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Toxicologic Pathology
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Journal Article

The Effects of Xenobiotics on the Structure and Function of Thyroid Follicular and C-Cells

Charles C. Capen

The Ohio State University, Departments of Veterinary Pathobiology and Veterinary Clinical Sciences, Columbus, Ohio 43210

Sharron L. Martin

The Ohio State University, Departments of Veterinary Pathobiology and Veterinary Clinical Sciences, Columbus, Ohio 43210

The mammalian thyroid gland is composed of 2 distinct endocrine cell populations concerned with the synthesis of 2 different classes of hormones. Follicular cells secrete the metabolically active iodothyronines whereas the C- (parafollicular) cells are concerned with the production of calcitonin, a hormone that influences blood levels of calcium and phosphorus, and bone cell metabolism. The synthesis of metabolic thyroid hormones is different than in other endocrine glands because the final assembly of hormone occurs within the follicular lumen. This extracellular synthesis of thyroid hormones is made possible by thyroglobulin, a glycoprotein synthesized by follicular cells. The secretion of thyroid hormones under the influence of pituitary thyrotrophin (TSH) from stores in the luminal colloid is initiated by elongation of microvilli and formation of pseudopods. FD&C Red No. 3 is a tetraiodinated derivative of fluorescein which in lifetime studies increases the incidence of thyroid follicular cell adenomas in male Sprague-Dawley rats. The striking changes in circulating levels of thyroid hormones and morphologic evidence of follicular cell stimulation are the result of alterations in the peripheral metabolism of thyroxine. An inhibition by FD&C Red No. 3 of 5'-deiodinase in the liver and kidney would explain the lower serum triiodothyronine (T3) levels. The pituitary, sensing the lowered circulating levels of T3, increased the secretion of thyroid stimulating hormone which resulted in the morphologic evidence of follicular cell stimulation in the long-term studies. Other xenobiotics increase the incidence of thyroid tumors in rodents by a direct effect on the thyroid gland to disrupt 1 of 3 or more possible steps in the biosynthesis of thyroid hormones. Physiologic perturbations alone, such as iodine deficiency or partial thyroidectomy, can disrupt thyroid hormone economy in rodents and, if sustained, increase the development of thyroid tumors. The wide variety of drugs, chemicals, and physiologic perturbations which increase thyroid tumor development appear to act through a secondary (indirect) mechanism to promote tumor development by causing a long-standing hypersecretion of thyroid stimulating hormone. Nodular and/or diffuse hyperplasia of C-cells occurs with advancing age in many strains of laboratory rats and in response to long-term hypercalcemia in certain animal species and human beings. Focal or diffuse hyperplasia of ten precedes the development of C-cell neoplasms. Radiation and the feeding of diets high in vitamin D resulting in hypercalcemia have been reported to increase the incidence of C-cell tumors in rats.

Key Words: FD&C Red No. 3 • polychlorinated biphenyls • secondary mechanism of oncogenesis • thyroid function • hyperplasia of follicular cells ("goiter") • mechanisms of goitrogenesis • iodine metabolism • proliferative lesions of thyroid C-cells

