, Volume 86, Issue 3, pp 321–329 | Cite as

Enzymatic and morphological response of the thymus to drugs in normal and zinc-deficient pregnant rats and their fetuses

  • R. Gossrau
  • H.-J. Merker
  • T. Günther
  • R. Graf
  • J. Vormann


In the thymus of normally fed pregnant rats the plasma membrane enzymes dipeptidyl peptidase IV (DPP IV) and alkaline phosphatase (alP) were found in cortical and medullary lymphocytes (thymocytes). Plasma membrane aminopeptidase A (APA) and adenosine monophosphate hydrolysing phosphatase (AMPP) were present in cortical reticular cells. In medullary reticular cells, aminopeptidase M (APM), γ-glutamyl transferase (GGT), adenosine triphosphate (ATPP) and thiamine pyrophosphate (TPPP) cleaving phosphatases were detected. Medullary reticular cells did not contain APA. Lysosomal DPP I and II, acid phosphatase, acid β-d-galactosidase, β-d-N-acetylglucosaminidase, β-d-glucuronidase and non-specific esterases occurred especially in macrophages at the corticomedullary junction. The 21-day-old fetal thymus showed a similar reaction pattern as the maternal organ except for APA which was absent before birth.—After treatment of the pregnant rats with valproic acid (VPA), salicylic acid (SA), streptozotocin (ST) and retinoic acid (RA) APA showed an increase in activity in the thymic cortex. In addition, ST and RA induced AMPP, ATPP and TPPP activity in cortical reticular cells up to the same pattern as in medullary reticular cells. After ethanol (ET) administration severe damages occurred. The thymic cortex was free of DPP IV-positive lymphocytes; the medullary reticular cells showed reduced or no GGT and occasionally an increased APM activity. Dexamethasone (DEXA) given to normal or zinc-deficient rats produced the most severe lesions; thymocytes with DPP IV activity were completely absent in the cortex and medulla. In Zn-deficient pregnant rats similar alterations were observed as after ET. When the drugs were applied to Zn-deficient pregnant rats, the alterations resembled those observed after drug treatment alone. In all cases of severe thymus degeneration, i.e. ET and DEXA treatment and Zn-deficiency, the number of macrophages and activities of lysosomal hydrolases in macrophages and reticular cells were increased; the lysosomal hydrolases were often homogeneously distributed over the cortex. Cell contacts between reticular cells and lymphocytes were reduced. Vacuoles occurred within the reticular cells.—The fetal thymus was reduced in size and the number of macrophages and the activities of their lysosomal enzymes were increased after Zn-deficiency, DEXA treatment and Zn-deficiency combined with ET administration.


