Role of Paraoxonase Enzyme Level and Polymorphisms in Pesticide Sensitivity

Clement Furlong, Toby Cole, Ph.D., and Lucio Costa, Ph.D.
University of Washington
P01ES09601, R01ES09883, P42ES04696, P30ES07033, and U19ES011387

Background: Human population studies have shown large variation in levels of an enzyme responsible for metabolizing organophosphate insecticides known as paraoxonase (PON1). These differences explain part of the large variability in sensitivity to the pesticides seen among people. These studies also led to the discovery that babies do not attain adult levels of PON1 until they reach 1-2 years of age, explaining in part the increased sensitivity of young children to specific organophosphate compounds. Mutations in the regulatory region of the PON1 gene have been shown to contribute to the widely different levels of PON1 in the population. Experiments showing that injected PON1 could provide resistance to organophosphate compounds provided impetus for considering PON1 as a possible therapeutic treatment for nerve agent exposure.

Advance: In new studies performed by NIEHS-supported researchers at the University of Washington, low-level exposure of PON1 knockout mice to chlorpyrifos oxon, an organophosphate metabolite, caused neurotoxic effects on the first day of exposure (post-natal day four) when PON1 levels are very low in wild-type mice. At post-natal day 22, and persisting as long as four months, chronic exposure to low doses of chlorpyrifos oxon resulted in perinuclear vacuolization of specific brain cells and an irregular distribution of neurons in the cortical plate. The studies also employed a transgenic mouse model in which human genes encoding either of two PON1 polymorphisms (hPON1Q192 or hPON1R192) were expressed at equal levels in place of mouse PON1. Expression of the genes followed the normal mouse time course and was identical, allowing these mice to be used to assess the importance of the Q192R polymorphism during development. Adult mice expressing hPON1R192 were significantly more resistant than hPON1Q192 mice to chlorpyrifos oxon toxicity.

Implications: These studies build on the previous results describing the susceptibility of young children to organophosphate insecticides. The most important conclusion is that PON1 enzyme level and individual phenotype are both critical for determining an individual’s response to organophosphate exposure. The results indicate that children less than 2 years old, especially those homozygous for PON1Q192, would be predicted to be particularly susceptible to chlorpyrifos oxon toxicity.

Citation: Furlong CE, Cole TB, Jarvik GP, Pettan-Brewer C, Geiss GK, Richter RJ, Shih DM, Tward AD, Lusis AJ, Costa LG. Role of paraoxonase (PON1) status in pesticide sensitivity: genetic and temporal determinants. Neurotoxicology. 2005 Aug;26(4):651-9.