International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


Pettan-Brewer C, Cole TB, Walter BJ, Fisher JC, Richter RJ, Burbacher TM, Costa LG, Furlong CE

University of Washington, Seattle, United States

Paraoxonase (PON1) is an HDL-associated enzyme involved in the metabolism of organophosphorous pesticides. We demonstrate that infants have very low PON1 levels and a variable onset of expression, reaching a plateau at 6-24 mo. To assess the importance of PON1 for protecting against the developmental toxicity of chlorpyrifos oxon (CPO), PON1 knockout (PON1-/-) and wild-type (WT) mice were exposed chronically (PN4 to PN21) to low levels of CPO. Endpoints included cholinesterase activity, histopathology, gene expression, and behavior. As early as PN4, PON1-/- 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, with an increase in the number of affected cells at 0.25 mg/kg/d. Surprisingly, none of the behaviors chosen for assessment were affected. However, from ~PN16-19, mice exposed to 0.18 or 0.25 mg/kg/d exhibited striking hyperactivity immediately following CPO administration. These studies revealed toxicity associated with low-level OP exposure and indicate that children less than 2 yr old represent a particularly susceptible population for OP exposure. Supported by T32 AG00057, ES09601/EPA-R826886, ES09883, ES04696, ES07033, ES11387.

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