PAH particles perturb prenatal processes and phenotypes

Protection from deficits in object discrimination afforded by dampening of brain oxidoreductase following In Utero exposure to inhaled benzo(a)pyrene

Zhu Li, Gayathri Chadalapaka, Aramandla Ramesh, Habibeh Khoshbouei, Mark Maguire, Stephen Safe, Raina E. Rhoades, Ryan Clark, George Jules, Monique McCallister, Michael Aschner, Darryl B. Hood

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The wild-type (WT) Cpr lox/lox (cytochrome P 450 oxidoreductase, Cpr) mouse is an ideal model to assess the contribution of P 450 enzymes to the metabolic activation and disposition of environmental xenobiotics. In the present study, we examined the effect of in utero exposure to benzo(a)pyrene [B(a)P] aerosol on Sp4 and N-methyl-D-aspartate (NMDA)-dependent systems as well as a resulting behavioral phenotype (object discrimination) in Cpr offspring. Results from in utero exposure of WT Cpr lox/lox mice were compared with in utero exposed brain-Cpr-null offspring mice. Null mice were used as they do not express brain cytochrome P 4501B1-associated NADPH oxidoreductase (CYP1B1-associated NADPH oxidoreductase), thus reducing their capacity to produce neural B(a)P metabolites. Subsequent to in utero (E14-E17) exposure to B(a)P (100 μg/m 3), Cpr lox/lox offspring exhibited: (1) elevated B(a)P metabolite and F 2-isoprostane neocortical tissue burdens, (2) elevated concentrations of cortical glutamate, (3) premature developmental expression of Sp4, (4) decreased subunit ratios of NR2B:NR2A, and (5) deficits in a novelty discrimination phenotype monitored to in utero exposed brain-Cpr-null offspring. Collectively, these findings suggest that in situ generation of metabolites by CYP1B1-associated NADPH oxidoreductase promotes negative effects on NMDA-mediated signaling processes during the period when synapses are first forming as well as effects on a subsequent behavioral phenotype.

Original languageEnglish (US)
Article numberkfr261
Pages (from-to)233-247
Number of pages15
JournalToxicological Sciences
Volume125
Issue number1
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

Benzo(a)pyrene
Polycyclic aromatic hydrocarbons
Brain
Oxidoreductases
Metabolites
NADP
Phenotype
N-Methylaspartate
Cytochrome P-450 Enzyme System
Isoprostanes
Xenobiotics
Cytochromes
Aerosols
Synapses
Glutamic Acid
Chemical activation
Tissue

Keywords

  • B(a)P metabolites
  • Benzo(a)pyrene
  • Neurogenesis
  • Neuronal activity
  • NMDA receptor
  • Object discrimination task
  • Polycyclic aromatic hydrocarbon
  • Susceptibility-exposure paradigm
  • Synaptogenesis

ASJC Scopus subject areas

  • Toxicology

Cite this

PAH particles perturb prenatal processes and phenotypes : Protection from deficits in object discrimination afforded by dampening of brain oxidoreductase following In Utero exposure to inhaled benzo(a)pyrene. / Li, Zhu; Chadalapaka, Gayathri; Ramesh, Aramandla; Khoshbouei, Habibeh; Maguire, Mark; Safe, Stephen; Rhoades, Raina E.; Clark, Ryan; Jules, George; McCallister, Monique; Aschner, Michael; Hood, Darryl B.

In: Toxicological Sciences, Vol. 125, No. 1, kfr261, 2012, p. 233-247.

Research output: Contribution to journalArticle

Li, Zhu ; Chadalapaka, Gayathri ; Ramesh, Aramandla ; Khoshbouei, Habibeh ; Maguire, Mark ; Safe, Stephen ; Rhoades, Raina E. ; Clark, Ryan ; Jules, George ; McCallister, Monique ; Aschner, Michael ; Hood, Darryl B. / PAH particles perturb prenatal processes and phenotypes : Protection from deficits in object discrimination afforded by dampening of brain oxidoreductase following In Utero exposure to inhaled benzo(a)pyrene. In: Toxicological Sciences. 2012 ; Vol. 125, No. 1. pp. 233-247.
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abstract = "The wild-type (WT) Cpr lox/lox (cytochrome P 450 oxidoreductase, Cpr) mouse is an ideal model to assess the contribution of P 450 enzymes to the metabolic activation and disposition of environmental xenobiotics. In the present study, we examined the effect of in utero exposure to benzo(a)pyrene [B(a)P] aerosol on Sp4 and N-methyl-D-aspartate (NMDA)-dependent systems as well as a resulting behavioral phenotype (object discrimination) in Cpr offspring. Results from in utero exposure of WT Cpr lox/lox mice were compared with in utero exposed brain-Cpr-null offspring mice. Null mice were used as they do not express brain cytochrome P 4501B1-associated NADPH oxidoreductase (CYP1B1-associated NADPH oxidoreductase), thus reducing their capacity to produce neural B(a)P metabolites. Subsequent to in utero (E14-E17) exposure to B(a)P (100 μg/m 3), Cpr lox/lox offspring exhibited: (1) elevated B(a)P metabolite and F 2-isoprostane neocortical tissue burdens, (2) elevated concentrations of cortical glutamate, (3) premature developmental expression of Sp4, (4) decreased subunit ratios of NR2B:NR2A, and (5) deficits in a novelty discrimination phenotype monitored to in utero exposed brain-Cpr-null offspring. Collectively, these findings suggest that in situ generation of metabolites by CYP1B1-associated NADPH oxidoreductase promotes negative effects on NMDA-mediated signaling processes during the period when synapses are first forming as well as effects on a subsequent behavioral phenotype.",
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AU - Maguire, Mark

AU - Safe, Stephen

AU - Rhoades, Raina E.

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