Role of Paraoxonase (PON1) Status in Pesticide Sensitivity: Genetic and Temporal Determinants Clement E. Furlong 1, * , Toby B. Cole 1,2 , Gail P. Jarvik 1 , Christina Pettan-Brewer 1 , Gary K. Geiss 1 , Rebecca J. Richter 1 , Diana M. Shih 3 , Aaron D. Tward 3 , Aldons J. Lusis 3 , Lucio G. Costa 2 1 Genome Sciences and Medicine, Division of Medical Genetics, University of Washington, Box 357720, Seattle, WA 98195-7720, USA 2 Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195-7720, USA 3 UCLA, Microbiology and Molecular Genetics, Los Angeles, CA, USA Received 14 June 2004; accepted 5 August 2004 Available online 29 September 2004 Abstract Individual differences in detoxication capacities for specific organophosphorous (OP) compounds are due largely to differences in catalytic efficiency or abundance of the HDL-associated enzyme, paraoxonase (PON1). First, we provide evidence that children less than 2 years of age represent a particularly susceptible population for OPexposure due to low abundance of PON1 and variable onset of plasma PON1 activity. Second, we describe studies examining the neurotoxic effects of chronic, low-level OP pesticide exposure in mice. PON1 knockout (PON1 À/À ) and wild-type mice were exposed chronically (PN4 to PN21) to low levels of chlorpyrifos oxon (CPO). Endpoints included cholinesterase activity, histopathology, gene expression, and behavior. Even at PN4, when PON1 levels were low in wild-type mice, PON1 À/À mice were more sensitive to inhibition of brain cholinesterase by CPO. At PN22, and persisting as long as 4 months, chronic developmental exposure to 0.18 mg/kg/d or 0.25 mg/kg/d CPO resulted in perinuclear vacuolization of cells in a discrete area of the neocortex and irregular distribution of neurons in the cortical plate, with an increase in the number of affected cells at 0.25 mg/kg/d. Third, we describe a transgenic mouse model in which human transgenes encoding either hPON1 Q192 or hPON1 R192 were expressed at equal levels in place of mouse PON1. The developmental onset of expression followed the mouse time course and was identical for the two transgenes, allowing these mice to be used to assess the importance of the Q192R polymorphism during development. Adult mice expressing hPON1 R192 were significantly more resistant than hPON1 Q192 mice to CPO toxicity. Our studies indicate that children less than 2 years old, especially those homozygous for PON1 Q192 , would be predicted to be particularly susceptible to CPO toxicity. # 2004 Elsevier Inc. All rights reserved. Keywords: Paraoxonase; PON1; Organophosphorous compound; Polymorphism INTRODUCTION This review focuses on specific genetic and temporal factors that influence sensitivity to the commonly used insecticides chlorpyrifos (Dursban 1 ) and diazinon, with a focus on the high-density lipoprotein (HDL)- associated enzyme paraoxonase (PON1). PON1 exhi- bits considerable variation among individuals due to a coding region polymorphism that alters its activity and to differences among individuals in plasma enzyme levels, which also vary temporally during develop- ment. Genetic and temporal variability in this enzyme affects not only sensitivity to pesticides, but also risk for vascular disease and pharmacokinetics of drug NeuroToxicology 26 (2005) 651–659 * Corresponding author. Tel.: +1 206 543 1193; fax: +1 206 543 3050. E-mail address: clem@u.washington.edu (C.E. Furlong). 0161-813X/$ – see front matter # 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neuro.2004.08.002