Cell and Tissue Research

, Volume 358, Issue 1, pp 257–269 | Cite as

Effects of maternal diabetes on male offspring: high cell proliferation and increased activity of MMP-2 in the ventral prostate

  • A. A. Damasceno
  • C. P. Carvalho
  • E. M. B. Santos
  • F. V. Botelho
  • F. A. Araújo
  • S. R. Deconte
  • T. C. Tomiosso
  • A. P. C. Balbi
  • R. G. Zanon
  • S. R. Taboga
  • R. M Góes
  • D. L. Ribeiro
Regular article

Abstract

This study presents a comprehensive view of the histological and functional status of the prostate of adult rat offspring of mothers subjected to gestational diabetes induced by alloxan. The ventral prostate of male adult offspring of diabetic (DP) or normal (CP) mothers was evaluated for collagen fibres, cell death, fibroblasts, smooth muscle cells, cell proliferation, matrix metalloproteinases (MMPs), androgen receptors (AR), transforming growth factor β1 (TGFβ-1), catalase and total antioxidant activity. The prostates of DP animals were lower in weight than those of the CP group. The DP group also exhibited hyperglycaemia and hypotestosteronemia, higher cell proliferation and AR expression, a reduction in α-actin (possibly interfering with the reproductive function of the prostate), and enhanced activity of MMP-2, although the absolute content of MMP-2 was lower in this group. These findings were associated with increased TGFβ-1 and decreased collagen distribution. The prostates of DP rats additionally exhibited reductions in catalase and total antioxidant activity. Thus, rats developing in a diabetic intrauterine environment have glycaemic and hormonal changes that impact on the structure and physiology of the prostate in adulthood. The increased AR expression possibly leads to elevated cell proliferation. Stromal remodelling was characterized by enhanced activity of MMP-2 and collagen degradation, even with increased TGFβ-1 activation. These changes associated with increased oxidative stress might interfere with tissue architecture and glandular homeostasis.

Keywords

Maternal diabetes Prostate Cell proliferation Metalloproteinase Androgen receptor Rat (Wistar) 

