, 20:727 | Cite as

Effects of chronic exposure to cadmium on prostate lipids and morphology

  • Silvina Mónica Alvarez
  • Nidia Noemí Gómez
  • Luis Scardapane
  • Miguel Walter Fornés
  • María Sofía Giménez


Cadmium is an environmental toxic metal implicated in human prostate carcinogenesis. The mechanism of its toxicity is not fully understood. Previously, we showed that cadmium exposure induces oxidative stress, especially lipid peroxidation. This study evaluates the effect of chronic exposure to 0.886 mM of cadmium (Cd) per liter in the drinking water on prostate lipid content and metabolism in Wistar rats. We determined the lipid profile and measured the expression of lipogenic enzymes: FAS, GPAT, LPL, DGAT-1, DGAT-2, ACO, CPT-1 and CT, and of certain factors involved in lipid regulation and fatty acid transporters: FAT/CD36, E-FABP, SREBP-2, PPAR-γ and PPAR-α by RT-PCR. Ultrastructure was analyzed by electron microscopy and, as prostate is an androgen controlled gland, AR expression was measured by RT-PCR and Western blot. Cd altered the prostatic lipid profile. Triglycerides (TG) and esterified cholesterol (EC) decreased, free cholesterol (FC) and phospholipids (PL) increased and total cholesterol (TC) did not change. FAS, MDH and IDH activities did not vary but G6PDH decreased significantly in Cd group. Regarding TG synthesis, DGAT-1 decreased while GPAT increased and FAS, LPL and DGAT-2 remained unchanged. Regarding beta oxidation, CPT-1 increased while ACO expression decreased in Cd group. In the PL pathway, CT expression was increased. All these results would justify the decrease of TG in Cd group when compared to control. In the cholesterol metabolic pathway, HMGCoAR and SREBP-2 increased. PPAR-α increased but PPAR-γ did not change. Regarding fatty acid transporters, FAT/CD36 decreased, while E-FABP increased. AR mRNA and protein expression decreased. Ultrastructural analysis showed a decrease in lipid droplets and signs of cellular damage in the Cd group.

Cadmium exposure induces important changes in prostatic lipid profile and metabolism, confirmed by the morphology analyses, which also showed signs of cellular damage. These results could be important to further understanding the complex mechanism of cadmium toxicity in prostate and in the development of better treatments for people and animals exposed to the heavy metal.


androgens cadmium lipids oxidative stress rat prostate 



medial lethal doses


fatty acid synthetase


hydroxymethylglutaryl coenzyme A reductase


glycerol-3-phosphate acyltransferase


diacyl glycerol acyl transferase


lipoprotein lipase


free cholesterol


esterified cholesterol




androgen receptor


CTP-phosphocholine cytidylyltransferase


diacyl glycerol


acyl CoA oxidase


carnitin palmitoil transferase




fatty acids


thiobarbituric acid – reactive susbtances



This work has been supported by grant, PIP 4931 from CONICET (National Investigation Council of Science and Technology, Argentina), and Project 8104 from San Luis University, Argentina. MSG, MWF are Career Scientists from CONICET, and SMA has fellowship from CONICET. Authors would like to thank Miss Isabel Sosa, Mr. R. Dominguez for their technical assistance, Dr. Luis D. Martinez for the analysis of cadmium content by ICP-AES in water and prostate samples and Dr. Graciela Jahn and Dr. Silvia Varas for critical reading of the manuscript.


