ABSTRACT
Human liver cancer is in part associated with obesity and related metabolic diseases. The present study was undertaken in a mouse model of diet-induced obesity (DIO) and hepatic steatosis, conditions which can be associated with hepatic neoplasia, to determine whether the rates of cell proliferation or hepatocarcinogen bioactivation were altered in ways which could facilitate hepatocarcinogenesis. DIO mice were generated by feeding C57BL/6 (B6) male mice a high-fat diet beginning at 4 weeks of age; age-matched conventional lean (LEAN) B6 mice fed a low fat diet (10% Kcal from fat) were used for comparison. Groups of 28 week old DIO and LEAN mice were dosed with the bioactivation-dependent DNA-reactive hepatocarcinogen 2-acetylaminofluorene (AAF), at 2.24 or 22.4 mg/kg, given by gavage 3 times per week for 31 days, or received no treatment (DIO and LEAN control groups). Compared with the LEAN control group, the DIO control group had a higher mean body weight (16.5 g), higher mean absolute (1.4 g) and mean relative (25.5%) liver weights, higher (394%) liver triglyceride concentrations, and an increased incidence and severity of hepatocellular steatosis at the end of the dosing phase. The DIO control group also had a higher mean hepatocellular replicating fraction (31% increase, determined by proliferating cell nuclear antigen immunohistochemistry). Hepatocarcinogen bioactivation, based on formation of AAF DNA adducts as measured by nucleotide (32)P-postlabeling, was similar in both DIO and LEAN AAF-dosed groups. Thus, hepatocellular proliferation, but not hepatocarcinogen bioactivation, was identified as an alteration in livers of DIO mice which could contribute to their susceptibility to hepatocarcinogenesis.
Subject(s)
Cell Proliferation/drug effects , Fatty Liver/physiopathology , Hepatocytes/drug effects , Obesity/complications , 2-Acetylaminofluorene/analogs & derivatives , 2-Acetylaminofluorene/toxicity , Animal Feed , Animals , Carcinogens/toxicity , DNA Adducts/analysis , DNA Adducts/biosynthesis , Diet, Fat-Restricted , Diet, High-Fat/adverse effects , Disease Models, Animal , Mice , Mice, Inbred C57BL , Obesity/physiopathologyABSTRACT
For serum vitamin B12 levels there was little apparent difference between a geriatric healthy reference group and a hospitalized group for the total population studied; however, the hospitalized males did have an increased prevalence of values less than normal range. The frequency distribution for both sexes of the geriatric reference group gave lower range limits than manufacturer's normal range. (68-632 vs 133-708 pmol/L for Becton Dickinson, and 125-609 vs 179-930 pmol/L for Bio-Rad, using 95% non-parametric limits). For folate there was an increased incidence in values of less than normal in the hospitalized group versus the geriatric reference group, but there was no difference in the ranges calculated for the latter compared to either manufacturer's normal range derived from a younger population. Comparison of results by two manufacturers' kit methods confirmed Bio-Rad's claim to increased low-end sensitivity of standard curve in range of clinical interest.
