Grantee Research Project Results
2014 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: October 1, 2013 through September 30,2014
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:
The goals of this grant have been to examine the cumulative toxicity of neurotoxic metals combined with stress in animal models. It is premised on the fact that neurotoxic metals and stress are often co-occurring risk factors, particularly in low socioeconomic status communities, and that they also share biological targets (HPA axis, mesocorticolimbic system of brain) and, correspondingly, produce common adverse outcomes, suggesting a biological basis for potential interactions. For that purpose, the impacts on brain and behavior of developmental exposures to lead or methylmercury in conjunction with prenatal stress and/or offspring stressors (behavioral experience) have been examined, as have relationships between brain and behavior changes as indices of mechanisms of effect. We have previously reported multiple, sex-dependent examples of enhanced neurotoxicity of lead by prenatal stress in the rat and mouse. The objective of the Community Based Participatory Research (CBPR) efforts was to engage diverse community partners in informing translational efforts, particularly with respect to the unique challenges of communicating about risks from cumulative, interactive, and prenatal exposures.
Progress Summary:
The focus of this project period was on combined effects of methylmercury exposures with prenatal stress, with studies in rats and another in mice that also included offspring stress challenges (early behavioral adversity vs. early behavioral positive experience). Methylmercury exposures began 2 weeks prior to breeding and continued through gestation. Prenatal stress was accomplished by restraint at gestational days 16-17 in rats and days 11-19 in mice. A third study compared the effects of type of early behavioral experience (positive vs. negative) on the trajectory of the consequences of developmental methylmercury exposure and prenatal stress. Importantly, because our earlier studies on this grant showed that behavioral testing alone can modify the effects of lead exposure and/or of prenatal stress (Cory-Slechta et al., 2013), experimental designs were modified and expanded to include animals in both studies with and without behavioral testing experience.
Sex-dependent and non-monotonic enhancement and unmasking of methylmercury neurotoxicity by prenatal stress in the absence of any changes in pregnancy-related conditions, maternal weight gain or offspring weight gain was seen in rats (Weston et al., 2014) that included impaired learning and short-term memory only seen under conditions of combined methylmercury and prenatal stress, and only in females. Similarly, many methylmercury-induced changes in brain monoamines occurred only with combined methylmercury and prenatal stress, and particularly in striatum in males, and in hippocampus and nucleus accumbens in females; both nucleus accumbens and hippocampus are critical to mediation of learning and short term memory, suggesting their potential involvement in the behavioral toxicity. Mechanisms by which prenatal stress enhances methylmercury neurotoxicity do not appear to include increases in brain mercury levels, nor differences in pre-behavioral testing levels of the stress hormone, corticosterone.
As in the rat model, behavioral toxicity of methylmercury was also found to be enhanced by prenatal stress in the mouse model in both sexes, although unmasked effects of methylmercury on learning were most evident in males in this case and also occurred at lower methylmercury exposure levels. Correspondingly, in analyses completed to date, methylmercury-induced changes in monoamines in frontal cortex, a region key to the learning baseline, were enhanced by prenatal stress in males. Non-monotonic effects of methylmercury (greater effects at lower doses) were seen in mice as had also been seen in rats. And, as in rats, these effects occur in the absence of any maternal toxicity or changes in maternal behavior or in offspring weight gain.
These studies carried out over the past year add significantly to our understanding of combined effects of neurotoxic metals and stress. First, they demonstrate that the potential for cumulative toxicity is not limited to lead, but occurs with both lead and methylmercury, neurotoxic metals that each act on brain mesocorticolimbic systems. In addition, the effects can be seen in both rat and mouse models, consistent with generalized effects. In both cases, corresponding enhanced toxicity of metal ± prenatal stress can occur in brain regions critical to mediation of the cognitive behaviors. In both instances, effects of the neurotoxic metal can be unmasked by prenatal stress, suggesting that assessment of health effects of such neurotoxic metals in isolation could underestimate their human health risks.
The CBPR project continued to disseminate information to identified key audiences (particularly perinatal health care and service providers) about interactions between chemical and non-chemical exposures. For example, we presented at two OB-GYN grand rounds on the implications of the lead and stress research findings for prenatal counseling. The CBPR team has also been working with CBPR teams from other STAR CRA projects to pool lessons learned from their experiences and integrate them into a paper for publication.
Future Activities:
Our future activities include completion of tissue analyses from the methylmercury and stress studies as well as 3 manuscripts for publication from these studies. For the rat model study, an assessment of the transmission of methylmercury ± prenatal stress effects is underway to begin to determine mechanisms by which multigenerational effects occur. For the two mouse studies of methylmercury and prenatal stress, the assessment of brain monoamine changes still needs to be completed so as to determine the impacts of differential early behavioral experience stressors on the trajectory of methylmercury ± stress changes and to examine maternal transmission of these effects across generations. We expect to submit at least one manuscript for publication based on the CBPR project.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
| Other project views: | All 43 publications | 7 publications in selected types | All 7 journal articles |
|---|
| Type | Citation | ||
|---|---|---|---|
|
|
Weston HI, Sobolewski ME, Allen JL, Weston D, Conrad K, Pelkowski S, Watson GE, Zareba G, Cory-Slechta DA. Sex-dependent and non-monotonic enhancement and unmasking of methylmercury neurotoxicity by prenatal stress. Neurotoxicology 2014;41:123-140. |
R834578 (2014) R834578 (Final) |
Exit Exit Exit |
|
|
Weston HI, Weston DD, Allen JL, Cory-Slechta DA. Sex-dependent impacts of low-level lead exposure and prenatal stress on impulsive choice behavior and associated biochemical and neurochemical manifestations. Neurotoxicology 2014;44:169-183. |
R834578 (2014) R834578 (Final) |
Exit Exit Exit |
Supplemental Keywords:
Cumulative risk, sensitive populations, stressors, public policy, neuroscienceRelevant Websites:
Cory-Slechta Lab - University of Rochester Medical Center Exit
Progress 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.