CYP1 and AhR expression in 7,12-dimethylbenz[a]anthracene-induced mammary carcinoma of rats prenatally exposed to 3,3',4,4',5-pentachlorobiphenyl.
We previously reported the finding that prenatal exposure to a relatively low dose of 3,3',4,4',5-pentachlorobiphenyl (PCB126) acted as an enhancing agent for 17-beta-estradiol (E2)-dependent 7,12-dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinoma, while a high dose decreased it. E2 is a known risk factor for mammary carcinoma, and CYP1A1 and 1B1 (CYP1) are the major enzymes catalyzing 2- and 4-hydroxylation of E2, respectively. We investigated the induction of CYP1 and aryl hydrocarbon receptor (AhR) in DMBA-induced mammary carcinoma using 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 13-19 post-conception. Immunohistochemical analysis revealed that the mammary carcinoma of the 250 ng group showed a significantly higher number of nuclei expressing estrogen receptor alpha (ER) and proliferating cell nuclear antigen (PCNA) compared to those of the other groups. Quantitative real-time RT-PCR analysis revealed that the 7.5 microg group showed a significantly higher level of CYP1A1 mRNA, and that the 250 ng group showed significantly higher levels of CYP1B1 mRNA. The level of AhR mRNA was significantly higher in both the 7.5 microg and 250 ng groups. Western blotting analysis was consistent with mRNA changes. It has been revealed that CYP1B1 catalyzes a step in the formation of 4-hydroxylated E2 metabolites, which show quite high mammary carcinogenicity. This study indicates that the enhancement of DMBA-induced mammary carcinogenicity in a relatively low PCB126 dose group might partially involve the higher expression of CYP1B1 and AhR in these carcinomas.
Wakui
Shin
S
Department of Toxicologic Pathology, Azabu University School of Veterinary Medicine, 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; D000230:Adenocarcinoma / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002274:Carcinogens, Environmental; 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