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Air Pollution Linked to Cognitive Deficits and Brain Abnormalities

By Shweta Trivedi
November 2008

Calderón-Garcidueñas wrote that the study offers "encouragement that future, large-scale work in this area has great potential to give much-needed answers."
Calderón-Garcidueñas wrote that the study offers “encouragement that future, large-scale work in this area has great potential to give much-needed answers.” (Photo courtesy of Lilian Calderón-Garcidueñas)

Maronpot is a board-certified veterinary pathologist and toxicologist
Maronpot is a board-certified veterinary pathologist and toxicologist who has designed, conducted, and evaluated animal carcinogenesis studies for 40 years, including 26 years at NIEHS/NTP. (Photo courtesy of Steve McCaw)

Because of the detrimental effects of air pollution on cognition and development manifest in the children and dogs from Mexico City, Engle emphasized, "Our findings have serious implications for public policy."
Because of the detrimental effects of air pollution on cognition and development manifest in the children and dogs from Mexico City, Engle emphasized, “Our findings have serious implications for public policy.” (Photo courtesy of the Georgia Institute of Technology)

A new NIEHS-funded study available online from the journal Brain and Cognition offers compelling evidence of the significant effects of ambient air pollution on structural alterations in brain and cognitive deficiencies in healthy children and dogs from two Mexican cities. According to an editorial that will accompany the manuscript's publication later this year, the study provides additional support for the hypothesis that “the effects of air pollution go well beyond the expected pulmonary and cardiovascular implications… [and] have serious mental health and neurodevelopmental implications for children.”

The trans-disciplinary team of investigators led by University of Montana pediatrician and neuroscientist Lilian Calderón-Garcidueñas, M.D., Ph.D., included specialists in psychiatry, psychology, radiology, toxicology, education and biostatistics. Among the contributing authors is former NIEHS/NTP Principal Investigator Robert Maronpot, D.V.M., who served as the veterinary pathologist on the study.

The study ( NIEHS builds on previous work by Calderón-Garcidueñas and others showing that children exposed to high levels of air pollution experience chronic respiratory tract inflammation, changes in inflammatory mediators in blood and changes in brain tissue (see text box). She and her colleagues have also established in past studies that dogs can serve as a model for the health effects of air pollution in humans since they show similar patterns of neuroinflammation in response to inhaled particulate matter (PM).

The study was conducted with 55 children and 14 dogs in Mexico City, where residents are chronically exposed to high levels of ozone, PM and xenotoxic lipopolysaccharides associated with PM. The study used 18 children from the city of Polotitlán and 7 dogs from the city of Tlaxcala as controls.

Unlike Mexico City, the control cities have levels of air pollution that are within the current U.S. National Ambient Air Quality Standards. Children were matched in terms of age, health status and socio-economic status in an attempt to isolate air pollution as the variable responsible for outcomes. Dogs were age matched and raised in similar kennel conditions. Work in Mexico was coordinated through the Instituto Nacional de Pediatria in Mexico City, where Calderón-Garcidueñas holds an adjunct appointment.

The team of investigators assessed cognitive performance of the children with the Wechsler Intelligence Scale for Children-Revised (WISC-R) and structural changes in their brains with Magnetic Resonance Imaging (MRI). They also genotyped the children's blood samples for Apolipoprotein E (APOE) and Toll-like receptor 4 TLR4) polymorphisms.

With the canine studies, the investigators used the same protocol for scanning as they did for the children's studies. Following euthanasia, canine brain tissues were examined for cyclooxygenase-2 (COX-2), glial fibrillary acidic protein (GFAP) and Zonula occludens-1 (ZO-1) localization via histopathology. Subsequently, COX-2, IL-1ß and CD14 mRNA were quantitated by real-time PCR.

Even after accounting for age differences among the subjects and controls, children from Mexico City received lower scores in terms of “performance age” than the children from Polotitlán on three important aspects of intelligence tested by the WISC-R - fluid cognition, memory and executive function. MRI tests showed that 56.5% of Mexico City children had evidence of hyperintense white matter prefrontal lesions compared to only 7.6% of the children from Polotitlán.

The investigators found evidence of neuroinflammation and vascular lesions in canine brains from Mexico City. Canine MRI results were comparable to results for children, suggesting that the children were experiencing similar damage to their brains. The inflammatory markers COX-2 and IL-1ß were also up-regulated in canine brain tissue pointing to the role of free-radical associated cell damage and modulation of cerebral function during neuroinflammation.

Senior author Randall Engle, Ph.D., professor and chair of the School of Psychology at the Georgia Institute of Technology, explained that “differences in cognition of the type measured in this study predict school performance, complex learning, ability to control attention and avoid distraction, reading and listening comprehension, reasoning, and the ability to block impulsive anti-social behavior.”

Citation: Calderón-Garcidueñas L, Mora-Tiscareño A, Ontiveros E, Gómez-Garza G, Barragán-Mejía G, Broadway J, Chapman S, Valencia-Salazar G, Jewells V, Maronpot RR, Henríquez-Roldán C, Pérez-Guillé B, Torres-Jardón R, Herrit L, Brooks D, Osnaya-Brizuela N, Monroy ME, González-Maciel A, Reynoso-Robles R, Villarreal-Calderon R, Solt AC, Engle RW ( NIEHS. 2008. Air pollution, cognitive deficits and brain abnormalities: A pilot study with children and dogs. Brain Cogn [Epub ahead of print], doi:10.1016/j.bandc.2008.04.008

(Shweta Trivedi, Ph.D., is a postdoctoral fellow in the Laboratory of Respiratory Biology Environmental Genetics Group)

Gold Standard Evidence of Pre-clinical Neurodegeneration

In February of this year, Calderón-Garcidueñas and collaborators in Mexico City and the United States published a study ( NIEHS in the journal Toxicologic Pathology that reported findings from 47 autopsies of clinically healthy, cognitively and neurologically intact children and adults who had died suddenly. Results indicated that lifelong exposure to high levels of pollutants was associated with neuroinflammation, altered immune response, ultrafine particulate deposition and disruption of the blood-brain barrier – along with an advanced rate of protein fibrillation and deposits of amyloid ß-42 and α-synuclein in the brains of children and young adults.

The cohort of 35 exposed subjects was comprised of residents of heavily polluted Mexico City. The 12 subjects in the control cohort were residents of two cities with lower levels of pollution, Tlaxcala and Vera Cruz. The subjects ranged in age from two to 45 years, with an average age of 25 ± 1.5 years. The researchers examined full histories and cause of death to exclude as much as possible pre-existing medical or lifestyle factors or causes of death that would confound results. Each of the 47 subjects was given a complete autopsy and tested for markers of inflammation and immune response.

The differences between the two groups led the researchers to speculate on the connection between pollution-induced neuroinflammation and the development of later-onset neurodegenerative disease. “We strongly propose that neuroinflammation as a result of exposure to air pollution could have a causative role in both Alzheimer's and Parkinson's diseases and that sustained brain inflammation confers a higher risk for the development of these two frequent neurodegenerative disorders.”

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