References

  1. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126PubMedCrossRefGoogle Scholar
  2. American Diabetes Association (2012) Standards of medical care in diabetes-2012. Diabetes Care 35 (Supplement 1):S11-S63 Google Scholar
  3. Arcolino FO, Ribeiro DL, Gobbo MG, Taboga SR, Góes RM (2010) Proliferation and apoptotic rates and increased frequency of p63-positive cells in the prostate acinar epithelium of alloxan-induced diabetic rats. Int J Exp Pathol 91:144–154PubMedCrossRefPubMedCentralGoogle Scholar
  4. Arsova-Sarafinovska Z, Eken A, Matevska N, Erdem O, Sayal A, Savaser A, Banev S, Petrovski D, Dzikova S, Georgiev V, Sikole A, Ozgök Y, Suturkova L, Dimovski AJ, Aydin A (1990) Increased oxidative/nitrosative stress and decreased antioxidant enzyme activities in prostate cancer. Clin Biochem 42:1228–1235Google Scholar
  5. Aumüller G, Seitz J (1990) Protein secretion and secretory processes in male accessory sex glands.Int Rev Cytol 121:127-231PubMedCrossRefGoogle Scholar
  6. Badr G, Mahmoud MH, Farhat K, Waly H, Al-Abdin OZ, Rabah DM (2013) Maternal supplementation of diabetic mice with thymoquinone protects their offspring from abnormal obesity and diabetes by modulating their lipid profile and free radical production and restoring lymphocyte proliferation via PI3K/AKT signaling. Lipids Health Dis 12:37PubMedCrossRefPubMedCentralGoogle Scholar
  7. Banerjee PP, Banerjee S, Brown TR (2001) Increased androgen receptor expression correlates with development of age-dependent, lobe-specific spontaneous hyperplasia of the brown Norway rat prostate. Endocrinology 142:4066–4075PubMedCrossRefGoogle Scholar
  8. Barrack ER, Bujnovszky P, Walsh PC (1983) Subcellular distribution of androgen receptors in human normal, benign hyperplastic, and malignant prostatic tissues: characterization of nuclear salt-resistant receptors. Cancer Res 43:1107–1116PubMedGoogle Scholar
  9. Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of "antioxidant power": the FRAP assay. Anal Biochem 239:70–76PubMedCrossRefGoogle Scholar
  10. Bhasin S, Enzlin P, Coviello A, Basson R (2007) Sexual dysfunction in men and women with endocrine disorders. Lancet 369:597–611PubMedCrossRefGoogle Scholar
  11. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254PubMedCrossRefGoogle Scholar
  12. Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMedCrossRefGoogle Scholar
  13. Burke JP, Jacobson DJ, McGree ME, Nehra A, Roberts RO, Girman CJ, Lieber MM, Jacobsen SJ (2007) Diabetes and sexual dysfunction: results from the Olmsted County study of urinary symptoms and health status among men. J Urol 177:1438–1442PubMedCrossRefGoogle Scholar
  14. Catalano PM, Hauguel-De Mouzon S (2011) Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic? Am J Obstet Gynecol 204:479–487PubMedCrossRefPubMedCentralGoogle Scholar
  15. Costa MM, Violato NM, Taboga SR, Góes RM, Bosqueiro JR (2012) Reduction of insulin signalling pathway IRS-1/IRS-2/AKT/mTOR and decrease of epithelial cell proliferation in the prostate of glucocorticoid-treated rats. Int J Exp Pathol 93:188–195PubMedCrossRefPubMedCentralGoogle Scholar
  16. Cunha GR, Cooke PS, Kurita T (2004) Role of stromal-epithelial interactions in hormonal responses. Arch Histol Cytol 67:417–434PubMedCrossRefGoogle Scholar
  17. Daubresse JC, Meunier JC, Wilmotte J, Luyckx AS, Lefebvre PJ (1978) Pituitary-testicular axis in diabetic men with and without sexual impotence. Diabetes Metab 4:233–237Google Scholar
  18. Dawood T, Williams MR, Fullerton MJ, Myles K, Schuijers J, Funder JW, Sudhir K, Komesaroff PA (2005) Glucocorticoid responses to stress in castrate and testosterone-replaced rams. Regul Pept 125:47–53PubMedCrossRefGoogle Scholar
  19. Dinulovic D, Radonjic G (1990) Diabetes mellitus/male infertility. Arch Androl 25:277–293Google Scholar