  • 1. Alexander NM (1959). Antithyroid action of 3-amino-1,2,4-triazole. J. Biol. Chem. 234: 148–150.[Free Full Text]
  • 2. Axelrad AA and Leblond CP (1955). Induction of thyroid tumors in rats by a low iodine diet. Cancer 8: 339–367.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 3. Baker HJ and Lindsey JR (1968). Equine goiter due to excess dietary iodide. J. Am. Vet. Med. Assn. 153: 1618–1630.[Web of Science][Medline] [Order article via Infotrieve]
  • 4. Bastenie PA, Ermans AM, Bonnyns M, Neve P, and Delespese G (1975). Lymphocytic thyroiditis as an autoimmune disease. In: Molecular Pathology, RA Good (ed). Charles C Thomas, Springfield, pp. 243–261.
  • 5. Bastomsky CH (1974). Effects of a polychlorinated biphenyl mixture (Arochlor 1254) and DDT on biliary thyroxine excretion in rats. Endocrinology 95: 1150–1155.[Abstract/Free Full Text]
  • 6. Bastomsky CH, Murthy PVN, and Banovac K (1976). Alterations in thyroxine metabolism produced by cutanous application of microscope immersion oil: Effects due to polychlorinated biphenyls. Endocrinology 98: 1309–1314.[Abstract/Free Full Text]
  • 7. Bastomsky CH and Murthy PVN (1976). Enhanced in vitro hepatic glucuronidation of thyroxine in rats following cutaneous application or ingestion of polychlorinated biphenyls. Can. J. Physiol. Pharmacol. 54: 23–26.[Web of Science][Medline] [Order article via Infotrieve]
  • 8. Bastomsky CH and Wyse JM (1975). Enhanced thyroxine metabolism following cutaneous application of microscope immersion oil. Res. Commun. Chem. Pathol. Pharmacol. 10: 725–733.[Web of Science][Medline] [Order article via Infotrieve]
  • 9. Belshaw BE (1982). Thyroid diseases. In: Textbook of Veterinary Internal Medicine, Diseases of the Dog and Cat. SJ Ettinger (ed). Saunders, Philadelphia, pp. 1592–1614.
  • 10. Belshaw BE and Becker DV (1971). Necrosis of follicular cells and discharge of thyroidal iodine induced by administering iodide to iodine-deficient dogs. J. Clin. Endocrinol. Metab. 36: 466–474.
  • 11. Belshaw BE and Rijnberk A (1979). Radioimmunoassay of plasma T4 and T3 in the diagnosis of primary hypothyroidism in dogs. J.A.A.H.A. 15: 17–26.
  • 12. Book SA (1976). Influence of age on thyroidal 131I uptake in Beagle pups. Lab. Anim. Sci. 26: 443–449.[Web of Science][Medline] [Order article via Infotrieve]
  • 13. Borzelleca JF and Hallagan JB (1987). A chronic toxicity/carcinogenicity study of FD&C Red No. 3 in mice. Fd. Chem. Toxic. 25: 735–738.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 14. Borzelleca JF, Capen CC, and Hallagan JB (1987). Lifetime toxicity/carcinogenicity study of FD&C Red No. 3 (erythrosine) in rats. Fd. Chem. Toxic. 25723:.
  • 15. Capen CC (1980). Criteria for the development of animal models of diseases of the endocrine system. Am. J. Path. 101: S141–S155.[Medline] [Order article via Infotrieve]
  • 16. Capen CC, Belshaw BE, and Martin SL (1975). Endocrine diseases. In: Textbook of Veterinary Internal Medicine–Diseases of the Dog and Cat, Chapter 50. W. B. Saunders, Philadelphia, pp. 1351–1452.
  • 17. Caylor HD, Schlotthauer CF, and de Pemberton JJ (1927). Observations on the lymphatic connections of the thyroid gland. Anat. Rec. 36: 325–333.[CrossRef]
  • 18. Cheville NJ (1972). Ultrastructure of canine carotid body and aortic body tumors. Comparison with tissues of thyroid and parathyroid origin. Vet. Path. 9: 166–189.[Web of Science][Medline] [Order article via Infotrieve]
  • 19. Collins WT Jr and Capen CC (1980). Biliary excretion of 125I-thyroxine and fine structural alterations in the thyroid glands of Gunn rats fed polychlorinated biphenyls (PCB). Lab. Invest. 43: 153–164.
  • 20. Collins WT Jr and Capen CC (1980). Structural lesions and hormonal alterations in thyroid glands of perinatal rats exposed in utero and by the milk to polychlorinated biphenyls. Am. J. Path. 99: 125–142.[Abstract]
  • 21. Collins WT Jr and Capen CC (1980). Ultrastructural and functional alterations of the rat thyroid gland produced by polychlorinated biphenyls compared with iodide excess and deficiency, and thyrotropin and thyroxine administration. Virchows Arch. B Cell Path. 33: 213–231.[CrossRef]
