Comparison of the Effects of Wyeth-14,643 in Crl:CD BR and Fisher-344 Rats

Abstract

Wyeth-14,643 (WY) belongs to a diverse class of compounds which have been shown to produce hepatic peroxisome proliferation and hepatocellular carcinoma in rodents. Based on a review of bioassay data, a relationship appears to exist between peroxisome proliferating compounds and Leydig cell adenoma formation. Most rat bioassays with peroxisome proliferators have been conducted in the Fisher-344 (F344) rat, which has a high spontaneous incidence of Leydig cell adenomas. Thus, it was necessary to use an alternative animal model to investigate this relationship further. Therefore the Crl:CD BR (CD) rat, which has a low spontaneous Leydig cell adenoma incidence, was chosen for a 2-year feeding study with WY. Before initiating this 2-year feeding study, it was necessary to investigate whether any strain differences existed between CD and F344 rats with respect to WY-induced peroxisome and cell proliferation. In this study, male CD and F344 rats were fed diets containing 0, 50, or 1000 ppm WY for 21 days. Peroxisome proliferation in the liver and testis was determined biochemically by measuring β-oxidation activity and was confirmed ultrastructurally. Serum hormone levels and cell proliferation rates in the liver and testis were also measured. In addition, basal β-oxidation activity and cell proliferation rates were compared between the CD and F344 rats. A significant decrease in final body weight was observed in the 1000 ppm WY groups for both CD and F344 rats. Similar increases in liver weights were observed in both strains of rat at 50 and 1000 ppm WY (1.96-and 2.15-fold increase in CD rats and 2.29-and 2.38-fold increase in F344 rats, respectively). Peroxisome proliferation, assessed by measuring hepatic β-oxidation activity, was also increased to a similar extent in both strains of rats at 50 and 1000 ppm WY (21.9-and 22.4-fold increase for CD rats and 33.7-and 27.6-fold increase for F344 rats, respectively). The increase in hepatic β-oxidation activity was confirmed by electron micrographs which demonstrated increased numbers of peroxisomes in the livers of WY-treated rats. Hepatic cell proliferation rate was similar in CD rats at 50 and 1000 ppm WY (3.7-fold increase above control at each concentration). However, hepatic cell proliferation rate increased with increasing dose in F344 rats (2.7-and 5.4-fold increase above control at 50 and 1000 ppm WY, respectively). Wy did not induce significant increases in the rate of Leydig cell β-oxidation activity or Leydig cell proliferation rate in either strain of rat. Treatment with 1000 ppm WY did not appear to affect the number of peroxisomes observed by electron microscopy in the Leydig cells of either strain of rat. Moreover, the rate of β-oxidation in Leydig cells of the control rats was approximately 20 times less than the rate of hepatic β-oxidation, irrespective of strain. Serum testosterone, estradiol, prolactin, and LH levels were unchanged in CD and F344 rats. There were, however, significant differences between the strains of rat with respect to β-oxidation activity and cell proliferation. The CD rats had basal and WY-induced rates of hepatic β-oxidation activity and hepatic cell proliferation that were significantly higher than those of the F344 rats. Rates of basal and WY-induced Leydig cell proliferation were also greater in the CD rats than in the F344 rats. These data demonstrate that there are subtle differences in the basal β-oxidation activity and cell proliferation rates between the two strains and that 50 ppm WY produces a maximal response in the CD rats for the parameters measured in this study.