Hepatitis B virus x gene and cyanobacterial toxins promote aflatoxin B1-induced hepatotumorigenesis in mice.
OBJECTIVE
To assess the combinative role of aflatoxin B1(AFB1), cyanobacterial toxins (cyanotoxins), and hepatitis B virus (HBV) x gene in hepatotumorigenicity.


METHODS
One-week-old animals carrying HBV x gene and their wild-type littermates were intraperitoneally (ip) injected with either single-dose AFB1 [6 mg/kg body weight (bw)], repeated-dose cyanotoxins (microcystin-LR or nodularin, 10 microg/kg bw once a week for 15 wk), DMSO (vehicle control) alone, or AFB1 followed by cyanotoxins a week later, and were sacrificed at 24 and 52 wk post-treatment.


RESULTS
AFB1 induced liver tumors in 13 of 29 (44.8%) transgenic mice at 52 wk post-treatment, significantly more frequent than in wild-type mice (13.3%). This significant difference was not shown in the 24-wk study. Compared with AFB1 exposure alone, MC-LR and nodularin yielded approximately 3-fold and 6-fold increases in the incidence of AFB(1)-induced liver tumors in wild-type animals at 24 wk, respectively. HBV x gene did not further elevate the risk associated with co-exposure to AFB1 and cyanotoxins. With the exception of an MC-LR-dosed wild-type mouse, no liver tumor was observed in mice treated with cyanotoxins alone at 24 wk. Neither DMSO-treated transgenic mice nor their wild-type littermates had pathologic alterations relevant to hepatotumorigenesis in even up to 52 wk.


CONCLUSIONS
HBV x gene and nodularin promote the development of AFB(1)-induced liver tumors. Co-exposure to AFB1 and MC-LR tends to elevate the risk of liver tumors at 24 wk relative to exposure to one of them. The combinative effect of AFB1, cyanotoxins and HBVx on hepatotumorigenesis is weak at 24 wk.
Lian
Min
M
School of Public Health, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China. min.lian@ttu.edu
Liu
Ying
Y
Yu
Shun-Zhang
SZ
Qian
Geng-Sun
GS
Wan
Shu-Guang
SG
Dixon
Kenneth-R
KR
D016604:Aflatoxin B1 / Q000494:pharmacology*; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics* / Q000473:pathology; D000087522:Cyanobacteria Toxins; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008387:Marine Toxins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D052998:Microcystins; D010456:Peptides, Cyclic / Q000494:pharmacology; D011042:Poisons / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D054334:Viral Regulatory and Accessory Proteins
D001427:Bacterial Toxins; D000087522:Cyanobacteria Toxins; D008387:Marine Toxins; D052998:Microcystins; D010456:Peptides, Cyclic; D011042:Poisons; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C063998:nodularin; D016604:Aflatoxin B1; C057862:cyanoginosin LR