Leydig cell hyperplasia

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. 

New Zealand white rabbits administered doses of 0.3 and 0.9 mg/kg/day as triphenyl tin hydroxide by gavage during the period of organogenesis failed to gain weight at the same rate as the controls or the animals given 0.1 mg/kg/day. Food consumption was also reduced (Rodwell 1987). Male rats fed this same compound at closes of 0.3 mg/kg/day and above displayed a dose- related increase in Leydig cell hyperplasia (p<0.0005) and tubular atrophy (p=0.004) of the testes (Tennekes et al. 

In utero exposure of male rats to dibutyl phthalate on gestational days 13-21 permanently alters the testis and produces foci of testicular dysgenesis (immature seminiferous tubules with undifferentiated Sertoli cells, Sertoli cell-only tubules, Leydig cell hyperplasia, morphologically distorted tubules, and the presence of abnormal germ cells), which persist in the adult animal (Fisher et al.,... 

After hypophysectomy there is a rapid loss of LH receptors and androgen secretion by the testis. Treatment with LH alone will restore Leydig cell steroidogenesis but also causes even further decreases in testicular LH receptors. Continued treatment with LH alone leads to Leydig cell hyperplasia and an increase in LH receptors. However, even with marked Leydig cell hyperplasia in response to sustained elevations of endogenous LH, as in the tfm rat (see Ref. 6 for other references), the LH receptor content of the testis remains subnormal. 

Clegg, E.D., J.C. Cook, R.E. Chapin, P.M. Foster, and G.P. Daston. 1997. Leydig cell hyperplasia and adenoma formation Mechanisms and relevance to humans. Reprod. Toxicol. 11 (1) 107-121. 

EPA has developed a chronic reference concentration (RfC) for chronic exposure of 80 mg/m3 (Integrated Risk Information System (IRIS) 1998), based primarily on a 2-year inhalation study in rats (Collins et al. 1995). Briefly, male rats exposed at concentrations of 10,000 ppm and 50,000 ppm had a significant increase in the incidence of Leydig cell hyperplasia compared with controls. The study is described below. 

Data on the toxicity of HFC-134a indicate that it is nontoxic in most circumstances. Most of the changes reported have been at high concentrations, which also induce narcosis. There is no evidence of genetic toxicity for HFC-134a. The primary effect reported is the induction of Leydig cell hyperplasia and adenomas in male rats exposed at 50,000 ppm for 6 h/d, 5 d/wk over a 2-yr period (Collins et al. 1995 Hext and Parr-Dobrzanski 1993). The NOAEL of 10,000 ppm from these data was the basis of the EPA s RfC. 

For chronic exposure, the subcommittee chose the NOAEL of 10,000 ppm for a 6-hr/d, 2-yr exposure based on a significant increase in the incidence of Leydig cell hyperplasia in treated rats (Collins et al. 1995 Hext and Parr-Dobrzanski 1993). Applying an aggregate uncertainty factor of 300 (3 for interspecies extrapolation, 10 for intraspecies differences, and 10 for deficiencies in the database), the UEL for reproductive and developmental toxicity is... 

Substances that have been associated with increases in Leydig cell tumours in mice are mainly chemicals with clear oestrogenic properties, e.g., diethylstilboestrol, methoxychlor, tri-p-anisylchloroethylene, stilboestrol, 17/3-oestradiol, oestradiol ester, tamoxifen and triphenylethylene [171-179]. Other compounds active in mice are finasteride, a 5a-reductase inhibitor that also induces Leydig cell hyperplasia, but not adenomas, in Sprague-Dawley rats [170,180] and M-nitrosodiethylamine [181]. In contrast to its effects in mice and Syrian and European hamsters [182], 17)d-oestradiol treatment of rats does not induce Leydig cell tumours and inhibits the appearance of the spontaneous tumours in the F344 strain [184]. 

Prentice DE, Meikle AW (1995) A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man. Human Exp Toxicol 14 562-572 Bosland MC (1996) Hormonal factors in carcinogenesis of the prostate and testis in humans and in animal models. In Huff J, Boyd J, Barett JC (eds) Cellular and Molecular Mechanisms of Hormonal Carcinogenesis Environmental influences. Wiley-Liss, New York, pp 309-352... 

PrahalandaS, MajkaJA, Soper KA, Nett TM, BagdonWJ, Peter CP, BurekJD, MacDonald JS, Van Zwieten MJ (1994) Leydig cell hyperplasia and adenomas in mice treated with finasteride, a 5a-reductase inhibitor a possible mechanism. Fundam Appl Toxicol 22 211-219... 

Yasuda Y, Konishi H, Tanimura T (1986) Leydig cell hyperplasia in fetal mice treated transplacentally with ethinyl estradiol. Teratology 33 281-288... 

Roe FJC, Dukes CE, Cameron KM, Pugh RCD, Mitchley BCV (1964) Cadmium neoplasia testicular atrophy and Leydig cell hyperplasia and neoplasia in rats and mice following the subcutaneous injection of cadmium salts. Br J Cancer 18 674-681... 

---