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

Cole, Toby B.a b c; Walter, Betsy J.a; Shih, Diana M.d; Tward, Aaron D.e; Lusis, Aldons J.d; Timchalk, Charlesf; Richter, Rebecca J.b c; Costa, Lucio G.a; Furlong, Clement E.b c

Pharmacogenetics and Genomics: August 2005 - Volume 15 - Issue 8 - p 589-598
doi: 10.1097/01.fpc.0000167327.08034.d2
ORIGINAL ARTICLES

Objectives 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.

Methods 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.

Results Mice expressing PON1 Q192 were significantly more sensitive to CPO, and to a lesser extent CPS, than were mice expressing PON1 R192. 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.

Conclusion 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.

Departments of aEnvironmental and Occupational Health Sciences

bMedicine, Division of Medical Genetics

cGenome Sciences, University of Washington, Seattle, Washington, USA

dDepartment of Microbiology and Molecular Genetics, and Division of Cardiology, Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA

eG.W. Hooper Foundation, UCSF, San Francisco, California, USA

fCenter for Biological Monitoring and Modeling, Battelle, Pacific Northwest Division, Richland, Washington, USA

Sources of support: ES09883, ES07033, ES-09601/EPA-R826886, ES04696, T32-AG00057, U19 ES11387, P01 HL30568 and CDC 5 R01 OH003629-03.

Correspondence and requests for reprints to C.E. Furlong, University of Washington, Division of Medical Genetics, Box 357720, Seattle, WA 98195-7720, USA

Fax: +1 206 543 3050; e-mail: clem@u.washington.edu

Received 1 March 2005 Accepted 14 April 2005

© 2005 Lippincott Williams & Wilkins, Inc.