Chlorpyrifos is used increasingly in the home and in agriculture because of its persistence and its relatively poor ability to elicit organophosphate (OP)-induced delayed neuropathy. Nevertheless, concern has been raised about exposure of pregnant women, infants and children. Animal studies indicate that chlorpyrifos is up to 100-fold more toxic in the newborn and that mechanisms other than cholinesterase inhibition may contribute to developmental neurotoxicity. This proposal will identify the cellular mechanisms underlying the developmental neurotoxicity. This proposal will identify the cellular mechanisms underlying the developmental neurotoxicity of chlorpyrifos, as well as the adverse behavioral outcomes consequent to developmental exposure, so as to provide appropriate biomarkers with which to estimate the NOAEL and to identify the window of vulnerability. We will examine two models, one for mammalian neurotoxicity (rat) and one for piscine neurotoxicity (zebrafish). The mammalian model will provide a closer model for human health effects and the piscine model will provide a potential biomarker for environmental monitoring. The zebrafish model is also valuable because the processes of neurodevelopment are readily observable since the embryo is transparent. In both cases we will concentrate on the specific targeting of brain development at exposure levels below the threshold of dysmorphogenesis or standard teratogenesis. There are three Aims: I. To determine the cellular mechanisms by which chlorpyrifos disrupts mammalian neural cell replication and differentiation; signaling cascades that control nuclear transcription factors involved in cell replication, differentiation and apoptosis; comparison to cholinesterase inhibition. II. To determine the functional consequence of chlorpyrifos' effects on cell development: behavioral responses and their corresponding, underlying neurochemical mechanisms; we will concentrate on neural pathways and neurotransmitter systems already identified in our preliminary results as likely targets. III. To develop a non-mammalian model of developmental neurotoxicity of chlorpyrifos for estimation of NOAEL in ectotoxicologic settings: zebrafish provides a relevant piscine species for ectotoxicologic risk determination while at the same time providing transgenic models for specific molecular/cellular events in neurodevelopment. Molecular mechanisms of developmental neurotoxicity can be determined and linked to eventual alterations in behavioral performance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES010387-03
Application #
6518174
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Kirshner, Annette G
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
3
Fiscal Year
2002
Total Cost
$192,500
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Slotkin, Theodore A; Seidler, Frederic J (2006) Anomalous regulation of beta-adrenoceptor signaling in brain regions of the newborn rat. Brain Res 1077:54-8
Aldridge, Justin E; Meyer, Armando; Seidler, Frederic J et al. (2005) Developmental exposure to terbutaline and chlorpyrifos: pharmacotherapy of preterm labor and an environmental neurotoxicant converge on serotonergic systems in neonatal rat brain regions. Toxicol Appl Pharmacol 203:132-44
Roy, Tara Sankar; Sharma, Vikram; Seidler, Frederic J et al. (2005) Quantitative morphological assessment reveals neuronal and glial deficits in hippocampus after a brief subtoxic exposure to chlorpyrifos in neonatal rats. Brain Res Dev Brain Res 155:71-80
Aldridge, Justin E; Levin, Edward D; Seidler, Frederic J et al. (2005) Developmental exposure of rats to chlorpyrifos leads to behavioral alterations in adulthood, involving serotonergic mechanisms and resembling animal models of depression. Environ Health Perspect 113:527-31
Qiao, Dan; Seidler, Frederic J; Slotkin, Theodore A (2005) Oxidative mechanisms contributing to the developmental neurotoxicity of nicotine and chlorpyrifos. Toxicol Appl Pharmacol 206:17-26
Aldridge, Justin E; Meyer, Armando; Seidler, Frederic J et al. (2005) Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure. Environ Health Perspect 113:1027-31
Meyer, Armando; Seidler, Frederic J; Aldridge, Justin E et al. (2005) Developmental exposure to terbutaline alters cell signaling in mature rat brain regions and augments the effects of subsequent neonatal exposure to the organophosphorus insecticide chlorpyrifos. Toxicol Appl Pharmacol 203:154-66
Slotkin, Theodore A; Seidler, Frederic J (2005) The alterations in CNS serotonergic mechanisms caused by neonatal chlorpyrifos exposure are permanent. Brain Res Dev Brain Res 158:115-9
Slotkin, Theodore A; Tate, Charlotte A; Cousins, Mandy M et al. (2005) Imbalances emerge in cardiac autonomic cell signaling after neonatal exposure to terbutaline or chlorpyrifos, alone or in combination. Brain Res Dev Brain Res 160:219-30
Slotkin, Theodore A; Oliver, Colleen A; Seidler, Frederic J (2005) Critical periods for the role of oxidative stress in the developmental neurotoxicity of chlorpyrifos and terbutaline, alone or in combination. Brain Res Dev Brain Res 157:172-80

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