In-Vivo 1H NMR Spectroscopy of Pesticide Induced Neurotoxicity
EMSL Project ID
39723
Abstract
The developing brain is uniquely vulnerable to xenobiotic exposures at levels that do not appear to adversely impact adult brain function. In children, learning disabilities, neurological developmental delays, attention deficit disorders and behavioral anomalies are of increasing concern, and emerging evidence implicates low-level chemical exposures as causative factors. Organophosphorus (OP) insecticides are well established neurotoxicants and recent mechanistic studies suggest that OP insecticide neurotoxicity can occur at extremely low doses - - even in the absence of brain AChE inhibition. We will test the hypothesis that low-dose exposures of juvenile rats to organophosphorus insecticides, like chlorpyrifos, will result in changes in regional brain chemistry that potentially contribute to subtle neurological effects. To overcome this limitation, we will employ in-vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to measure changes in both localized brain structure and chemistry associated with OP pesticide exposures. Hence, the current project will establish a quantitative understanding of age-dependent low-dose pesticide brain dosimetry and their potential to result in adverse neurological outcomes. Moreover, the proposed MRI/MRS studies will establish a novel in vivo live animal imaging strategy that is better suited for understanding how low-dose effects result in adverse localized biological response. The following Specific Aims will be pursued: 1. To quantify age- and dose-dependent in vivo regional brain dosimetry (parent and metabolites) and biological response in preweanling rats exposed to chlorpyrifos. 2. To exploit magnetic resonance (MR) imaging and proton (1H) or phosphorus (31P) MR spectroscopy to quantify localized changes in brain structure and/or chemistry associated with low-dose chlorpyrifos exposure in preweanling rats. 3. To enhance the brain compartment in an existing age-dependent chlorpyrifos physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model to accomodate regional metabolism, dosimetry and biological response in the preweanling rat. The focus of the EMSL proposal is to demonstrate the capability to apply 1H MRS and MRSI in live neonatal rat pups as outlined in Specific Aim 2. We request rapid access to EMSL's Bruker 500 imaging system to collect initial experimental data with which to prepare an NIH funding proposal, to be submitted in June 2010. The high-field MRS/I capabilities of EMSL are required to achieve this goal. All animal procedures will be conducted in accordance with the NIH/NRC Guide and Use of Laboratory Animals, and will be approved by the Institutional Animal and Care Use Committee (IACUC) of Battelle, Pacific Northwest Division. Impact: This research will establish a novel in vivo live animal imaging/spectroscopy strategy that will enable assessment of subtle changes in regional brain chemistry resulting from low-dose exposure to environmental neurotoxicants. This novel approach has potentially broad implications for evaluation of subtle neurodevelopmental effects; hence, it will be a particularly strong research tool that can be exploited to understand low dose neurotoxicity associated with chemical, drug and radiological exposures. This research focus is also well aligned with the laboratories 2010 critical outcomes, specifically the focus on multi-modal in situ chemical imaging and analysis, with the focus on high resolution structural and chemical imaging in biological systems (i.e. developing brain).
Project Details
Project type
Limited Scope
Start Date
2010-04-26
End Date
2010-06-26
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members