Journal
TOXICOLOGICAL SCIENCES
Volume 125, Issue 1, Pages 233-247Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfr261
Keywords
NMDA receptor; neuronal activity; neurogenesis; synaptogenesis; polycyclic aromatic hydrocarbon; benzo(a)pyrene; susceptibility-exposure paradigm; B(a)P metabolites; object discrimination task
Categories
Funding
- National Institutes of Health [S11ES014156-05, U54NS041071, 1R56ES017448-01A1, 1R01CA142845-01A1, 1R01NS071122-01A1, 1R01DA026947-01A1]
- Simons Foundation Autism Research Initiative, Institutional [G12RRO3032]
- Nuclear Regulatory Commission [NRC-27-10-515]
- Meharry Medical College [T32MH065782]
- U.S. Nuclear Regulatory Commission
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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(450)1B1-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 mu g/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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