Abstract
Cancer of the prostate is an important and potentially fatal disease in humans but the etiology is yet undefined. Cadmium and cadmium compounds are known to be human carcinogens based on findings of increased risk to lung cancer among exposed workers, but a relationship between cancer of the prostate and/or testis in humans is unclear in spite of suggestive results in rats. Parenteral administration or oral exposure to cadmium can result in proliferate lesions and tumors of the prostate in rats. The ability of cadmium to produce neoplasms in the prostate of rats is atypically dose-related and only occurs in rats at doses below the threshold for significant testicular toxicity. Testicular androgen production is essential for the maintenance of the prostate and prostate tumors. The rat testis may also develop tumors if cadmium is given parenterally at high doses. Subsequent to testicular hemorrhagic necrosis, there will be loss of testosterone production and hyperplasia and neoplasia of testicular interstitial cells, thought to be a response to trophic hormone release from the pituitary. The pathogenesis of prostatic cadmium carcinogenesis might include aberrant gene expression resulting in stimulation of cell proliferation or blockage of apoptosis. Activation of transcription factors such as the metallothionein gene and activation of some proto-oncogenes may enhance cell proliferation with damaged DNA. Suppression of DNA repair would add to the population of cells with damaged DNA. Chemically induced apoptosis can be blocked by cadmium, facilitating aberrant cell accumulation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abshire MK, Buzard GS, Shirasi MP, Waalkes MP. 1996 Induction of c-myc proto-oncogene expression in rat L6 myoblasts by cad-mium is inhibited by zinc preinduction of the metallothionein gene. J Toxicol Environ Health 48, 359–377.
Achanzar WE, Diwan BA, Liu J, Quader ST, Webber J, Waalkes MP. 2001 Cadmium-induced malignant transformation of human prostate epithelial cells. Cancer Res 61, 455–458.
Achanzar WE, Webber MW, Waalkes MP. 2002 Altered apoptotic gene expression and acquired apoptotic resistance in cadmium-transformed human epithelial cells. The Prostate 52, 236–244.
American Cancer Society, Facts and Figures 2003.
Bako G, Smith ESO, Hanson J, Dewar R. 1982 The geographical distribution of high cadmium concentrations in the environment and prostate cancer in Albert. Can J Public Health 73, 92–94.
Elinder C-C, Kjellstrom T, Hogstedt C, Anderson K, Spang G. 1985 Cancer mortality in cadmium workers. Brit J Ind Med 42, 651–655.
Goering PI, Waalkes MP, Klaassen CP. 1995 Toxicology of Cad-mium. In Goyer RA, Cherian MG eds, Handbook of Exper-imentalPharmacology. New York: Springer-Verlag; pp. 189–214.
Hartwig A. 1998 Carcinogenicity of metal compounds: Possible role of DNA repair inhibition. 235, 102–103.
Klaassen CD, Liu J, Choudhuri S. 1999 Metallothionein: an in-tracellular protein to protect against cadmium toxicity.Ann Rev Pharmacol Toxicol 39, 267–294.
NTP Report on Carcinogens: Background Document for Cadmium, March 1999 National Toxicology Program Research Triangle Park, NC, 27709. NIEHS Contract No. NO1-ES-25346.
Poirier LA, Viasova TI. 2002 The prospective role of abnormal methyl metabolism in cadmium toxicity. Environ Health Pro-spect 110(Suppl), 793–795.
Potts CL. 1965 Cadmium proteinuria. The health of battery workers exposed to cadmium oxide dust. Ann Occup Hygiene8, 55–61.
Shigematsu IS, Kitamaru J, Takeuchi M, Minowa M, Nagai T, Usui T, Fukushima M. 1993 A retrospective mortality study on cadmium-exposed populations in Japan. In Wilson D, Volpe RA, eds, Proceedings of the Third International Cadmium Confer-ence, pp. 115–118.
Shirai T, Fukushima S, Ikawa E, Tagawa Y, Ito N. 2003 Induction of prostate cancer in situ at high incidence in F344 rats by a com-bination of 3-2' dimethyl-4-aminobiphenyl and ethinyl estradiol. Cancer Res 46, 6423–6426.
Strayner L, Smith R, Thun M, Schnorr T, Lennen R. 1982 A dose-response analysis and quantitative assessment of lung cancer risk and occupational cadmium exposure. Ann Epidemiol2, 177–194.
Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP. 2003 Effects of cadmium on DNA-(cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286, 355–365.
Thompson IM, Goodman PG, Tangen CM, Lucia MS, Miller G, Ford LG, Lieber MM, Cespedes RD. 2003 The influence of finas-teride on the development of prostate cancer. N EngJ Me d349, 215–224.
Van den Gulden JW, Kolk JJ, Verbeeck ALM. 1995 Work environ-ment and prostate risk. Prostate (NY) 27, 250–257.
Verougstraete V, Lison D, Hotz P. 2003 Cadmium, lung and pro-state cancer: a systematic review of recent epidemiological data. J Toxicol Environ Health6, 227–255.
Waalkes MP, Kovatch R, Rehm S. 1991 Effect of chronic dietary zinc-deficiency on cadmium toxicity and carcinogenesis in the male Wistar [Hsd(WI)BR] rat. Toxicol Appl Phamacol 108, 448–456.
Waalkes MP, Rehm S. 1992 Carcinogenicity of oral cadmium in the male-Wistar (WF/NCr) rat: Effect of chronic dietary zinc deficiency. Fund Appl Toxicol 19, 5–12.
Waalkes MP, Rehm, S, Riggs CW, Bare RM, Devor DE, Poirior LA, Wenk ML, Henneman JR. 1988 Cadmium carcinogenesis in male Wistar [Crl:(WI)BR] rats: Dose-response analysis of effects of zinc on tumor induction in the prostate, in the testes, and at the injection site. Cancer Res 48, 4656–4263.
Waalkes MP, Rehm S, Riggs SW, Bare RM, Devor DE, Poirier, LA, Weenk ML, Henneman JR. 1989 Cadmium carcinogenesis in male Wistar [Crl:(WI)BR] rats: Dose-response analysis of effects of zinc on tumor induction in the prostate, in the testes, and at the injection site. Cancer Res 49, 4282–4288.
Waalkes MP, Anver M, Diwan BA. 1999 Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: induction of pituitary, testicular and injection site tumors and intraepithelial proliferate lesions of the dorsolateral prostate. Toxicol Sci2, 154–161.
Waalkes M P, Rehm S, Devor DE. 1997 The effects of continu-ous testosterone exposure on spontaneous and cadmium-induced tumors in the male Fischer (F344/NCr) rat: Loss of testicular response. Toxicol Appl Pharmacol 142, 50–57.
Waalkes MP, Rehm S, Cherian MG. 2000 Repeated cadmium ex-posures enhance the malignant progression of ensuing tumors in rats. Toxicol Sci 54, 104–109.
Zheng H, Liu J, Choo KH, Michalska AE, Klaassen CD. 1996 Metallothionein-I and II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53. J Toxicol Pharmacol 136, 228–235.