Salicylic Acid Retinoic Acid Reticular Cell DEXA Treatment Lysosomal Hydrolase 
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  1. Averdunk R, Bippus PH, Günther T, Merker H-J (1982) Development and properties of malignant lymphoma induced by magnesium deficiency in rats. J Cancer Res Clin Oncol 104:63–73Google Scholar
  2. Beach RS, Gershwin ME, Hurley LS (1979) Altered thymic structure and mitogenic responsiveness in postnatally zinc-deprived mice. Dev Comp Immunol 3:725–738Google Scholar
  3. Beach RS, Gershwin ME, Hurley LS (1982) Gestational zinc-deprivation in mice: persistence of immunodeficiency for three generations. Science 218:469–471Google Scholar
  4. Becking GC (1976) Trace elements and drug metabolism. Med Clin North Am 60:813–830Google Scholar
  5. Blackburn WR, Kaplan HS (1963) Effects of prednisolone on the developing rat fetus with special reference to the thymus. Fed Proc 22:601Google Scholar
  6. Burke JP, Fenton MR (1985) Effect of a Zn-deficient diet on lipid peroxidation in liver and tumor subcellular membranes. Proc Soc Exp Biol Med 179:187–191Google Scholar
  7. Chandra RK, Heresi G, Bing AV (1980) Serum thymic factor activity in deficiencies of calories, zinc, vitamin A and pyrodoxine. Clin Exp Immunol 42:332–335Google Scholar
  8. Chavpil M (1976) Effect of zinc on cells and biomembranes. Med Clin North Am 60:799–812Google Scholar
  9. Cousins RJ, Swerdel MR (1985) Ceruloplasmin and metallothionein induction by zinc and 13-cis-retinoic acid in rats with adjuvant inflammation. Proc Soc Exp Biol Med 179:168–172Google Scholar
  10. Cortijo J, Esplugues JV, Sarria B, Marti-Caberra M, Esplugues J (1985) Zinc as a calcium antagonist: a pharmacological approach in strips of rat aorta. IRCS Med Sci Biochem 13:292–293Google Scholar
  11. Dardenne M, Pleau JM, Nabarra B, Lefranvier P, Derien M, Choay J, Bach JF (1982) Contribution of zinc and other metals to the biological activity of serum thymic factor. Proc Natl Acad Sci USA 79:5370–5373Google Scholar
  12. Durant S, Homo F, Duval D (1980) Calcium and A 23187-induced cytolysis of mouse thymocyta. Biochem Biophys Res Commun 93:385–391Google Scholar
  13. Etzel KR, Cousius RJ (1981) Hormal regulation of liver metallothionein zinc: Independent and synergistic action of glucagon and glucocorticoids. Proc Soc Exp Biol Med 16:233–236Google Scholar
  14. Farber JL (1981) The role of calcium in cell death. Life Sci 29:1289–1295Google Scholar
  15. Gaudecker B, Steinmann GG, Hausmann M-L, Harpprecht J, Milicevic NM, Müller-Hermelink H-K (1986) Immunohistochemical characterization of the thymic microenvironment. A light-microscopic and ultrastructural immunocytochemical study. Cell Tissue Res 244:403–412Google Scholar
  16. Geyer G (1973) Ultrahistochemie. Histochemische Arbeitsvorschriften für die Elektronenmikroskopie. 2. Aufl. Gustav Fischer, StuttgartGoogle Scholar
  17. Gossrau R (1981) Investigation of proteinases in the digestive tract using 4-methoxy-2-naphthylamine (MNA) substrates. J Histochem Cytochem 29:464–480Google Scholar
  18. Gossrau R, Graf R (1986) Zur Proteasenentwicklung in der Nagerplacenta. Verh Anat Ges 81 (in press)Google Scholar
  19. Gossrau R, Vormann J, Günther T (1984) Enzyme cytochemistry of malignant T cell lymphoma due to chronic magnesium deficiency in rats. Histochemistry 80:183–186Google Scholar
  20. Gossrau R, Graf R, Günther T, Merker H-J, Vormann J, Nau H, Stahlmann R, Heger W (1986) Usefulness of enzyme cytochemistry for the study of side effects of drugs with special reference to proteases. Histochem J (Abstr) (in press)Google Scholar
  21. Hirokawa K, Saitoh K, Hatakeyama S (1983) Enzyme histochemical study on human thymus and its age change. Acta Pathol Jpn 33:275–285Google Scholar
  22. Johnson WT, Canfield WK (1985) Intestinal absorption and excretion of zinc in streptozotocin-diabetic rats as affected by dietary zinc and protein. J Nutr 115:1217–1227Google Scholar
  23. Kaiser N, Edelman IS (1978) Further studies on the role of calcium in glucocorticoid-induced lympocytolyses. Endocrinology 103:936–942Google Scholar
  24. Lojda Z, Gossrau R, Schiebler TH (1979) Enzyme histochemistry. A laboratory manual. Springer, Berlin Heidelberg New YorkGoogle Scholar
  25. Mercalli ME, Seri S, Aquilio E, Granarossa L, Del Gobbo V, Acciumi L, Toniette G (1984) Zinc deficiency and thymus ultrastructure in rats. Nutr Res 4:665–671Google Scholar
  26. Metcalf D (1966) The thymus. Springer, Berlin Heidelberg New York, p 16Google Scholar
  27. Müller-Hermelink HK, Mariono M, Palestro G (1986) Pathology of thymic epithelial tumors. Curr Top Pathol 75:207–268Google Scholar
  28. Nicolas JF, Savino W, Reano A, Viac J, Brochier J, Dardenne M (1985) Heterogeneity of thymic epithelial cell (TEC) keratins. J Histochem Cytochem 33:687–694Google Scholar
  29. Prasad AS (1979) Clinical, biochemical and pharmacological role of zinc. Annu Rev Pharmacol Toxicol 20:393–426Google Scholar
  30. Romeis B (1968) Mikroskopische Technik. R. Oldenbourg, MünchenGoogle Scholar
  31. Rothenberg E, Lugo JP (1985) Differentiation and cell division in mammalian thymus. Dev Biol 112:11–17Google Scholar
  32. Singh J (1981) The ultrastructure of epithelial reticular cells. In: Kendall MD (ed) The thymus. Anatomical Society Symposion, vol I. Academic Press, London, pp 133–177Google Scholar
  33. Swerdel MR, Cousins RJ (1984) Changes in rat liver metallothionein and metallothionein mRNA induced by isopropanol. Proc Soc Exp Biol Med 175:522–529Google Scholar
  34. Ushiki T (1986) A scanning electron-microscopic study of the rat thymus with special reference to cell types and migration of lymphocytes into general circulation. Cell Tissue Res 244:285–298Google Scholar
  35. Vallee BL, Galdes A (1984) The metallobiochemistry of zinc enzymes. Adv Enzymol 56:283–430Google Scholar
  36. Vormann J, Höllriegl V, Merker HJ, Günther T (1986a) Effect of salicylate on zinc metabolism in fetal and maternal rats fed normal and zinc-deficient diets. Biol Trace Elem Res 9:55–64Google Scholar
  37. Vormann J, Höllriegl V, Merker HJ, Günther T (1986b) Effect of valporate on zinc metabolism in fetal and maternal rats fed normal and zinc-deficient diets. Biol Trace Elem Res (in press)Google Scholar
  38. Waalkes MP, Hjelle JJ, Klaasen CD (1984) Transient induction of hepatic metallothionein following oral ethanol administration. Toxicol Appl Pharmacol 74:230–236Google Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • R. Gossrau
    • 1
  • H.-J. Merker
    • 1
  • T. Günther
    • 2
  • R. Graf
    • 1
  • J. Vormann
    • 2
  1. 1.Department of AnatomyFree University of BerlinBerlin 33Germany
  2. 2.Department of Molecular Biology and BiochemistryFree University of BerlinBerlin 33Germany

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