Carcinogenicity assessment of the pan-caspase inhibitor, emricasan, in Tg.rasH2 mice.

Emricasan, formerly IDN-6556, is a small molecule currently being evaluated in clinical trials to reduce hepatic injury and liver fibrosis. Since emricasan is an irreversible pan-caspase inhibitor that potently inhibits caspase-mediated apoptosis and inflammation, its carcinogenic potential was evaluated in a humanized mouse model. Tg.rasH2 mice received LabDiet formulated with 0, 10, 25, and 75mg/kg/day of emricasan, for 26weeks. At terminal sacrifice, blood was collected for clinical pathology analysis and tissues were collected, processed, and evaluated microscopically. There were no treatment related deaths or overt signs of toxicity for the duration of the study. There was no evidence of a carcinogenic effect in the peripheral blood leukocyte counts. Liver microgranulomas, which are background lesions, were slightly increased, especially in males. Increases in the incidence of the activated germinal centers were seen in the spleens and mesenteric lymph nodes of males and females, and in the mandibular lymph nodes of male mice. Atrophy of ovaries and testicular degeneration were also seen in emricasan treated animals. Although several non-neoplastic lesions were observed, there was no evidence of emricasan-related tumor formation in any tissue. In addition, the non-neoplastic lesions were not considered pre-neoplastic. Thus, emricasan is not considered carcinogenic.

Fluorosis in a wild cotton rat (Sigmodon hispidus) population inhabiting a petrochemical waste site.

We have developed an in situ mammalian model for evaluating environmental contamination using wild cotton rats. In a series of experiments, 200 male cotton rats were captured during 4 collection periods (spring 1991 = 35; fall 1991 = 60; spring 1992 = 53; fall 1992 = 52). A total of 103 of these cotton rats were captured from control sites, and the remaining 97 were captured from an abandoned oil refinery. All sites were located in the vicinity of Cyril, Oklahoma. There were alterations in the incisors of cotton rats captured from the refinery site. Normal color of cotton rat incisors is deep yellow-orange, which is imparted by a pigment normally produced by ameloblasts. Grossly, the upper incisors of 37 of 97 rats and lower incisors of 54 of 97 rats were affected. The affected incisors were white, chalky, and thin with striations and erosions of the enamel. Microscopic examination revealed that there were dysplastic and necrotic changes in the ameloblasts. The bone fluoride levels were significantly higher in rats captured from the refinery as compared to the rats captured from the control sites.

Spontaneous altered hepatocellular foci (AHF) in captive aged male cotton rats (Sigmodon hispidus).

Spontaneous altered hepatocellular foci (AHF) of basophilic type were observed in adult male cotton rats. The histological features of these foci were similar to those observed in Fischer 344 rats. However, an immunohistochemical technique with antibody to glutathione S-transferase placental form (GST-P) failed to stain these foci. Also normal bile ducts were not immunoreactive for GST-P. The presence of a gall bladder and of non-GST-P immunoreactive liver foci and bile ducts suggests that these cotton rats are phylogenetically closer to mice than rats.

Calcification of the urinary bladder in the wild cotton rat (Sigmodon hispidus).

Calcification of the urinary bladder epithelium was observed in 19 of 30 and 18 of 30 wild cotton rats from control and petrochemical-contaminated sites, respectively. The rats in the two sites did not differ significantly in respect of serum calcium and phosphorus concentrations. The calcification was considered to be dystrophic in nature. An unidentified factor common to both control and petrochemical-contaminated sites was considered to be responsible for this syndrome.