title: Repeated gestational exposure of mice to chlorpyrifos oxon is associated with paraoxonase 1 (PON1) modulated effects in maternal and fetal tissues.
abstract: 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 enzyme 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 day (GD) 6 through 17 were sacrificed on GD18. Biomarkers of CPO exposure inhibited in maternal tissues included brain acetylcholinesterase (AChE), red blood cell acylpeptide hydrolase (APH), and 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. Weighted gene co-expression network analysis identified five gene modules based on clustering of the correlations among their fetal-brain expression values, allowing for correlation of module membership with the phenotypic data on enzyme inhibition. One module that correlated highly with maternal brain AChE activity had a large representation of homeobox genes. Gene set enrichment analysis revealed multiple gene sets affected by gestational CPO exposure in tgHuPON1Q192 but not tgHuPON1R192 mice, including gene sets involved in protein export, lipid metabolism, and neurotransmission. These data indicate that maternal PON1 status modulates the effects of repeated gestational CPO exposure on fetal-brain gene expression and on inhibition of both maternal and fetal biomarker enzymes.
authors: Department of Medicine, Division of Medical Genetics Department of Environmental and Occupational Health Sciences Department of Genome Sciences Center on Human Development and Disability clem@u.washington.edu.
authors: Toby B
authors: TB
authors: Cole
authors: Department of Medicine, Division of Medical Genetics clem@u.washington.edu.
authors: Wan-Fen
authors: WF
authors: Li
authors: Department of Medicine, Division of Medical Genetics Department of Genome Sciences.
authors: Aila L
authors: AL
authors: Co
authors: Department of Medicine, Division of Medical Genetics Department of Genome Sciences.
authors: Ariel M
authors: AM
authors: Hay
authors: Department of Environmental and Occupational Health Sciences Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington 98195.
authors: James W
authors: JW
authors: MacDonald
authors: Department of Environmental and Occupational Health Sciences Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington 98195.
authors: Theo K
authors: TK
authors: Bammler
authors: Department of Environmental and Occupational Health Sciences Center for Ecogenetics and Environmental Health, University of Washington, Seattle, Washington 98195.
authors: Federico M
authors: FM
authors: Farin
authors: Department of Environmental and Occupational Health Sciences Department of Neuroscience, University of Parma, Parma, Italy.
authors: Lucio G
authors: LG
authors: Costa
authors: Department of Medicine, Division of Medical Genetics Department of Genome Sciences clem@u.washington.edu.
authors: Clement E
authors: CE
authors: Furlong
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D043303:Aryldialkylphosphatase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002091:Butyrylcholinesterase / Q000097:blood; D043182:Carboxylesterase / Q000097:blood; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055106:Genome-Wide Association Study; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D007306:Insecticides / Q000633:toxicity*; D018811:Maternal Exposure; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010447:Peptide Hydrolases / Q000097:blood; D010641:Phenotype; D011110:Polymorphism, Genetic; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D058851:GPI-Linked Proteins; D007306:Insecticides; D012333:RNA, Messenger; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; D043182:Carboxylesterase; D000110:Acetylcholinesterase; C548245:Ache protein, mouse; D002091:Butyrylcholinesterase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; C560867:PON1 protein, mouse; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase; D004390:Chlorpyrifos
keywords: Chlorpyrifos oxon; microarrays; neurotoxicity; organophosphorus insecticides; paraoxonase-1; transgenic mice