  1. Abell LL, Levy BB, Brodie BB, Kendal FE (1952) A simplified method for the estimation of total cholesterol in serum and demonstration of its specificity. J Biol Chem 195:357–366Google Scholar
  2. Alberts AW, Ferguson K, Hennesy S, Vagelos PR (1974) Regulation of lipid synthesis in cultured animal cells. J Biol Chem 24:5241–5249Google Scholar
  3. Alvarez SM, Gomez NN, Scardapane L, Zirulnik F, Martinez D, Gimenez MS (2004) Morphological changes and oxidative stress in rat prostate exposed to a non-carcinogenic dose of cadmium. Toxicol Lett 153:365–376PubMedCrossRefGoogle Scholar
  4. Arienti G, Carlini E, Polci A, Cosmi EV, Palmerini CA (1998) Fatty acid pattern of human prostasome lipid. Arch Biochem Biophys 358:391–395PubMedCrossRefGoogle Scholar
  5. Brown MS, Goldstein JL (1999) A proteolytic pathway that controls the cholesterol content of membranes, cells and blood. Proc Natl Acad Sci USA 96:11041–11048PubMedCrossRefGoogle Scholar
  6. Caisová D, Eybl V (1997) The influence of repeated administration of cadmium and lead on the activity of glutathion peroxidase and lipid peroxidation in mice. Biomarkers Environ 2:57–60CrossRefGoogle Scholar
  7. Calderoni AM, Oliveros L, Jahn G, Anton R, Luco J, Giménez MS (2005) Alterations in the lipid content of pituitary gland and serum prolactin and growth hormone in cadmium treated rats. BioMetals 18:213–220PubMedCrossRefGoogle Scholar
  8. Carter JM, Waite KA, Campenot RB, Vance JE, Vance DE (2003) Enhanced expression and activation of CTP:phosphocoline cytidylyltransferase β2 during neurite outgrowth. J Biol Chem 278:44988–44994PubMedCrossRefGoogle Scholar
  9. Caviglia JM, Gómez Dumm de INT, Coleman RA, Igal RA (2004) Phosphatidylcholine deficiency upregulates enzymes of triacylglycerol metabolism in CHO cells. J Lipid Res 45:1500–1509PubMedCrossRefGoogle Scholar
  10. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ (2002) Nuclear receptor and lipid phisiology: opening the X-files. Science 294:1866–1870PubMedCrossRefGoogle Scholar
  11. Clegg MS, Keen CL, Lonnerdal B, Hurley LS (1981) Influence of ashing techniques on the analysis of trace elements in animal tissue. I. Wet-ashing. Biol Trace Elem Res 3:107–115CrossRefGoogle Scholar
  12. El-Demerdash FM, Yousef MI, Kedwany FS, Baghdadi HH (2004) Cadmium-induced changes in lipid peroxidation, blood hematology, biochemical parameters and semen quality of male rats: protective role of vitamin E and β-carotene. Food Chem Toxicol 42:1563 – 1571PubMedCrossRefGoogle Scholar
  13. Farrell HM (1980) Purification and properties of NADP-isocitrate dehydrogenase from lactating bovine mammary gland. Archiv Biochem Biophys 204:551–559CrossRefGoogle Scholar
  14. Finney RE, Nudelman E, White T, Bursten S, Klein P, Leer LL, Wang N, Waggoner D, Singer JW, Lewis RA. 2000. Pharmacological inhibition of phosphatidylcholine biosynthesis is associated with induction of phosphatidylinositol accumulation and cytolysis of neoplastic cell lines. Cancer Res. 60, 5204–5213Google Scholar
  15. Folch J, Less M, Sloane-Stanley GH (1968) A simple method for the isolation and purification of total lipid from animal tissues. J Biol Chem 226:497–509Google Scholar
  16. Glock GE, Mc Lean P (1953) Further studies on the properties and assay of glucose-6-phosphate dehydrogenase and 6-phospho-gluconate dehydrogenase of rat liver. Biochem J 55:400–408PubMedGoogle Scholar
  17. Guthmann F, Haupt R, Looman C, Spener F, Rustow B (1999) Fatty acid translocase/CD36 mediates the uptake of palmitate by type II pneumocytes. Am J Physiol 277:191–196Google Scholar
  18. Guthmann F, Hohoff C, Fechner H et al. (1998) Expression of fatty-acid-binding proteins in cells involved in lung-specific lipid metabolism. Eur J Biochem 253:430–436PubMedCrossRefGoogle Scholar
