Prenatal 3,3',4,4',5-pentachlorobiphenyl exposure modulates induction of rat hepatic CYP 1A1, 1B1, and AhR by 7,12-dimethylbenz[a]anthracene.
We previously reported the finding that prenatal exposure to a relatively low dose of PCB126 increases the rate of DMBA-induced rat mammary carcinoma, while a high dose decreased it. One of the most important factors determining the sensitivity to mammary carcinogenesis is the metabolic stage at administration of the carcinogenic agent. DMBA is a procarcinogen that recruits the host metabolism to yield its ultimate carcinogenic form, and CYP1A1 and CYP1B1 (CYP1) conduct this metabolism. We investigated the hepatic expression of CYP1 and AhR following oral administration of DMBA (100 mg/kg b.w.) (i.g.) to 50-day-old female Sprague-Dawley rats whose dams had been treated (i.g.) with 2.5 ng, 250 ng, 7.5 microg of PCB126/kg or the vehicle on days 13 to 19 post-conception. Real-time quantitative RT-PCR analysis revealed that the prenatal exposure to a relatively low dose of PCB126 (the 250 ng group) prolonged the higher expression of CYP1A1, CYP1B1, and AhR mRNA, while prenatal exposure to a high dose of PCB126 (the 7.5 microg group) prolonged the higher expression of CYP1A1 and AhR mRNA. Western blotting and immunohistochemical analyses were consistent with mRNAs changes. Because DMBA oxidation produces a highly mutagenic metabolite and is finally catalyzed by CYP1B1, a relatively low PCB126 dose might produce the biological character to potentially increase the risk of DMBA-induced mammary carcinoma.
Wakui
Shin
S
Department of Toxicologic Pathology, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Kanagawa 229-8501, Japan. wakui@azabu-u.ac.jp
Yokoo
Kiyofumi
K
Takahashi
Hiroyuki
H
Muto
Tomoko
T
Suzuki
Yoshihiko
Y
Kanai
Yoshikatsu
Y
Hano
Hiroshi
H
Furusato
Masakuni
M
Endou
Hitoshi
H
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D004790:Enzyme Induction; D005260:Female; D008099:Liver / Q000378:metabolism / Q000473:pathology; D018811:Maternal Exposure; D011078:Polychlorinated Biphenyls / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002274:Carcinogens, Environmental; D004785:Environmental Pollutants; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D015127:9,10-Dimethyl-1,2-benzanthracene; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C023035:3,4,5,3',4'-pentachlorobiphenyl