Further Development of the Mouse Genetic Model
Further insights into the ability of PON1 to protect against exposure to chlorpyrifos oxon were obtained from studies with “PON1 humanized mice”. These mice were generated by Dr. Diana Shih and collaborators at UCLA. Essentially, these mice have their mouse PON1 replaced with human PON1-R192 or PON1-Q192. From the original “founder mice”, animals that expressed the same levels of each PON1-192 alloform were chosen for establishing colonies. By choosing animals producing the same levels of each alloform in their plasma, the efficacy in protecting against OP exposure could be tested at any time without having to inject purified human paraoxonase, i.e. they were designed genetically to produce their own human PON1s in the absence of mouse PON1.
The next slide shows that the animals expressing human PON1-R192 were much more resistant to cholinesterase inhibition by chlorpyrifos oxon exposure than PON1 deficient animals with PON1-Q192 expressing animals demonstrating intermediate sensitivity except at high doses, where the PON1-Q191 mice were essentially as sensitive as the PON1 deficient mice. This is a very significant observation, since ~50% of individuals of Northern European origin are homozygous for PON1-Q192.
[Cole TB, Walter BJ, Shih DM, Tward AD, Lusis AJ, Timchalk C, Richter RJ, Costa LG, Furlong CE. 2005. Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenet and Genomics 15:589-598].