  20. D'Souza A, Howarth FC, Yanni J, Dobrzynski H, Boyett MR, Adeghate E, Bidasee KR, Singh J (2014) Chronic effects of mild hyperglycaemia on left ventricle transcriptional profile and structural remodelling in the spontaneously type 2 diabetic Goto-Kakizaki rat. Heart Fail Rev 19:65–74PubMedCrossRefGoogle Scholar
  21. De Marzo AM, Platz EA, Sutcliffe S, Xu J, Grönberg H, Drake CG, Nakai Y, Isaacs WB, Nelson WG (2007) Inflammation in prostate carcinogenesis. Nat Rev Cancer 7:256–269PubMedCrossRefPubMedCentralGoogle Scholar
  22. Detsch JC, Almeida AC, Bortolini LG, Nascimento DJ, Oliveira FC Jr, Réa RR (2011) Marcadores para o diagnóstico e tratamento de 924 gestações com diabetes melito gestacional. Arq Bras Endocrinol Metab 55:389–398CrossRefGoogle Scholar
  23. Forgiarini LA Jr, Kretzmann NA, Tieppo J, Picada JN, Dias AS, Marroni NA (2010) Alterações pulmonares em um modelo de diabetes mellitus em ratos: o efeito da terapia antioxidante. J Bras Pneumol 36:579–587Google Scholar
  24. Frenkel GP, Homonnai ZT, Drasnin N, Sofer A, Kaplan R, Kraicer PF (1978) Fertility of the streptozotocin-diabetic male rat. Andrologia 10:127–136PubMedCrossRefGoogle Scholar
  25. Friedgood CA, Miller AA (1945)Alloxan in pregnant rats.Proc Soc Exp Biol Med 59:62CrossRefGoogle Scholar
  26. Gharagozlian S, Svennevig K, Bangstad HJ, Winberg JO, Kolset SO (2009) Matrix metalloproteinases in subjects with type 1 diabetes. BMC Clin Pathol 9:7PubMedCrossRefPubMedCentralGoogle Scholar
  27. Gobbo MG, Taboga SR, Ribeiro DL, Góes RM (2012a) Short-term stromal alterations in the rat ventral prostate following alloxan-induced diabetes and the influence of insulin replacement. Micron 43:326–333PubMedCrossRefGoogle Scholar
  28. Gobbo MG, Ribeiro DL, Taboga SR, de Almeida EA, Góes RM (2012b) Oxidative stress markers and apoptosis in the prostate of diabetic rats and the influence of vitamin C treatment. J Cell Biochem 113:2223–2233PubMedCrossRefGoogle Scholar
  29. Góes RM, Zanetoni C, Tomiosso TC, Ribeiro DL, Taboga SR (2007) Surgical and chemical castration induce differential histological response in prostate lobes of Mongolian gerbil. Micron 38:231–236PubMedCrossRefGoogle Scholar
  30. Hsieh HL, Lin CC, Hsiao LD, Yang CM (2013) High glucose induces reactive oxygen species-dependent matrix metalloproteinase-9 expression and cell migration in brain astrocytes. Mol Neurobiol 48:601–614PubMedCrossRefGoogle Scholar
  31. Ikeda K, Wada Y, Foster HE Jr, Wang Z, Weiss RM, Latifpour J (2000) Experimental diabetes-induced regression of the rat prostate is associated with an increased expression of transforming growth factor-beta. J Urol 164:180–185PubMedCrossRefGoogle Scholar
  32. International Diabetes Federation (2013) Diabetes: facts and figures. IDF Diabetes Atlas, 6th edn. International Diabetes Federation, Brussels. http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures
  33. Jelodar G, Khaksar Z, Pourahmadi M (2009) Endocrine profile and testicular histomorphometry in adult rat offspring of diabetic mothers. J Physiol Sci 59:377–382PubMedCrossRefGoogle Scholar
  34. Kolset SO, Reinholt FP, Jenssen T (2012) Diabetic nephropathy and extracellular matrix.J Histochem Cytochem 60:976-986PubMedCrossRefPubMedCentralGoogle Scholar
  35. Krzyzanowska K, Zemany L, Krugluger W, Schernthaner GH, Mittermayer F, Schnack C, Rahman R, Brix J, Kahn BB, Schernthaner G (2008) Serum concentrations of retinol-binding protein 4 in women with and without gestational diabetes. Diabetologia 51:1115–1122PubMedCrossRefPubMedCentralGoogle Scholar
  36. Lamers ML, Gimenes FA, Nogueira FN, Nicolau J, Gama P, Santos MF (2007) Chronic hyperglycaemia increases TGFβ2 signaling and the expression of extracellular matrix proteins in the rat parotid gland. Matrix Biol 26:572–582PubMedCrossRefGoogle Scholar