  19. Hoekstra M, Kruijt JK, Van Eck M, Van Berkel TJ (2003) Specific gene expression of ATP-binding cassette transporters and nuclear hormone receptors in rat liver parenchymal, endothelial, and Kupffer cells. J Biol Chem 278:25448–25453PubMedCrossRefGoogle Scholar
  20. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans. 1993 Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. International Agency for Research on Cancer, Lyon, France 58:119–238Google Scholar
  21. Igal RA, Caviglia JM, Gomez Dumm IN, Coleman RA (2001) Diacylglicerol generated in CHO cell plasma membrane by phospholipase C is used for tracylglycerol synthesis. J Lipid Res 42:88–95PubMedGoogle Scholar
  22. Ihnat M. 1990 Metals and other elements at trace levels in food: arsenic, cadmium, lead, selenium and zinc in food. In: Official Methods of Analysis of AOAC International. Virginia, USA. Chapt. 9Google Scholar
  23. Koizumi T, Shirakura H, Kumagai H, Tatsumoto H, Suzuki KT (1996) Mechanism of cadmium-induced cytotoxicity in rat hepatocytes: cadmium-induced active oxygen – related permeability changes of the plasma membrane. Toxicology 114:125–134PubMedCrossRefGoogle Scholar
  24. Koonen DPY, Glatz JFC, Bonen A, Luiken JJFP (2005) Long-chain fatty acid uptake and FAT/CD36 translocation in hert and skeletal muscle. Bioch et Biophys Acta 1736:163–180Google Scholar
  25. Kudo N, Nakagawa Y, Waku K (1990) The effect of cadmium on the composition and metabolism of hepatic fatty acids in zinc-adequate and zinc-deficient rats. Toxicol Lett 50:203–212PubMedCrossRefGoogle Scholar
  26. Kudo N, Nakagawa Y, Waku K (1992) Inhibition of the liberation of arachidonic acid by cadmium ions in rabbit alveolar macrophages. Arch Toxicol 66:131–136PubMedCrossRefGoogle Scholar
  27. Kudo N, Waku K (1996) Cadmium suppresses delta 9 desaturase activity in rat hepatocytes. Toxicology 114:101–111PubMedCrossRefGoogle Scholar
  28. Li M, Kondo T, Zhao QL et al. (2000) Apoptosis induced by cadmium in human lymphoma U937 cells through Ca2+-calpain and caspase-mitochondria-dependent pathways. J Biol Chem 275:39702–39709PubMedCrossRefGoogle Scholar
  29. Martin JJ, Martin R, Codesal J, Fraile B, Paniagua R, Santamaria L (2001) Cadmium chloride – induced dysplastic changes in the ventral rat prostate: an immunohistochemical and quantitative study. Prostate 46:11–20PubMedCrossRefGoogle Scholar
  30. Martin MB, Voeller HJ, Gelmann EP et al. (2002) Role of cadmium in the regulation of AR gene expression and activity. Endocrinology 143:263–275PubMedCrossRefGoogle Scholar
  31. Michaut M, Carrasco M, Gimenez MS (1992) Effects of castration on the incorporation of [3H2O] in lipids of male rat liver. Horm Metab Res 24:593–594PubMedCrossRefGoogle Scholar
  32. Nakamura MT, Cheon Y, Li Y, Nara TY (2004) Mechanisms of regulation of gene expression by fatty acids. Lipids 39:1077–1083PubMedCrossRefGoogle Scholar
  33. Nordberg G (1972) Cadmium metabolism and toxicity. Environ Physiol Biochem 2:7–36Google Scholar
  34. Ochoa S, Mehler AH, Kornberg A (1948) Biosynthesis of dicarboxylic acids by carbon dioxide fixation I. Isolation and properties of an enzyme from pigeon liver catalyzing the reversible oxidation of L-malic acid. J Biol Chem 174:979–1000PubMedGoogle Scholar
  35. Ogunlewe JO, Osegbe DN (1989) Zinc and cadmium concentrations in indigenous blacks with normal, hypertrophic, and malignant prostate. Cancer 63:1388 – 1392PubMedCrossRefGoogle Scholar
  36. Ojeda MS, Gomez NN, Gimenez MS (1997) Androgen regulation of lung lipids in the male rat. Lipids 32:57–62PubMedCrossRefGoogle Scholar
  37. Ramírez DC, Gimenez MS (2002) Lipid modification in mouse peritoneal macrophages after chronic cadmium exposure. Toxicology 172:1 – 12PubMedCrossRefGoogle Scholar
