Superfund Research Program

Developmental Neurotoxicity of Superfund Pesticides: Biomarkers and Mechanisms

Project Leader: Theodore A. Slotkin (Duke University Medical Center)
Grant Number: P42ES010356
Funding Period: 2000-2011

Project-Specific Links

Final Progress Reports

Year:   2004 

Exposure of pregnant women and children to pesticides represents one of the major problems of neurodevelopment. This project examines the widely used organophosphate insecticide, chlorpyrifos, evaluating both the mechanisms underlying its adverse effects on the developing brain and the critical periods delineating developmental vulnerability. In addition, project investigators are exploring non-mammalian test systems that might permit rapid detection of developmental neurotoxicity by related or unrelated pesticides.  The research spans all levels of organization, from the cellular and molecular events underlying the toxic mechanisms, through the morphological assembly of the nervous system and the eventual behavioral outcomes.  The research team at Duke University has completed major studies focusing on the specific targets in the developing brain, on the long-term consequences of exposure during early development, and on use of lower organisms or cell cultures for surrogate screening of developmental neurotoxicity.  Using both neural cell culture systems and in vivo treatment of developing rats, the investigators found that the active agent was chlorpyrifos itself, not chlorpyrifos oxon, the active metabolite that inhibits cholinesterase.  As a consequence of the direct targeting of neural cell development, the adverse effects of chlorpyrifos extend to neural systems beyond those typically studied for organophosphate insecticides, and in the past year, the researchers have made significant strides toward understanding adverse effects on acetylcholine and serotonin systems; these systems are especially important in learning and memory, and in the regulation of appetite and mood, so that chlorpyrifos-induced effects may be expressed as cognitive impairment, obesity or depression. Because some of the cellular events extend to signaling mediated in peripheral organs, such as liver and heart, the researchers are exploring the relationship of developmental chlorpyrifos exposure to later disorders such as diabetes. Finally, investigators have initiated studies to identify factors that render subpopulations especially vulnerable to organophosphate pesticides, focusing on the pharmacotherapies used in preterm labor, which affects 10% of the US population. 

The researcher’s results are important for three reasons:  the vulnerable period for developmental neurotoxicity of chlorpyrifos extends from early prenatal stages through childhood, an unusually wide window of action. Second, since chlorpyrifos itself is the culprit, the use of cholinesterase activity as a biomarker for these adverse effects is inappropriate, necessitating a revised approach to the detection of developmental neurotoxicity. Third, the fact that a wide variety of neurotransmitter systems are affected means that heretofore unsuspected types of behavioral damage are likely to result.  These results open up new areas for exploration of the consequences of developmental exposure to pesticides. Finally, the project investigators began evaluating the use of an avian species (chicken) for high-throughput screening for developmental neurotoxicity of chlorpyrifos and related pesticides.