Environmental Factor, March 2011, National Institute of Environmental Health Sciences
Combined effects of lead exposure and stress on cognitive deficits
While Cory-Shlecta is confident of the effects she's seen in her experiments, she's raised questions about the adequacy of mouse models to reflect the kinds of stress humans of lower socioeconomic status experience in their daily lives. (Photo courtesy of Steve McCaw)
NIEHS grantee(http://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=R01ES012712) Deborah Cory-Slechta Ph.D. addressed a capacity audience from NIEHS and the Environmental Protection Agency (EPA) Feb. 3 on the interaction of lead and stress and their combined effects on cognitive function. Cory-Slechta(http://www2.envmed.rochester.edu/envmed/tox/faculty/cory-slechta.html) is a professor of Environmental Medicine in the Molecular Toxicology and Environmental Medicine Cluster at the University of Rochester School of Medicine and Dentistry.
Cory-Slechta and colleagues are examining the hypothesis that lead and stress interact by altering corticosterone, which then modulates mesocorticolimbic (MES) function and associated behavioral and neurochemical effects of lead. Their current results show that any lead exposure appears to permanently alter corticosterone levels.
"These changes are dynamic across time, and differ markedly by gender, prenatal stress, and offspring stress challenges," said Cory-Slechta during the talk. Her presentation was hosted by NIEHS Health Scientist Administrator Annette Kirshner, Ph.D., as part of the NIEHS Division of Extramural Research and Training Keystone Lecture Series.
Learning deficits in a mouse model
Cory-Slechta's rat and mouse model studies showed a strong association of elevated lead exposure with impulsivity, one of the three diagnostic components of attention deficit hyperactivity disorder. Female rats exhibited synergistic effects from exposure to lead and prenatal and offspring stresses. Continuous lead and prenatal stress synergistically increased impulsivity in male mice, with similar, but non-significant trends in females.
At the molecular level, it is very hard to pinpoint the mechanisms of lead and stress in causing learning impairments. Cory-Slechta and colleagues have found lead enhanced glucocorticoid receptor (GR) activation. Further studies are needed to confirm this result. Cory-Slechta has shown that lead causes hypothalamic-pituitary-adrenal (HPA) axis dysfunction, including elevated and blunted cortisol levels, altered glucocorticoid negative feedback regulation, and altered GR function. In addition, researchers also suspect catecholamines and serotonin are involved in MES pathways. They are looking further into lead and stress effects on trophic factors and cytokines.
An interesting observation Cory-Slechta made was that exposure to lead and stress causes learning deficits in female mice but leads to learning enhancement in male mice. This gender-influenced response to environmental toxicants has been observed for glucocorticoids. It has further illustrated that environmental toxics and stresses can influence very complicated systems that involve many neural signaling components and hormonal components. Cory-Slechta cautioned that future biochemical studies or therapeutic interventions should keep gender differences in mind.
What the findings mean for children
According to Cory-Slechta, the combined effects of lead and stress are translatable to humans. The Rochester cohort study with children at age 6 suggests that stress can enhance elevated blood lead-associated IQ reductions.
"Caveats exist in these studies," Cory-Slechta pointed out. Brain hemisphere plays a role in differences in neurochemical outcome. Furthermore, study results differ between behaviorally tested subjects and untested subjects in responses to dopamine and norepinephrine.
As Cory-Slechta explained, lower socioeconomic status (SES) children in the U.S. are now the primary target of elevated lead exposure. Low SES is already a recognized risk factor for disease and behavioral dysfunctions, including learning disorders in children, an effect believed due to greater environmental stress in low SES populations and associated prolonged cortisol elevation. Lead and stress both affect brain MES systems and produce similar behavioral deficits.
Cory-Slechta receives additional grant support(http://tools.niehs.nih.gov/portfolio/index.cfm?action=portfolio.grantdetail&grant_number=R21ES019105) from NIEHS to investigate postnatal exposure to ultrafine particles in ambient air pollution. She was at NIEHS for a two-day NIEHS air pollution workshop held at EPA. Her research has focused largely on environmental neurotoxicants as risk factors for behavioral disorders and neurodegenerative disease. She has also begun to examine mixtures of neurotoxic chemicals and risk modifiers to help explain the additive and synergistic effects of exposures to multiple stressors.
(Emily Zhou, Ph.D., is a research fellow in the NIEHS Laboratory of Signal Transduction Inositol Signaling Group.)