Transcriptional response and DNA adduct analysis of murine liver exposed to aflatoxin B₁ by Jeanette Louise Allen Fiala.

Abstract

Human dietary exposure to aflatoxin B1 (AFB1) is linked to hepatocellular carcinoma (HCC), especially in areas where significant hepatitis B infection is concurrent. Susceptibility to this carcinogen varies among species. Neonatal mice, like rats and most other species, are highly sensitive to the hepatotoxic and carcinogenic effects of AFB1; unlike other species, however, maturation of the mouse is accompanied by a transition to almost complete resistance to the toxin over a short period of a few weeks. This study compares age-specific differences in hepatic gene expression in B6C3F1 mice as they transition from their sensitive to refractory periods of life. Herein, 1-day old mice (highly susceptible to acute AFB1 toxicity), 4-day old mice (modestly affected by toxicity but highly susceptible to tumorigenesis), 7-day old mice (even less sensitive to toxicity and carcinogenesis) and adult mice (highly resistant to both the toxic and carcinogenic effects of AFB1) are compared. At each time point the AFB1-DNA adduction level was used as a predictive biomarker of genetic risk. Enzymes that detoxify the AFB1-8,9-epoxide, the metabolite of AFB1 responsible for genetic effects, were expressed at lower levels in neonates, resulting in formation of a high level of DNA adducts; this parameter, together with markers of aggressive cell proliferation, correlated well with the enhanced susceptibility of the neonates. AFB1 treatment of neonates caused strong and wide ranging transcriptional responses.

(cont.) Newborn animals,in response to AFB1, robustly expressed genes involved in cell cycle regulation, apoptosis and, in some cases, oncogenesis; such changes were absent in AFB1-treated adult mice, which is in line with their low sensitivity to the toxin. This study revealed a dynamic pattern of changes in gene expression that accompanied the diminished sensitivity of the mouse to this potent human carcinogen during the aging process, shedding light on the basis of AFB1 susceptibility. In addition, gene transcription profiles of three mouse strains were compared to probe the genetic basis of their differential susceptibilities to spontaneous and inducible HCC. In parallel, a 1.6-fold difference in AFB1-DNA adduct level was observed between the HCC-susceptible C3H/He strain and the HCC-resistant C57BL/6 strain.