Grantee Research Project Results

2011 Progress Report: Combined Effects of Metals and Stress on Central Nervous System Function

EPA Grant Number: R834578
Title: Combined Effects of Metals and Stress on Central Nervous System Function
Investigators: Cory-Slechta, Deborah , Korfmacher Smith, Katrina
Institution: University of Rochester School of Medicine and Dentistry
EPA Project Officer: Hahn, Intaek
Project Period: October 1, 2010 through September 30, 2014 (Extended to September 30, 2015)
Project Period Covered by this Report: October 11, 2010 through March 8,2012
Project Amount: $1,250,000
RFA: Understanding the Role of Nonchemical Stressors and Developing Analytic Methods for Cumulative Risk Assessments (2009) RFA Text | Recipients Lists
Research Category: Human Health

Objective:

Prenatal stress can have long-term adverse consequences for offspring, including impairments in cognitive functions. In prior studies, we observed the enhanced effects of developmental exposure to lead when it occurs in combination with prenatal stress. The goals of this grant are as follows:

(1) To determine whether such enhanced effects occur more broadly to include the cognitive effects of developmental lead exposure.

(2) Additionally, the grant seeks to determine how general such enhanced effects are by examining whether similar enhanced cognitive effects occur for other neurotoxic metals combined with prenatal stress, specifically methyl-mercury and arsenic, both of which, like lead, act on the body's stress systems. Our community-based participatory research component is geared towards facilitating the translation of cumulative risk and risk factor interactions.

Progress Summary:

We are in the process of completing the first aim of the grant, to examine the effects of developmental lead exposure and prenatal stress on impulsivity, a component of attention deficit disorder. In the behavioral studies, more pronounced effects of developmental lead, particularly when combined with prenatal stress were found in male rats. While not more 'impulsive' per se, males treated with lead and prenatal stress were slower to shift their behavior as conditions of reward shifted; they also omitted more trials and responded prematurely more frequently. Females treated with lead and prenatal stress tended to respond excessively during delay periods. Assessment of brain neurotransmitters in littermates of these animals showed notable reductions in serotonin levels in frontal cortex, nucleus accumbens and striatum related to lead exposure, particularly in males, as well as reductions in levels of dopamine and its metabolites. While these reductions were not explicitly enhanced by prenatal stress, both dopamine and serotonin are important brain regulators of impulsive behavior. Thus, both males and females treated with lead and prenatal stress exhibit behaviors that would be considered 'disruptive' in the behavioral paradigm. Additionally, lead exposure reduces serotonin which may contribute to this and be additionally enhanced under conditions of combined lead and stress by reduction in striatal dopamine levels.

These data provide additional support for the inclusion of non-chemical stressors in risk assessment, in that assessment of lead alone could yield underestimates of the risks to human health from exposures to the chemical alone.

Future Activities:

Further evaluation of potential mechanisms of combined effects of lead and prenatal stress on impulsivity will be undertaken to complete the first aim of the grant. In the meanwhile, we are in the process of setting up conditions to initiate the next experiment of the grant that will begin to explore combined effects on brain and behavior of combined developmental methyl-mercury exposure

Journal Articles:

No journal articles submitted with this report: View all 43 publications for this project

Supplemental Keywords:

exposure, health effects, human health, sensitive populations, stressor, cumulative effects, public policy, neuroscience, toxicology

Progress and Final Reports:

Original Abstract

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.