Repeated development exposure of mice to chlorpyrifos oxon is associated with paraoxonase 1 (PON1)-modulated effects on cerebellar gene expression

Microarray analysis was used to examine effects of repeated postnatal exposure to chlorpyrifos oxon (CPO) on gene expression in the cerebellum of genetically modified mice. The high-density lipoprotein-associated enzyme paraoxonase 1 (PON1) plays a significant role in the detoxication of CPO, which is present in exposures and generated from chlorpyrifos (CPF) in vivo following exposure. Two factors are important in modulating toxicity of CPO, the Q192R PON1 polymorphism and PON1 plasma level, which is low at birth and increases throughout postnatal development. Mice used in these studies included wild type (PON1(+/+)), PON1 knockout (PON1(-/-)), and two transgenic lines (tgHuPON1(Q192), tgHuPON1(R192)) expressing either human PON1(Q192) or PON1(R192) on the PON1(-/-) background. PON1(R192) hydrolyzes CPO more efficiently than PON1(Q192). All four genotypes exposed to CPO (0.35 or 0.50 mg/kg/day) daily from postnatal day (PND) 4 to PND 21 showed significant differences in gene expression on PND 22 compared with controls. Pathway analysis and Gene Set Analysis revealed multiple pathways and gene sets significantly affected by CPO exposure, including genes involved in mitochondrial dysfunction, oxidative stress, neurotransmission, and nervous system development. Comparison between genotypes revealed specific genes, gene sets, and pathways differentially affected between tgHuPON1(Q192) and tgHuPON1(R192) mice and between PON1(-/-) and PON1(+/+) mice following CPO exposure. Repeated CPO exposure also resulted in a dose-related decrease in brain acetylcholinesterase activity during postnatal development in PON1(-/-) and tgHuPON1(Q192) mice but not in PON1(+/+) or tgHuPON1(R192) mice. These findings indicate that PON1 status plays a critical role in modulating the effects of neonatal CPO exposure in the developing brain