

By Negin Martin
October 2009

Christopher Brubaker, Ph.D.
First author Christopher Brubaker, Ph.D., did his graduate work in neuroscience as part of UC's Physician Scientist Program, where he was Cecil's first graduate student. He is now in his third year of medical school. (Photo courtesy of UC)

Principal Investigator Kim Cecil
Principal Investigator Kim Cecil built upon her graduate training in chemistry with a post-doctoral fellowship in magnetic resonance spectroscopy and imaging at the Hospital of the University of Pennsylvania. She joined the Radiology Department and the Imaging Research Center at Cincinnati Children's Hospital Medical Center in 1998. (Photo courtesy of UC)

Bruce Lanphear, M.D
Bruce Lanphear, M.D (http://www.cincinnatichildrens.org/svc/find-professional/l/bruce-lanphear.htm)Exit NIEHS, a collaborator and a co-author on this study, is a pioneer in the field of children's environmental health research and an expert on lead exposure. He is director of the Cincinnati Children's Environmental Health Center and the Research Fellowship Training Program. (Photo courtesy of UC)

Kim Dietrich, Ph.D.
Study co-author Kim Dietrich, Ph.D. (http://www.eh.uc.edu/dir_individual_details.asp?qcontactid=52)Exit NIEHS, served as Associate Director of the Cincinnati Children's Center for Environmental Health and Disease Prevention at the Children's Hospital Medical Center of Cincinnati. Cecil said Dietrich is "the sole reason this cohort remains intact after almost 30 years." (Photo courtesy of UC)

In a recent NIEHS-funded study published in Neurotoxicology, imaging research scientist Kim M. Cecil, Ph.D. describes the long-term effects of childhood lead exposure on brain microstructure. According to her research, neurotoxic insults caused by childhood lead exposure are associated with changes in myelination and axonal integrity in brain white matter that persist into adulthood. These findings add to the understanding of how lead alters brain development and present a detailed, quantitative assessment to supplement the known adverse neurophysiological effects of childhood lead exposure.

Cecil (http://www.cincinnatichildrens.org/svc/find-professional/c/kim-cecil.htm)Exit NIEHS is a Professor of Radiology, Pediatrics and Neuroscience at the University of Cincinnati (UC) College of Medicine. She uses magnetic resonance (MR) spectroscopy and state-of-the-art imaging techniques to evaluate the effects of environmental neurotoxicants on brain function.

In this study (http://www.ncbi.nlm.nih.gov/pubmed/19619581?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum)Exit NIEHS, 91 adults ranging in age from 20-26 years who had previously participated in the Cincinnati Lead Study (CLS) underwent diffusion tensor imaging (DTI), a recently developed MR imaging technique. The CLS was a longitudinal birth cohort study designed to determine the effects of low to moderate lead exposure on children. From late 1979 to early 1984, the CLS enrolled pregnant women in their first or early second trimester and collected blood samples from their children prenatally, at birth and until the children were almost seven years old. Scientists on Cecil's team accessed these and relevant demographic records for their study.

Knowing the childhood lead exposure levels, Cecil's group used a sensitive microscopic imaging technique to evaluate water-diffusion properties in the white matter of the subjects' brains. Mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA) - indicators of the degree of freedom in the water-diffusion process - were measured and calculated from the brain images of all subjects.

The analysis revealed an inverse association between FA and the mean childhood blood lead levels. The observed decrease in FA in participants with higher lead exposure can be interpreted as a general measure of disorganization within the specific areas of white matter in brain.

Further analysis of diffusion parameters such as MD, AD and RD points to significant neurological insults. Damage was evident in the corona radiata, where axon sheets in white matter carry all neuronal traffic to and from the cerebral cortex. Increased water diffusion in all directions in the corona radiata suggests axonal injury and myelination damage in individuals with childhood lead exposure. The corona radiata develops over a long period of time extending beyond infancy and requires prolonged maturation of cortical connections.

Abnormalities in myelination were also observed in the corpus callosum and the superior longitudinal fasciculus of exposed individuals. The corpus callosum connects the two hemispheres of the brain, and the superior longitudinal fasciculus connects the front and the back of the cerebrum. The myelination of these structures is completed within the first year of life. The increased myelination of the corpus callosum and superior longitudinal fasciculus may have served as a measure of protection or compensation against the early lead insult.

Despite altered brain circuitry, none of the individuals in Cecil's study presented with the typical clinical symptoms of white matter damage found in predominately white matter diseases such as multiple sclerosis. The mean of the childhood blood lead levels of participants in this study averaged approximately 13 µg/dl, but ranged from 5-37 µg/dl. Therefore, the majority of participants had moderate childhood lead exposures by contemporary standards. Combining imaging findings with differences in the cognitive, behavior and motor skills of this group may help define a set of sub-clinical characteristics for low-level early childhood lead exposure.

Citation: Brubaker CJ, Schmithorst VJ, Haynes EN, Dietrich KN, Egelhoff JC, Lindquist DM, Lanphear BP, Cecil KM. (http://www.ncbi.nlm.nih.gov/pubmed/19619581?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum)Exit NIEHS 2009. Altered myelination and axonal integrity in adults with childhood lead exposure: A diffusion tensor imaging study. Neurotoxicology. Epub ahead of print. doi:10.1016/j.neuro.2009.07.007

(Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core Facility and a 2009 Science Communication Fellow with Environmental Health Sciences. She recently completed a postdoctoral fellowship with the NIEHS Membrane Signaling Group.)



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