  • 22. Collins WT Jr, Capen CC, Kasza L, Carter C, and Dailey RE (1977). Effect of polychlorinated biphenyl (PCB) on the thyroid gland of rats. Am. J. Path. 89: 119–130.[Web of Science][Medline] [Order article via Infotrieve]
  • 23. Collins TF and Long EL (1976). Effects of chronic oral administration of erythrosine in the Mongolian gerbil. Fd. Cosmet. Toxicol. 14: 233–248.[CrossRef]
  • 24. Cristov K and Raichev R (1972). Experimental thyroid carcinogenesis. Curr. Topics Pathol. 56: 79–114.[Medline] [Order article via Infotrieve]
  • 25. DeLellis RA, Nunnemacher G, and Wolfe HJ (1977). C-cell hyperplasia: An ultrastructural analysis. Lab. Invest. 36: 237–248.[Web of Science][Medline] [Order article via Infotrieve]
  • 26. de Vijlder JJM, van Voorthuizen WF, van Dijk JE et al (1978). Hereditary congenital goiter with thyroglobulin deficiency in a breed of goats. Endocrinology 102: 1214–1222.[Abstract/Free Full Text]
  • 27. Ekholm R and Wollman SH (1975). Site of iodination in the rat thyroid gland deduced from electron microscopic autoradiographs. Endocrinology 97: 1432–1444.[Abstract/Free Full Text]
  • 28. Falconer IR (1966). Studies of the congenitally goitrous sheep: The iodinated compounds of serum and circulating thyroid-stimulating hormone. Biochem. J. 100: 190–196.[Web of Science][Medline] [Order article via Infotrieve]
  • 29. Furth J (1968). Pituitary cybernetics and neoplasia. In: The Harvey Lecture Series. Academic Press, New York, pp. 47–71.
  • 30. Godwin MC (1936). The early development of the thyroid gland in the dog with special reference to the origin and position of accessory thyroid tissue within the thoracic cavity. Anat. Rec. 66: 233–251.[CrossRef]
  • 31. Gosselin SJ, Martin SL, Capen CC et al (1980). Biochemical and immunological investigations of hypothyroidism in dogs. Canad. J. Comp. Med. 44: 158–168.
  • 32. Hammarström S, Sterling K, Milch PO et al (1977). Thyroid hormone action: The mitochondrial pathway. Science 197: 996–999.[Abstract/Free Full Text]
  • 33. Hiasa Y, Oshima M, Kitahori Y, Konishi N, Shimoyama T, Sakaguchi Y, Hashimoto H, Minami S, and Kato Y (1988). The promoting effects of food dyes erythrosine (Red 3) and Rose Bengal (Red 105) on thyroid tumors in partially thyroidectomized N-bis-(2-hydroxypropyl)-nitrosamine-treated rats. Jpn. J. Cancer Res. (Gann) 79: 314–319.
  • 34. Hiasa Y, Oshima M, Kitahori T, Yuasa T, Fujita T, and Iwata C (1982). Promoting effects of 3-amino-1,2,4-triazole on the development of thyroid tumors in rats treated with N-bis-(2-hydroxypropyl) nitrosamine. Carcinogenesis 3: 381–384.[Abstract/Free Full Text]
  • 35. Ingbar SH (1986). Further studies on the effect of erythrosine on peripheral thyroxine metabolism in the rat. Unpublished report.
  • 36. Ingbar SH, Garber J, and Burrows BA (1987). Further studies of the absorption and metabolism of ingested erythrosine in man. Unpublished report.
  • 37. Kameda Y (1972). The accessory thyroid glands of the dog around the intrapericardial aorta. Arch. Histol. Jap. 34375:.
  • 38. Laurberg P (1978). Non-parallel variations in the preferential secretion of 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) from dog thyroid. Endocrinology 102: 757–766.[Abstract/Free Full Text]
  • 39. Leav I, Schiller AI, Rijnberk A et al (1976). Adenomas and carcinomas of the canine and feline thyroid. Am. J. Path. 83: 61–122.[Web of Science][Medline] [Order article via Infotrieve]
  • 40. Lin GHY and Brusick DJ (1986). Mutagenicity studies on FD&C Red No. 3. Mutagenesis 1: 253–260.[Abstract/Free Full Text]
  • 41. MacKenzie K, Puhl J, LeVan L, Obrist J, Borzelleca J, and Hallagan J (1989). Metabolism of FD&C Red No. 3 in rats. Manuscript in preparation.
  • 42. Mason JW (1987). Medical intelligence–Amiodarone. N. Engl. J. Med. 316: 455–466.[Web of Science][Medline] [Order article via Infotrieve]
  • 43. McClain RM, Posch RC, Bosakowski T, and Armstrong JM (1988). Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital. Toxicol. Appl. Pharmacol. 94: 254–265.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 44. Nunez EA, Becker DV, Furth ED et al (1970). Breed differences and similarities in thyroid function in purebred dogs. Am. J. Physiol. 218: 1337–1341.[Free Full Text]
