title: 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.
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(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 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.
authors: Department of Neuroscience and Pharmacology, Center for Molecular and Behavioral Neuroscience, Meharry Medical College, Nashville, Tennessee 37208, USA.
authors: Zhu
authors: Z
authors: Li
authors: Gayathri
authors: G
authors: Chadalapaka
authors: Aramandla
authors: A
authors: Ramesh
authors: Habibeh
authors: H
authors: Khoshbouei
authors: Mark
authors: M
authors: Maguire
authors: Stephen
authors: S
authors: Safe
authors: Raina E
authors: RE
authors: Rhoades
authors: Ryan
authors: R
authors: Clark
authors: George
authors: G
authors: Jules
authors: Monique
authors: M
authors: McCallister
authors: Michael
authors: M
authors: Aschner
authors: Darryl B
authors: DB
authors: Hood
mesh_terms: D000336:Aerosols; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000201:enzymology / Q000503:physiopathology; D004193:Discrimination Learning / Q000187:drug effects*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D019570:Inhalation Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D010316:Particle Size; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D053260:Soot / Q000633:toxicity; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D016194:Receptors, N-Methyl-D-Aspartate; D053260:Soot; D001564:Benzo(a)pyrene; D018698:Glutamic Acid; D009251:NADPH-Ferrihemoprotein Reductase