  37. Lauer-Fields JL, Juska D, Fields GB (2002) Matrix metalloproteinases and collagen catabolism. Biopolymers 66:19–32PubMedCrossRefGoogle Scholar
  38. Leask A (2010) Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res 106:1675–1680PubMedCrossRefGoogle Scholar
  39. Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51(2):216–226Google Scholar
  40. Lira LQ, Dimenstein R (2010) Vitamin A and gestational diabetes. Rev Assoc Med Bras 56:355–359PubMedCrossRefGoogle Scholar
  41. Marion MMH van (2006) Matrix metalloproteinases and collagen remodeling: a literature review. BMTE, 06.55. http://www.mate.tue.nl/mate/pdfs/7435.pdf
  42. Nakayama M, Bennett CJ, Hicks JL, Epstein JI, Platz EA, Nelson WG, De Marzo AM (2003) Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. Am J Pathol 163:923–933PubMedCrossRefPubMedCentralGoogle Scholar
  43. Naveen Kumar T(2013) Animalmodels as an experimental tool in diabetes research. J Drug DelivTher 3:152–154Google Scholar
  44. Nelles JL, Hu WY, Prins GS (2011) Estrogen action and prostate cancer. Expert Rev Endocrinol Metab 6:437–451PubMedCrossRefPubMedCentralGoogle Scholar
  45. Porto EM, Dos Santos SA, Ribeiro LM, Lacorte LM, Rinaldi JC, Justulin LA Jr, Felisbino SL (2011) Lobe variation effects of experimental diabetes and insulin replacement on rat prostate. Microsc Res Tech 74:1040–1048PubMedCrossRefGoogle Scholar
  46. Prins GS (2008) Endocrine disruptors and prostate cancer risk. Endocr Relat Cancer 15:649–656PubMedCrossRefPubMedCentralGoogle Scholar
  47. Ramamani A, Aruldhas MM, Govindarajulu P (1999) Differential response of rat skeletal muscle glycogen metabolism to testosterone and estradiol. Can J Physiol Pharmacol 77:300–304PubMedCrossRefGoogle Scholar
  48. Ribeiro DL, Caldeira EJ, Cândido EM, Manzato AJ, Taboga SR, Cagnon VH (2006) Prostatic stromal microenvironment and experimental diabetes. Eur J Histochem 50:51–60PubMedGoogle Scholar
  49. Ribeiro DL, Marques SF, Alberti S, Spadella CT, Manzato AJ, Taboga SR, Dizeyi N, Abrahamsson PA, Góes RM (2008) Malignant lesions in the ventral prostate of alloxan-induced diabetic rats. Int J Exp Pathol 89:276–283PubMedCrossRefPubMedCentralGoogle Scholar
  50. Ribeiro DL, Taboga SR, Góes RM (2009) Diabetes induces stromal remodelling and increase in chondroitin sulphate proteoglycans of the rat ventral prostate. Int J Exp Pathol 90:400–411PubMedCrossRefPubMedCentralGoogle Scholar
  51. Robertson RP, Harmon J, Tran PO, Tanaka Y, Takahashi H (2003) Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52:581–587PubMedCrossRefGoogle Scholar
  52. Roy S, Sala R, Cagliero E, Lorenzi M (1990) Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci U S A 87:404–408PubMedCrossRefPubMedCentralGoogle Scholar
  53. Sanai T, Sobka T, Johnson T, el-Essawy M, Muchaneta-Kubara EC, Ben Gharbia O, Oldroyd S el, Nahas AM (2000) Expression of cytoskeletal proteins during the course of experimental diabetic nephropathy. Diabetologia 43:91–100Google Scholar
  54. Scarano WR, Messias AG, Oliva SU, Klinefelter GR, Kempinas WG (2006) Sexual behavior, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats. Int J Androl 29:482–488PubMedCrossRefGoogle Scholar
  55. Scarano WR, de Sousa DE, Campos SG, Corradi LS, Vilamaior PS, Taboga SR (2008) Oestrogen supplementation following castration promotes stromal remodelling and histopathological alterations in the Mongolian gerbil ventral prostate. Int J Exp Pathol 89:25–37PubMedCrossRefPubMedCentralGoogle Scholar
  56. Sciarra A, Di Silverio F, Salciccia S, Autran Gomez AM, Gentilucci A, Gentile V (2007) Inflammation and chronic prostatic diseases: evidence for a link? Eur Urol 52:964–972PubMedCrossRefGoogle Scholar
  57. Soudamani S, Yuvaraj S, Malini T, Balasubramanian K (2005) Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats. Anat Rec 287:1281–1289CrossRefGoogle Scholar
