title: Increased incidence of aflatoxin B1-induced liver tumors in hepatitis virus C transgenic mice.
abstract: Viral hepatitis and aflatoxin B1 (AFB1) exposure are common risk factors for hepatocellular carcinoma (HCC). The incidence of HCC in individuals coexposed to hepatitis C (HCV) or B virus and AFB1 is greater than could be explained by the additive effect; yet, the mechanisms are poorly understood because of the lack of an animal model. Our study investigated the outcomes and mechanisms of combined exposure to HCV and AFB1. We hypothesized that HCV transgenic (HCV-Tg; expressing core, E1, E2 and p7, nucleotides 342-2771) mice will be prone to hepatocarcinogenesis when exposed to AFB1. Neonatal (7 days old) HCV-Tg or C57BL/6J wild-type (WT) mice were exposed to AFB1 (6 μg/g bw) or tricaprylin vehicle (15 μl/g bw), and male offspring were followed for up to 12 months. No liver lesions were observed in vehicle-treated WT or HCV-Tg mice. Tumors (adenomas or carcinomas) and preneoplastic lesions (hyperplasia or foci) were observed in 22.5% (9 of 40) of AFB1-treated WT mice. In AFB1-treated HCV-Tg mice, the incidence of tumorous or pretumorous lesions was significantly elevated (50%, 18 of 36), with the difference largely due to a 2.5-fold increase in the incidence of adenomas (30.5 vs. 12.5%). Although oxidative stress and steatohepatitis were observed in both AFB1-treated groups, molecular changes indicative of the enhanced inflammatory response and altered lipid metabolism were more pronounced in HCV-Tg mice. In summary, HCV proteins core, E1, E2 and p7 are sufficient to reproduce the cocarcinogenic effect of HCV and AFB1, which is a known clinical phenomenon.
authors.affiliation: Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7431, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jeannot
authors.forename: Gary A
authors.initials: GA
authors.lastname: Boorman
authors.forename: Oksana
authors.initials: O
authors.lastname: Kosyk
authors.forename: Blair U
authors.initials: BU
authors.lastname: Bradford
authors.forename: Svitlana
authors.initials: S
authors.lastname: Shymoniak
authors.forename: Batbayar
authors.initials: B
authors.lastname: Tumurbaatar
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weinman
authors.forename: Stepan B
authors.initials: SB
authors.lastname: Melnyk
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Tryndyak
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D005234:Fatty Liver / Q000473:pathology; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000150:complications*; D007249:Inflammation / Q000473:pathology; D050356:Lipid Metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress
chemical_list: D016604:Aflatoxin B1