  38. Rhomberg W, Schmoll HJ, Schneider B (1995) High frequency of metal workers among patients with seminomatous tumors of the testis: a case–control study. Am J Ind Med 28:79 – 87PubMedCrossRefGoogle Scholar
  39. Rong Y, Geng Z, Lau BSH (1996) Ginko biloba attenuates oxidative stress in macrophages and endotelial cells. Free Rad Biol Med 20:121–127PubMedCrossRefGoogle Scholar
  40. Rouser G, Fluster S, Yamamoto A (1970) Two-dimensional thin-layer chromatographic separation of polar lipid and determination of phospholipids analysis of spots. Lipids 5:494–496PubMedCrossRefGoogle Scholar
  41. Sardesai VM, Manning JA (1968) Determination of triglycerides in plasma and tissues. Clin Chem 14:156–161Google Scholar
  42. Shiratori Y, Houweling M, Zha X, Tabas I (1995) Stimulation of CTP:phosphocholine cytidylyltransferase by free cholesterol loading of macrophages involves signaling through protein dephosphorylation. J Biol Chem 270:29894–29903PubMedCrossRefGoogle Scholar
  43. Swinnen JV, Ubrix W, Heyns W, Verhoeven G (1997) Coordinate regulation of gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc Natl Acad Sci USA 94:12975–12980PubMedCrossRefGoogle Scholar
  44. Swinnen JV, Verhoeven G (1998) Androgens and the control of lipid metabolism in human prostate cancer cells. J Steroid Biochem Molec Biol 65:191–198PubMedCrossRefGoogle Scholar
  45. Terracio L, Nachtigal M (1986) Transformation of prostatic epithelial cells and fibroblasts with cadmium chloride in vitro. Archives of Toxicology 58:141–151PubMedCrossRefGoogle Scholar
  46. US Public Health Service. (1985) Guide to the care and use of laboratory animals. National Institutes of Health, Bethesda MD, 85–23Google Scholar
  47. USAF. 1990 Cadmium. In: Installation Restoration Program Toxicology Guide, vol. 5. Harry G, ed. Armstrong Aerospace Medical Research Laboratory, Wright Patterson AFB, OH)Google Scholar
  48. Waalkes MP, Rehm S, Riggs CW et al. (1988) Cadmium carcinogenesis in male Wistar [Crl: (WI)BR] rats: dose–response analysis of tumor induction in the prostate and testes and at the injection site. Cancer Res 48:4656–4663PubMedGoogle Scholar
  49. Waalkes MP, Rehm S (1994) Cadmium and prostate cancer. J Toxicol Environ Health 43:251–259PubMedCrossRefGoogle Scholar
  50. Wang C, Smith RL (1975) Lowry determination of protein in the presence of Triton X-100. Anal Biochem 63:414–417PubMedCrossRefGoogle Scholar
  51. Waterman IJ, Price NT, Zammit VA (2002) Distinct ontogenic patterns of overt and latent DGAT activities of rat liver microsomes. J Lipid Res 43:1555–1562PubMedCrossRefGoogle Scholar
  52. Zack B, Moss N, Boyle AS, Zlatkis A (1954) Reaction of certain unsaturated steroids with acid iron reagent. Anal Chem 26:776–777CrossRefGoogle Scholar
  53. Zha S, Ferdinandusse S, Hicks JL et al. (2005) Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer. Prostate 63:316–323PubMedCrossRefGoogle Scholar
  54. Zhou YT, Wang ZW, Higa M, Newgard CB, Unger RH (1999) Reversing adipocyte differenciation: implication for treatment of obesity. Proc Natl Acad Sci USA 96:2391–2395PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Silvina Mónica Alvarez
    • 1
  • Nidia Noemí Gómez
    • 1
  • Luis Scardapane
    • 2
  • Miguel Walter Fornés
    • 3
  • María Sofía Giménez
    • 1
  1. 1.Laboratorio de Bioquímica Molecular, Departamento de Bioquímica y Ciencias Biológicas. Facultad de Química, Bioquímica y FarmaciaUniversidad Nacional de San LuisSan LuisArgentina
  2. 2.Histología y Embriología. Facultad de Química, Bioquímica y FarmaciaUniversidad Nacional de San LuisSan LuisArgentina
  3. 3.IHEM, Universidad Nacional de CuyoMendozaArgentina

Personalised recommendations