  58. Symonds ME, Stephenson T, Gardner DS, Budge HA (2009)Tissue specific adaptations to nutrient supply: more than just epigenetics? Adv Exp Med Biol 646:113-118PubMedCrossRefGoogle Scholar
  59. Thandavarayan RA, Watanabe K, Ma M, Gurusamy N, Veeraveedu PT, Konishi T, Zhang S, Muslin AJ, Kodama M, Aizawa Y (2009) Dominant-negative p38α mitogen-activated protein kinase prevents cardiac apoptosis and remodeling after streptozotocin-induced diabetes mellitus. Am J Physiol Heart Circ Physiol 297:H911–H919PubMedCrossRefGoogle Scholar
  60. Thomson AA, Cunha GR, Marker PC (2008) Prostate development and pathogenesis. Differentiation 76:559–564PubMedCrossRefGoogle Scholar
  61. Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR (2002) Reactive stroma in human prostate câncer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res 8:2912–2923PubMedGoogle Scholar
  62. Ueha S, Shand FH, Matsushima K (2012) Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Front Immunol 3:71PubMedCrossRefPubMedCentralGoogle Scholar
  63. Vikram A, Jena G (2011) Role of insulin and testosterone in prostatic growth: who is doing what? Med Hypotheses 76:474–478PubMedCrossRefGoogle Scholar
  64. Vilamaior PS, Felisbino SL, Taboga SR, Carvalho HF (2000) Collagen fiber reorganization in the rat ventral prostate following androgen deprivation: a possible role for smooth muscle cells. Prostate 45:253–258PubMedCrossRefGoogle Scholar
  65. Weibel ER (1963) Principles and methods for the morphometric study of the lung and other organs. Lab Invest 12:131–155PubMedGoogle Scholar
  66. Weinert LS, Silveiro SP, Oppermann ML, Salazar CC, Simionato BM, Siebeneichler A, Reichelt AJ (2011) Diabetes gestacional: um algoritmo de tratamento multidisciplinar. Arq Bras Endocrinol Metab 55:435–445CrossRefGoogle Scholar
  67. Yan J, Brown TR (2008) Cell proliferation and expression of cell cycle regulatory proteins that control the G1/S transition are age dependent and lobe specific in the brown Norway rat model of prostatic hyperplasia. Endocrinology 149:193–207PubMedCrossRefPubMedCentralGoogle Scholar
  68. Yang Y, Lane AN, Ricketts CJ, Sourbier C, Wei MH, Shuch B, Pike L, Wu M, Rouault TA, Boros LG, Fan TW, Linehan WM (2013) Metabolic reprogramming for producing energy and reducing power in fumarate hydratase null cells from hereditary leiomyomatosis renal cell carcinoma. PLoS One 8:e72179PubMedCrossRefPubMedCentralGoogle Scholar
  69. Ye C, Li X, Wang Y, Zhang Y, Cai M, Zhu B, Mu P, Xia X, Zhao Y, Weng J, Gao X, Wen X (2011) Diabetes causes multiple genetic alterations and downregulates expression of DNA repair genes in the prostate. Lab Invest 91:1363–1374PubMedCrossRefGoogle Scholar
  70. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 97:1784–1789PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • A. A. Damasceno
    • 1
  • C. P. Carvalho
    • 1
  • E. M. B. Santos
    • 2
  • F. V. Botelho
    • 2
  • F. A. Araújo
    • 3
  • S. R. Deconte
    • 3
  • T. C. Tomiosso
    • 1
  • A. P. C. Balbi
    • 3
  • R. G. Zanon
    • 4
  • S. R. Taboga
    • 5
  • R. M Góes
    • 5
  • D. L. Ribeiro
    • 1
  1. 1.Histology Sector, Institute of Biomedical Sciences—ICBIMFederal University of UberlândiaUberlândiaBrazil
  2. 2.Institute of Genetics and Biochemistry—INGEBFederal University of UberlândiaUberlândiaBrazil
  3. 3.Physiology Sector, Institute of Biomedical Sciences—ICBIMFederal University of UberlândiaUberlândiaBrazil
  4. 4.Anatomy Sector, Institute of Biomedical Sciences—ICBIMFederal University of UberlândiaUberlândiaBrazil
  5. 5.Institute of Biosciences, Letters and Exact Sciences—IBILCE, Department of Biology University Estadual PaulistaPaulistaBrazil

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