Miwa Okamura

Possible mechanisms underlying the testicular toxicity of oxfendazole in rats

To clarify the mechanisms underlying the testicular toxicity of oxfendazole (OX), adult Wistar rats were orally administered a dose of 100 mg/kg/day for 3, 7, or 14 days. Assays of sex-related hormones showed a significant decrease in only the estradiol serum level at days 3 and 7, as compared with the control group. Histopathologically, marked degeneration of meiotic spermatocytes was observed in stage XIV—I seminiferous tubules from day 3 onwards, and these spermatocytes gave positive results on terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL). Abnormalities of spermiogenesis such as megakaryospermatids and binucleated spermatids were also observed in the testes of OX-treated rats. Under the electron microscope, lipid accumulation and dilatation of the endoplasmic reticulum were frequently found in the cytoplasm of the Sertoli cells on day 3. These results strongly suggest that OX induces both apoptosis of meiotic spermatocytes, most probably due to disruption of the microtubules, and degeneration of the Sertoli cells, characterized by distended endoplasmic reticulum and prominent cytosolic lipid accumulation.

Carcinogenic susceptibility to N-bis(2-hydroxypropyl)nitrosamine (DHPN) in rasH2 mice.

To evaluate the susceptibility of rasH2 mice to N-bis(2-hydroxypropyl)nitrosamine (DHPN), a potent carcinogen targeting the lung, liver, thyroid, and kidney, male, 6-week old, rasH2 mice and wild-type littermates (non-Tg mice) were given DHPN in drinking water at 0, 20 or 200 ppm, and 0 or 200 ppm, respectively, for 26 weeks. The experiment using rasH2 mice given 200 ppm DHPN and non-Tg mice given 200 and 0 ppm DHPN was completed at 20 weeks, since mortality in these groups was remarkably increased due to hemangiosarcomas of the liver. Histologically, tumors developed in the lung and liver in both rasH2 and non-Tg mice treated with DHPN. In addition, proliferative lesions were observed in the forestomach, urethra, and excretory duct of salivary glands in rasH2 mice given 200 ppm DHPN. RT-PCR analysis showed no marked difference in expression of mRNAs for the transgene and the endogenous mouse ras gene between the whole lung tissue containing a neoplasm and normal lung tissue. Our results suggest that rasH2 mice are highly susceptible to DHPN, the target organs including the forestomach, salivary gland and urethra, which have not been found to develop tumors in previous long-term carcinogenicity studies of DHPN in rats and mice.

A 26-Week Carcinogenicity Study of 2-Amino-3-Methylimidazo(4,5-f)Quinoline in rasH2 Mice

To evaluate the carcinogenic susceptibility of rasH2 mice to 2-amino-3-methylimidazo[4,5- f ]quinoline (IQ), 7-week-old rasH2 mice and their wild-type littermates (non-Tg mice) of both the sexes were fed a diet containing 0 or 300 ppm IQ for 26 weeks. Microscopical examinations revealed that the proliferative lesions of the forestomach, including squamous cell hyperplasias, papillomas, and carcinomas, were frequently encountered in male and female rasH2 mice fed with IQ. In non-Tg mice, no significant differences in the incidence of forestomach lesions were observed between the 0 ppm and 300 ppm groups. Histopathological changes such as periportal hepatocellular hypertrophy and oval cell proliferation in the liver were more apparent in female rasH2 and non-Tg mice than in males, and the incidence of hepatocellular altered foci significantly increased in female rasH2 mice in the 300 ppm group as compared to that in the 0 ppm group. These results suggest that the carcinogenic potential of IQ can be detected in rasH2 mice by a 26-week, short-term carcinogenicity test.