Assessment of metabolites and AhR and CYP1A1 mRNA expression subsequent to prenatal exposure to inhaled benzo(a)pyrene.
Few studies have focused on environmental aerosol contaminant, mechanistically-based, dose-related neurotoxicity with respect to development of the central nervous system. To fill this important data gap and to highlight possible mechanistic pathways, a study was undertaken to determine metabolite concentrations associated with the transplacental disposition of inhaled benzo(a)pyrene (B(a)P) and the resulting effects on the status of aryl hydrocarbon receptor (AhR), and cytochrome P450 1A1 (CYP1A1) mRNA in preweaning F1 generation animals. In this study, laparotomy on GD 8 was performed on timed-pregnant rats followed by dosing via nose-only exposure for 4h a day for 10 days (GD 11-GD 20) to three concentrations of a B(a)P: carbon black aerosol (25, 75 and 100 microg/m(3)). A dose-dependent decrease in birth index was observed in the B(a)P exposed group as compared to the controls (P<0.05). Analysis of cerebrocortical extracts from F1 generation pups revealed a dose-dependent (P<0.05) increase in total B(a)P metabolites. Analysis of cerebrocortical and hippocampal mRNA developmental expression profiles for AhR and CYP1A1 using 18sRNA as the internal standard, revealed that inhaled B(a)P upregulates AhR during the first postnatal month. The present study suggest that prenatal exposure to inhaled B(a)P upregulates hepatic aryl hydrocarbon receptor dependent mechanisms in the F1 generation. Hepatic upregulation of the aryl hydrocarbon receptor may modulate the potential for benzo(a)pyrene toxicity via the activation of cytochrome P450 and the subsequent deposition of lipophillic metabolites to developing central nervous system structures such as cerebral cortex and hippocampus.
Wu
Jie
J
Department of Pharmacology, Meharry Medical College, 1005 D. B. Todd Blvd, Nashville, TN 37208, USA.
Ramesh
Aramandla
A
Nayyar
Tultul
T
Hood
Darryl B
DB
D000280:Administration, Inhalation; D000336:Aerosols / Q000633:toxicity; D000393:Air Pollutants / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000633:toxicity*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D046508:Culture Techniques; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*
D000336:Aerosols; D000393:Air Pollutants; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1