Grantee Research Project Results
2013 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, 2012 through September 30,2013
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 the first two aims of the grant. The first was to examine whether enhanced or unmasked effects of lead by prenatal stress extend to behaviors other than those in which it was originally observed, namely Fixed Interval schedule controlled behavior. Since impulsivity or delay of reward is considered a surrogate for fixed interval behavior, the effects of lead and prenatal stress on impulsivity, a component of attention deficit disorder were examined in our animal model using a delay of reward paradigm that offered a choice between a short delay and small reward or a long delay followed by a large reward. Data showed that lead exposure appeared to increase aversion exclusively in male offspring to the task itself, particularly in those that also were subjected to prenatal stress (although not statistically enhanced), in that such exposures increased the numbers of omissions of choice responses and longer latencies to make a choice. Although not directly supported by the grant, neurochemical assessments suggest a particular relevance of alterations in brain serotonin to these changes in male offspring. While these reductions were not explicitly enhanced by prenatal stress, both dopamine and serotonin are important brain regulators of impulsive behavior. Thus, while enhanced effects of lead in the presence of prenatal stress were seen in terms of aversion to delay of reward, these effects may be less pronounced than seen in our prior studies using a different behavioral baseline.
However, interestingly, in analyses directed at dams of these offspring, assessments again not directly supported by the grant, exposure to lead and prenatal stress resulted in a reduction in testosterone that was not seen with lead or prenatal stress alone, thus indicative of a cumulative toxicity. A series of correlational analyses also revealed that such changes are important in that they correlate directly with changes in offspring corticosterone plasma sex hormone levels as well as with altered hypothalamic serotonin function. These findings are described in two manuscripts currently under review for publication.
We have also now completed the second aim of the grant. It assesses the potential extension of enhanced effects of prenatal stress to enhance the neurotoxicity of other metals. The first such study examined combined effects of developmental methyl mercury exposures and prenatal stress in a rat model and its effects on a fixed interval (FI) schedule of food reward. It revealed sex-specific effects, including decreased response rates and longer post-reinforcement pause times of female rats exposed to methyl mercury plus prenatal stress. This study has shown that, indeed, prenatal stress can enhance the behavioral toxicity of developmental methylmercury exposure: methylmercury alone reduced fixed interval response rates which were further reduced in the presence of prenatal stress, effects seen only in female offspring. Further, many effects of developmental methylmercury were non-monotonic and were actually of greater magnitude at the lower as compared to a higher methylmercury exposure concentration. Further, deficits in short-term memory in female offspring were only seen in the presence of combined exposures to methylmercury and prenatal stress. In a series of studies not supported directly by the grant, numerous examples were found in which neurochemical changes were seen in both sexes, albeit in different regions/neurotransmitters, only in the presence of combined methylmercury and prenatal stress. Notably, these cumulative effects of methylmercury and prenatal stress occurred in the absence of any effects on reproductive outcomes or in maternal behavior. These findings are reported in a manuscript currently under revision.
These data provide strong additional support for the inclusion of non-chemical stressors in risk assessment, in that assessment of lead or methylmercury effects alone, i.e., in the absence of other pertinent risk factors such as prenatal stress, could yield underestimates of the risks to human health from exposures to the chemical alone. Furthermore, these studies make increasingly clear that vulnerable populations for neurotoxic metal exposure effects need to include women who are pregnant or considering pregnancy, particularly those from high stress communities.
Community Outreach – In prior years of this project, we conducted focus groups with stakeholders and health care providers representing a range of perspectives on perinatal risks and children’s health. The findings of these focus groups emphasized the importance of developing educational messages and outreach initiatives directed at pre-natal care providers. At the same time, these community members and professionals advised against directly targeting high risk women with this information. In related work, but not directly supported by this grant, we surveyed new mothers in Monroe County and found that of 17 prenatal counseling topics, lead and mercury risks during pregnancy were among the topics least-frequently mentioned by health care providers. To respond to the insights of our focus groups and research, we focused on outreach to OB-GYNs.
These efforts were advanced through two presentations to the URMC OB-GYN research group, as well as several individual conversations with members of that department and community-based care providers. These outreach efforts yielded an invitation for a joint presentation by Drs. Cory-Slechta and Korfmacher to the OB-GYN grand rounds. As part of this effort, we have also coordinated with the Western New York Lead Poisoning Resource Center as that group enhances its outreach efforts related to lead screening, education, and testing during pregnancy.
Additionally, we have built on our partnership with the Perinatal Network to collaborate with their efforts to promote group prenatal care in our community. Group prenatal care offers an opportunity to develop relationships and targeted, in-depth education with high-risk pregnant women around a variety of educational, counseling, and resource-referral topics. However, existing curricula for group prenatal visits do not include environmental health. In the next year, we will build on these connections to develop materials on lead, mercury, and stress in pregnancy and integrate them into these programs.
During this past year, we collaborated with the community-based research component of another STAR grant (WEACT) to compare approaches, findings, and potential to inform each other’s efforts at community education. During two in-person meetings and several phone/email exchanges, we updated each other on progress in the two programs and shared ideas about educational messages. We plan to move forward by reviewing each others’ educational messages for communities at risk for both environmental exposures and elevated levels of stress.
Future Activities:
The findings that methylmercury effects can be enhanced and/or unmasked by prenatal stress will now be extended to additional behavioral baselines known to be adversely affected by methylmercury and prenatal stress separately, using mouse models. In addition, the effects of combined methylmercury and prenatal stress in rat dams from the studies described above are being examined and the extent to which alterations in dams drive changes in offspring will be assessed. Finally, the extent to which prenatal stress can enhance the effects of a third neurotoxic metal, arsenic, will be studied. We will continue to develop our prenatal education and health care provider outreach efforts and broader educational messaging.
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.