International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 27 - GENETIC VARIABILITY IN PARAOXONASE (PON1): RELEVANCE FOR ACUTE PESTICIDE EXPOSURE DURING DEVELOPMENT

Walter BJ 1, Cole TB 1, Pettan-Brewer C 1, Fisher JC 1, Shih DM 1, Tward A 2, Lusis AJ 2, Costa LG 1, Furlong CE 2

1 University of Washington, Seattle, United States, 2 UCLA, Los Angeles, United States,

Paraoxonase (PON1) is an HDL-associated enzyme that metabolizes organophosphorous (OP) pesticides, drugs, and oxidized lipids. PON1 activity is determined in part by a coding region polymorphism (Q192R) that affects its catalytic efficiency and in part by differences in PON1 levels, which vary widely (>13-fold). To assess the importance of the Q192R polymorphism for OP detoxication during development, transgenic mice were used that expressed human transgenes encoding hPON1Q192 or hPON1R192 at equal levels in place of mouse PON1. Dose-response curves were generated for exposure of developing mice (PND 4, 13, or 21) to chlorpyrifos, diazinon, and their oxon metabolites. Mice expressing hPON1R192 were more resistant than hPON1Q192 mice to CPO toxicity during development, despite a similar onset of expression between the two transgenic lines. These studies, together with other studies in our laboratory, indicate that children less than 2 yr old, especially those homozygous for PON1Q192, are particularly susceptible to OP toxicity. Supported by T32 AG00057, ES09601/EPA-R826886, ES09883, ES04696, ES07033, ES11387.

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