Testicular tumors Leydig cell

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. 

The vasoconstriction, which is caused by cadmium, may underlie the hypertension observed in experimental animals. Cadmium is also carcinogenic in experimental animals, causing tumors at the site of exposure. Also, Leydig cell tumors occur in the testis of animals after acute doses of cadmium sufficient to cause testicular necrosis. This seems to be an indirect effect due to the reduced level of testosterone in the blood, which follows testicular damage. This causes Leydig cell hyperplasia and tumors to occur. 

The numbers of males with testicular Leydig cell tumors was increased in animals exposed to 5.2 mg/kg/day triphenyltin hydroxide for 104 weeks (16.7% as opposed to 1.7% in the controls). 

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. 

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. 

TESTICULAR SEX CORD TUMORS Leydig Cell Tumor... 

Sato B, Spomer W, Huseby RA, Samuels LT (1979) The testicular estrogen receptor system in two strains of mice differing in susceptibUity to estrogen-induced Leydig cell tumors. Endocrinology 104 822-831... 

Fowler KA, Gill K, Kirma N, Dillehay DL, Tekmal RR (2000) Overexpression of aro-matase leads to development of testicular leydig cell tumors an in vivo model for hormone-mediated Testicular Cancer. Am J Pathol 156 347-353... 

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). 

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 21 boys treated with carmustine or lomnstine alone or in combination with procarbazine and vincristine for brain tumors, there were 20 cases of persistent testicnlar damage (21). From assessment of testicular size it was thought that most those affected would remain infertile. This supports the idea that germinal epithehnm is more susceptible than Leydig cells to cytostatic-indnced damage. 

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