Grantee Research Project Results
2012 Progress Report: Combined Effects of Metals and Stress on Central Nervous System Function
EPA Grant Number: R834578Title: 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: September 1, 2011 through August 31,2012
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 have observed enhanced effects of developmental exposure to lead when it occurs in combination with prenatal stress. The goals of this grant are to determine whether such enhanced effects occur more broadly to include the cognitive effects of developmental lead exposure. Additionally, it 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:
Animal Studies - We have completed most of the first aim of the grant, i.e., to examine the effects of developmental lead exposure and prenatal stress on impulsivity, a component of attention deficit disorder. This objective was established to determine the extent to which enhancement of behavioral toxicity of developmental lead and stress extended to behaviors other than that seen in our original study (Fixed interval schedule-controlled behavior). In the behavioral studies, more pronounced effects of developmental lead, particularly when combined with prenatal stress were found in males. 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 reduced serotonin, which may contribute to this and be additionally enhanced under conditions of combined lead and stress by reduction in striatal dopamine levels.
Although not included in the grant objectives per se, brain sections were also saved from this experiment to pursue additional mechanisms of serotonergic involvement in behavioral effects that include measures of serotonin transporters, BDNF and NMDA receptors. Once these Westerns are completed, we will be able to examine correlations between neurotransmitters, protein levels and behavioral outcome.
We have now begun pursuing the second aim of the grant, i.e., the potential extension of enhanced effects of other neurotoxic metals with prenatal stress. The first such study is examining combined effects of developmental methyl mercury exposures and prenatal stress. Assessment of behavioral testing, using a fixed interval (FI) schedule of food reward shows gender-specific effects, including decreased response rates and longer post-reinforcement pause times of female rats exposed to methyl mercury plus prenatal stress. Brain and blood collected from littermates of these rats will be used to evaluate early biochemical and neurotransmitter changes in response to methyl mercury alone vs. methyl mercury combined with stress. 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.
Community Outreach - We conducted four focus groups in order to assess varied community members’ current understanding of chemical/non-chemical stressors, the questions they have, and the type of communication tools they recommend. In order to conduct these focus groups, we:
- Developed, reviewed, and piloted a presentation on lead and stress as a basis for focus group discussion.
- Developed protocol and received RSRB approval for all materials.
- Partnered with four different community groups to recruit, host, and conduct focus groups.
Focus groups were conducted with:
- Staff of the Perinatal Network who provide counseling and referral to high risk low income mothers in Rochester.
- Nurses and other staff of the Woodyard Health Center, which serves primarily low-income and minority populations in southwest Rochester.
- Members of the Just Green Collaborative, a statewide coalition of groups focused on chemicals policy reform and toxins reduction, as part of their annual retreat.
- Members of the African American Health Leadership Task force, hosted by the Finger Lakes Health Systems Agency.
Input from these focus groups will be used to develop, test, and disseminate communications materials, program responses, and policy strategies in years two through four of the study.
We also reached out to the community outreach programs of other STAR grantees in order to coordinate and share approaches to communicating about interactions between chemical and non-chemical stressors. Based on initial conversations, it appeared that the other grantees planned to develop communications materials later in their programs, and we agreed to communicate further as they progress. There is great potential to unify the findings of the community outreach components of these projects to develop effective and appropriate messages about the research findings for different groups.
Future Activities:
Further evaluation of potential biochemical and neurochemical mechanisms of combined effects of lead and prenatal stress on impulsivity will be undertaken to complete the first aim of the grant. Similarly, following completion of biochemical and neurochemical analyses, we will be able to examine such impacts of methyl mercury with and without stress at two time points as well as their correspondence to behavioral outcomes at the second time point. After those analyses are completed, we will begin aim 3 of the grant which involves additional behavioral studies of methylmercury and prenatal stress in a mouse model with a focus on the ability of these combined exposures to induce depressive behavior phenotypes.
Journal Articles:
No journal articles submitted with this report: View all 43 publications for this projectSupplemental Keywords:
exposure, health effects, human health, sensitive populations, stressor, cumulative effects, public policy, neuroscience, toxicologyProgress and Final Reports:
Original AbstractThe 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.