Leydig Cell Tumors in Rats

In the studies of long-term exposure of rats to both triphenyltin hydroxide and bis(tributyltin)oxide, most of the tumors were found in endocrine glands. In addition to the pituitary adenomas associated with bis(tributyltin)oxide and triphenyltin hydroxide, there was also an increased incidence of pheochromocytomas of the adrenal gland, parathyroid carcinomas and pancreatic adenocarcinomas in animals from at least one sex. Triphenyltin hydroxide was associated with an increased incidence of testicular Leydig cell tumors in male rats at the highest dose. Hepatic tumors were found in male and female mice following 80 weeks of triphenyltin hydroxide administration. 

Bartke A, Sweeney CA, Johnson L, Castracane VD, Doherty PC (1985) Hyperprolactinemia inhibits development of Leydig cell tumors in aging Fischer rats. Exp Aging Res 11 123-127... 

In male Sprague-Dawley rats, there was a dose-related increase in testicular Leydig cell tumors and a slight increase in tubular renal adenocarcinoma at the 600-ppm exposure level after exposure for 104 weeks (Maltoni et al. 1986, 1988). EPA and other groups regard such increases as indicative of a hazard potential unless there are reasons to rule this out. However, other authorities believe testicular tumors are common in rats that are not exposed to toxic substances. 

Although there was an increased incidence of testicular Leydig cell adenomas in male rats administered 50,000 ppm for 104 wk (Collins et al. 1995), these tumors do not progress to malignancy (Boorman et al. 1990) and have little significance in humans (Cook et al. 1999). The lack of genotoxicity also supports the conclusion that there is no carcinogenic risk for humans. 

In mice and rats exposed to 500, 2500, or 5000 ppm 6 hours/day, 5 days/week for up to 104 weeks, the only neoplastic lesion showing an increased incidence was interstitial cell (Leydig cell) adenomas in male rats. The tumor was not considered to be treatment related because of its occurrence in control rats. The lARC has determined that there is inadequate evidence for the carcinogenicity of isopropyl alcohol in experimental animals and humans. 

Carcinogenesis In rats, acarbose treatment resulted in a significant increase in the incidence of renal tumors (adenomas and adenocarcinomas) and benign Leydig cell tumors. Further studies showed that the increased incidence of renal tumors found in the original studies did not occur. 

Chronic oral carcinogenicity studies of NDMA have been conducted with rats, mice and mink. Tumors at sites other than the liver and testis have not been associated with chronic treatment. Terao et al. (1978) observed a 47% increase in the incidence of testicular Leydig-cell tumors, but no tumors in the liver or other tissues, in rats that were treated with 0.5 mg/kg daily doses of NDMA in the diet for 54 weeks. Increased incidences of liver tumors, but not testicular interstitial cell tumors, occurred in rats that received 0.05 or 0.5 mg/kg/day doses of NDMA in the diet for 96 weeks (Arai et al. 1979). In this study, liver tumor incidences were generally higher in female rats than in male rats. Increased incidences of liver tumors also occurred in rats that were treated with NDMA in the diet for 96 weeks at a dose of 10.0 mg/kg/day (Ito et al. 1982) similar treatment with doses of 0.1 or 1.0 mg/kg/day did not produce increased incidences of liver tumors. It should be noted that Wistar rats were tested in both the Ito et al. (1982) and Arai et al. (1979) studies. The reason for the lack of liver... 

In addition to fiver tumors, many PPARa activators also induce testicular Leydig cell tumors as well as pancreatic acinar cell tiunors in rats but not mice (also known as the tumor triad ). Little progress has been made to refine the proposed modes of action for the pancreatic and testicular rat tumors as detailed in Klaunig et al. (2003). As such, the present chapter will focus on the mode of action of PPARa activator-induced fiver tumors. 

Turek, F. W, and Desjardins, C. (1979). Development of Leydig cell tumors and onset of changes in the reproductive and endocrine systems of aging F344 rats. J Natl Cancer Inst 63, 969-975. 

Zinc acetate reduced or prevented cadmium carcinogenesis in the prostate, in the testes, or at the injection site in rats (Gunn et al. 1963a, 1964 Waalkes et al. 1989). The effect of zinc on the cadmium-induced carcinogenesis appeared to be dependent on dose, route, and target site. Sustained levels of zinc inhibited cadmium-induced injection sarcomas but had no effect on the incidence of testicular Leydig cell tumors (Waalkes et al. 1989). 

Rats fed diets containing 30 or 300ppm ammonium perfluorooctanoate for 2 years had increased liver weights with occasional necrosis and an apparent dose-dependent increase in Leydig cell adenomas, but there was no evidence of an increased incidence of hepatocellular carcinoma. In a follow-up study in male mice, 300ppm in the diet for 2 years caused increases in liver, Leydig cell, and pancreatic acinar cell tumors that may have been associated with the peroxisome-proliferating capabilities of the compound. Ammonium perfluorooctanoate also produced sustained increases in serum estradiol concentrations. ... 

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