PMID- 25070982
OWN - NLM
STAT- MEDLINE
DCOM- 20151102
LR  - 20211021
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 141
IP  - 2
DP  - 2014 Oct
TI  - Repeated gestational exposure of mice to chlorpyrifos oxon is associated with 
      paraoxonase 1 (PON1) modulated effects in maternal and fetal tissues.
PG  - 409-22
LID - 10.1093/toxsci/kfu144 [doi]
AB  - 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.
CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the Society 
      of Toxicology. All rights reserved. For permissions, please email: 
      journals.permissions@oup.com.
FAU - Cole, Toby B
AU  - Cole TB
AD  - 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.
FAU - Li, Wan-Fen
AU  - Li WF
AD  - Department of Medicine, Division of Medical Genetics clem@u.washington.edu.
FAU - Co, Aila L
AU  - Co AL
AD  - Department of Medicine, Division of Medical Genetics Department of Genome 
      Sciences.
FAU - Hay, Ariel M
AU  - Hay AM
AD  - Department of Medicine, Division of Medical Genetics Department of Genome 
      Sciences.
FAU - MacDonald, James W
AU  - MacDonald JW
AD  - Department of Environmental and Occupational Health Sciences Center for 
      Ecogenetics and Environmental Health, University of Washington, Seattle, 
      Washington 98195.
FAU - Bammler, Theo K
AU  - Bammler TK
AD  - Department of Environmental and Occupational Health Sciences Center for 
      Ecogenetics and Environmental Health, University of Washington, Seattle, 
      Washington 98195.
FAU - Farin, Federico M
AU  - Farin FM
AD  - Department of Environmental and Occupational Health Sciences Center for 
      Ecogenetics and Environmental Health, University of Washington, Seattle, 
      Washington 98195.
FAU - Costa, Lucio G
AU  - Costa LG
AD  - Department of Environmental and Occupational Health Sciences Department of 
      Neuroscience, University of Parma, Parma, Italy.
FAU - Furlong, Clement E
AU  - Furlong CE
AD  - Department of Medicine, Division of Medical Genetics Department of Genome 
      Sciences clem@u.washington.edu.
LA  - eng
GR  - U54 HD083091/HD/NICHD NIH HHS/United States
GR  - P42-ES04696/ES/NIEHS NIH HHS/United States
GR  - P30-HD02274/HD/NICHD NIH HHS/United States
GR  - U19-ES11387/ES/NIEHS NIH HHS/United States
GR  - R01-ES09883/ES/NIEHS NIH HHS/United States
GR  - R01-ES09601/ES/NIEHS NIH HHS/United States
GR  - P30-ES07033/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140728
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (GPI-Linked Proteins)
RN  - 0 (Insecticides)
RN  - 0 (RNA, Messenger)
RN  - 5598-15-2 (O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate)
RN  - EC 3.1.1.1 (Carboxylesterase)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
RN  - EC 3.1.1.7 (Ache protein, mouse)
RN  - EC 3.1.1.8 (Butyrylcholinesterase)
RN  - EC 3.1.8.1 (Aryldialkylphosphatase)
RN  - EC 3.1.8.1 (PON1 protein, human)
RN  - EC 3.1.8.1 (PON1 protein, mouse)
RN  - EC 3.4.- (Peptide Hydrolases)
RN  - EC 3.4.19.1 (acylaminoacyl-peptidase)
RN  - JCS58I644W (Chlorpyrifos)
SB  - IM
MH  - Acetylcholinesterase/metabolism
MH  - Animals
MH  - Aryldialkylphosphatase/deficiency/genetics/*metabolism
MH  - Brain/*drug effects/enzymology
MH  - Butyrylcholinesterase/blood
MH  - Carboxylesterase/blood
MH  - Chlorpyrifos/*analogs & derivatives/toxicity
MH  - Erythrocytes/drug effects/enzymology
MH  - Female
MH  - GPI-Linked Proteins/metabolism
MH  - Gene Expression Profiling/methods
MH  - Gene Expression Regulation, Developmental/drug effects
MH  - Genome-Wide Association Study
MH  - Genotype
MH  - Gestational Age
MH  - Humans
MH  - Insecticides/*toxicity
MH  - Maternal Exposure
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Oligonucleotide Array Sequence Analysis
MH  - Peptide Hydrolases/blood
MH  - Phenotype
MH  - Polymorphism, Genetic
MH  - Pregnancy
MH  - RNA, Messenger/metabolism
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC4271046
OTO - NOTNLM
OT  - Chlorpyrifos oxon
OT  - microarrays
OT  - neurotoxicity
OT  - organophosphorus insecticides
OT  - paraoxonase-1
OT  - transgenic mice
EDAT- 2014/07/30 06:00
MHDA- 2015/11/03 06:00
PMCR- 2015/10/01
CRDT- 2014/07/30 06:00
PHST- 2014/07/30 06:00 [entrez]
PHST- 2014/07/30 06:00 [pubmed]
PHST- 2015/11/03 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - kfu144 [pii]
AID - 10.1093/toxsci/kfu144 [doi]
PST - ppublish
SO  - Toxicol Sci. 2014 Oct;141(2):409-22. doi: 10.1093/toxsci/kfu144. Epub 2014 Jul 
      28.