Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Cole TB

PROVIDER: S-EPMC3164442 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Cole Toby B TB Beyer Richard P RP Bammler Theo K TK Park Sarah S SS Farin Federico M FM Costa Lucio G LG Furlong Clement E CE

Toxicological sciences : an official journal of the Society of Toxicology 20110614 1

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, wh ...[more]

PMID: 21673326

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Project description:Chlorpyrifos oxon (CPO), the toxic metabolite of the organophosphorus (OP) insecticide chlorpyrifos, causes developmental neurotoxicity in humans and rodents. CPO is hydrolyzed by paraoxonase-1 (PON1), with protection determined by PON1 levels and the human Q192R polymorphism. To examine how the Q192R polymorphism influences fetal toxicity associated with gestational CPO exposure, we measured biomarker inhibition and fetal-brain gene expression in wild-type (PON1+/+), PON1-knockout (PON1-/-), and tgHuPON1R192 and tgHuPON1Q192 transgenic mice. Pregnant mice exposed dermally to 0, 0.50, 0.75 or 0.85 mg/kg/d CPO from gestational days (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), RBC acylpeptide hydrolase (APH), plasma butyrylcholinesterase (BChE) and carboxylesterase (CES). Fetal plasma BChE was inhibited in PON1-/- and tgHuPON1Q192, but not PON1+/+ or tgHuPON1R192 mice. Fetal brain AChE and plasma CES were inhibited in PON1-/- mice, but not in other genotypes. Pregnant mice (wild type (WT), PON1-knockout (KO), tgHuPON1R192 (R-tg) and tgHuPON1Q192 (Q-tg)) were exposed to various amounts of CPO (0, 0.5, 0.75 and 0.85 mg/kg/d) for 12 days (gestational days 6-17). On gestational day 18, dams were sacrificed and fetal brains were collected. A total of 264 fetal brains from 80 dams were processed to extract total RNA using TRIZOL and the QIAamp Tissue kit from QIAGEN. Microarray analysis was performed using the fetuses of 5 dams per experimental group (total RNA was pooled from individual fetal brains from each dam). The dams used for fetal-brain microarray analysis were selected using a random-number generator, after first eliminating dams with brain AChE activities > 1.5 SD compared to the mean for their treatment group. RNA samples isolated from individual fetal brains from each dam were combined, then labeled and hybridized to Affymetrix Mouse Gene 1.0 ST microarrays.

Project description:Chlorpyrifos (CPF), one of the most widely-used organophosphorus (OP) insecticides in agriculture, is degraded in the field to its oxon form, chlorpyrifos-oxon (CPO), which can represent a significant contaminant in exposures to adults and children. CPO is also responsible for the acetylcholinesterase (AChE) inhibition associated with CPF exposures; CPF is converted by liver CYP450 enzymes to CPO, which binds to and inhibits AChE and other serine active-site esterases, lipases and proteases. Young children represent a particularly susceptible population for exposure to CPF and CPO, in part because levels of the plasma enzyme, paraoxonase (PON1), which hydrolyzes CPO, are very low during early development. While a number of studies have demonstrated developmental neurotoxicity associated with CPF exposure, including effects at or below the threshold levels for AChE inhibition, it is unclear whether these effects were due directly to CPF or to its active metabolite, CPO. PON1 knockout (PON1-/-) mice, which lack PON1, represent a highly sensitive mouse model for toxicity associated with exposure to CPF or CPO. To examine the neurobehavioral consequences of CPO exposure during postnatal development, PON1-/- mice were exposed daily from PND 4 to PND 21 to CPO at 0.15, 0.18, or 0.25 mg/kg/d. A neurobehavioral test battery did not reveal significant effects of CPO on early reflex development, motor coordination, pre-pulse inhibition of startle, startle amplitude, open field behavior, or learning and memory in the contextual fear conditioning, Morris water maze, or water radial-arm maze tests. However, body weight gain and startle latency were significantly affected by exposure to 0.25 mg/kg/d CPO. Additionally, from PNDs 15-20 the mice exposed repeatedly to CPO at all three doses exhibited a dose-related transient hyperkinesis in the 20-min period following CPO administration, suggesting possible effects on catecholaminergic neurotransmission. Our previous study demonstrated wide-ranging effects of neonatal CPO exposure on gene expression in the brain and on brain AChE inhibition, and modulation of both of these effects by the PON1(Q192R) polymorphism. The current study indicates that the neurobehavioral consequences of these effects are more elusive, and suggests that alternative neurobehavioral tests might be warranted, such as tests of social interactions, age-dependent effects on learning and memory, or tests designed specifically to assess dopaminergic or noradrenergic function.

Dataset Information

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

Publications

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

Similar Datasets

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