TY - JOUR
T1 - PAH particles perturb prenatal processes and phenotypes
T2 - Protection from deficits in object discrimination afforded by dampening of brain oxidoreductase following In Utero exposure to inhaled benzo(a)pyrene
AU - Li, Zhu
AU - Chadalapaka, Gayathri
AU - Ramesh, Aramandla
AU - Khoshbouei, Habibeh
AU - Maguire, Mark
AU - Safe, Stephen
AU - Rhoades, Raina E.
AU - Clark, Ryan
AU - Jules, George
AU - McCallister, Monique
AU - Aschner, Michael
AU - Hood, Darryl B.
N1 - Funding Information:
This research was supported in part by an appointment to the U.S. Nuclear Regulatory Commission HBCU Research Participation Program administered by the Oak Ridge Institute for Science and Education.
Funding Information:
This work was supported, in part, by National Institutes of Health (S11ES014156–05, U54NS041071, and 1R56ES017448-01A1 to D.B.H, 1R01CA142845-01A1 to A.R., 1R01NS071122-01A1 and 1R01DA026947-01A1 to H.K). Also critical to the conduct of these studies were grants from the Simons Foundation Autism Research Initiative, Institutional Grant (G12RRO3032), Nuclear Regulatory Commission Grant (NRC-27-10-515) as well as Meharry Medical College-Vanderbilt University Alliance for Research Training in Neuroscience Grant (T32MH065782).
PY - 2012/1
Y1 - 2012/1
N2 - The wild-type (WT) Cprlox/lox (cytochrome P450 oxidoreductase, Cpr) mouse is an ideal model to assess the contribution of P450 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 Cprlox/lox mice were compared with in utero exposed brain-Cpr-null offspring mice. Null mice were used as they do not express brain cytochrome P4501B1-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/m3), Cprlox/lox offspring exhibited: (1) elevated B(a)P metabolite and F2-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.
AB - The wild-type (WT) Cprlox/lox (cytochrome P450 oxidoreductase, Cpr) mouse is an ideal model to assess the contribution of P450 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 Cprlox/lox mice were compared with in utero exposed brain-Cpr-null offspring mice. Null mice were used as they do not express brain cytochrome P4501B1-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/m3), Cprlox/lox offspring exhibited: (1) elevated B(a)P metabolite and F2-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.
KW - B(a)P metabolites
KW - Benzo(a)pyrene
KW - NMDA receptor
KW - Neurogenesis
KW - Neuronal activity
KW - Object discrimination task
KW - Polycyclic aromatic hydrocarbon
KW - Susceptibility-exposure paradigm
KW - Synaptogenesis
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U2 - 10.1093/toxsci/kfr261
DO - 10.1093/toxsci/kfr261
M3 - Article
C2 - 21987461
AN - SCOPUS:84555195336
VL - 125
SP - 233
EP - 247
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 1
ER -