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Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism.

Authors
Cole-TB; Walter-BJ; Shih-DM; Tward-AD; Lusis-AJ; Timchalk-C; Richter-RJ; Costa-LG; Furlong-CE
Source
Pharmacogenet Genomics 2005 Aug; 15(8):589-598
NIOSHTIC No.
20030078
Abstract
The Q192R polymorphism of paraoxonase (PON1) has been shown to affect hydrolysis of organophosphorus compounds. The Q192 and R192 alloforms exhibit equivalent catalytic efficiencies of hydrolysis for diazoxon, the oxon form of the pesticide (DZ). However, the R192 alloform has a higher catalytic efficiency of hydrolysis than does the Q192 alloform for chlorpyrifos oxon (CPO), the oxon form of the pesticide chlorpyrifos (CPS). The current study examined the relevance of these observations for in-vivo exposures to chlorpyrifos and chlorpyrifos oxon. Using a transgenic mouse model we examined the relevance of the Q192R polymorphism for exposure to CPS and CPO in vivo. Transgenic mice were generated that expressed either human PON1Q192 or PON1R192 at equivalent levels, in the absence of endogenous mouse PON1. Dose-response and time course experiments were performed on adult mice exposed dermally to CPS or CPO. Morbidity and acetylcholinesterase (AChE) activity in the brain and diaphragm were determined in the first 24 h following exposure. Mice expressing PON1Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1R192. The time course of inhibition following exposure to 1.2 mg/kg CPO revealed maximum inhibition of brain AChE at 6-12 h, with PON1R192, PON1Q192, and PON1 mice exhibiting 40, 70 and 85% inhibition, respectively, relative to control mice. The effect of PON1 removal on the dose-response curve for CPS exposure was remarkably consistent with a PBPK/PD model of CPS exposure. These results indicate that individuals expressing only the PON1Q192 allele would be more sensitive to the adverse effects of CPO or CPS exposure, especially if they are expressing a low level of plasma PON1Q192.
Keywords
Toxins; Toxic-effects; Models; Laboratory-animals; Animals; Animal-studies; Organo-phosphorus-compounds; Pesticides; Pesticides-and-agricultural-chemicals; Exposure-levels; Exposure-assessment
Publication Date
20050801
Document Type
Journal Article
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2005
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
Issue of Publication
8
ISSN
1744-6872
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Pharmacogenetics and Genomics
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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