  • 45. Nunez EA, Belshaw BE, and Gershon MD (1972). A fine structural study of the highly active thyroid follicular cell of the African Basenji dog. Am. J. Anat. 133: 463–482.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 46. Oppenheimer JH, Schwartz HL, Surks MI et al (1976). Nuclear receptors and the initiation of thyroid hormone action. Recent Prog. Hormone Res. 32: 529–565.[Medline] [Order article via Infotrieve]
  • 47. Pammenter M, Albrecht C, Liebenberg W et al (1978). Afrikander cattle congenital goiter: Characteristics of its morphology and iodoprotein pattern. Endocrinology 102: 954–965.[Abstract/Free Full Text]
  • 48. Paynter OE, Burin GJ, Jaeger RB, and Gregorio CA (1988). Goitrogens and thyroid follicular cell neoplasia: Evidence for a threshold process. Regulatory Toxicol. Pharmacol. 8: 102–119.[CrossRef]
  • 49. Pelletier G, Puviani R, and Dussault JH (1976). Electron microscope immunohistochemical localization of thyroglobulin in the rat thyroid gland. Endocrinology 98: 1253–1259.[Abstract/Free Full Text]
  • 50. Peterson ME (1983). Diagnosis and treatment of feline hyperthyroidism. In: Proceedings 6th Kal Kan Symposium for Treatment of Small Animal Diseases, E van Marthens, (ed). Vet. Learning Systems, pp. 63–66.
  • 51. Purves HD and Griesbach WE (1947). Studies on experimental goiter. VIII. Thyroid tumors in rats treated with thiourea. Br. J. Exper. Pathol. 28: 46–53.
  • 52. Rac R, Hill GN, Pain RW et al (1968). Congenital goitre in Merino sheep due to an inherited defect in the biosynthesis of thyroid hormone. Res. Vet. Sci. 9: 209–223.[Web of Science][Medline] [Order article via Infotrieve]
  • 53. Refetoff S, Robin NI, and Fang VS (1970). Parameters of thyroid function in serum of 16 selected vertebrate species: A study of PBI, serum T4, free T4, and the pattern of T4 and T3 binding to serum proteins. Endocrinology 86: 793–805.[Abstract/Free Full Text]
  • 54. Rijnberk A (1971). Iodine metabolism and thyroid disease in the dog. University of Utrecht, Utrecht, The Netherlands, Thesis.
  • 55. Rijnberk A, deFijlder JJM, van Dijk JE et al (1977). Clinical aspects of iodine metabolism in goats with congenital goitre and hypothyroidism. Br. Vet. J. 133: 495–503.[Web of Science][Medline] [Order article via Infotrieve]
  • 56. Ruiz M and Ingbar SH (1982). Effect of erythrosine (2',4',5',7'-tetra-iodofluorescein) on the metabolism of thyroxine in rat liver. Endocrinology 110: 1613–1617.[Abstract/Free Full Text]
  • 57. Starling JR and Hopps BA (1980). The effect of excess iodine on thyroid and liver lysosomal enzymes. J. Surg. Res. 28: 57–64.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 58. Sterns EE and Doris P (1968). Thyroid lymphography of the dog. Cancer 21: 468–476.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • 59. Stoll R, Faucounau N, and Maraud R (1978). Les adenomes à cellules folliculaires et parafolliculaires de la thyroide du rat soumis au thiamazole. Ann. Endocrinol. (Paris) 39: 179–189.[Medline] [Order article via Infotrieve]
  • 60. Thake DC, Cheville NF, and Sharp RK (1971). Ectopic thyroid adenomas at the base of the heart of the dog: Ultrastructural identification of dense tubular structures in endoplasmic reticulum. Vet. Path. 8: 421–432.[Web of Science]
  • 61. Thurston V and Williams ED (1982). Experimental induction of C-cell tumors of the thyroid by increased dietary content of vitamin D3. Acta Endocrinol. 100: 41–45.[Abstract/Free Full Text]
  • 62. Triggs SM and Williams ED (1977). Experimental carcinogenesis in the rat thyroid follicular and C-cells. Acta Endocrinol. 85: 84–92.[Abstract/Free Full Text]
  • 63. Tsuda H, Takahashi M, Muraski G, Ogiso T, and Tatematsu M (1976). Tumorigenic effect of 3-amino-1 H-1–2,2,4-triazole on the rat thyroid. J.N.C.I. 57: 861–864.[Web of Science][Medline] [Order article via Infotrieve]
  • 64. Ulland B (1972). Thyroid cancer in rats from ethylenethiourea intake. J.N.C.I. 49: 583–584.[Web of Science][Medline] [Order article via Infotrieve]
  • 65. van Herle AJ, Vassart G, and Dunmont JE (1979). Control of thyroglobulin synthesis and secretion. N. Engl. J. Med. 301: 239–249, 307–314.[Web of Science][Medline] [Order article via Infotrieve]
  • 66. van Voorthuizen WF, Dinsort C, Flavell RA et al (1978). Abnormal cellular localization of thyroglobulin deficiency. Proc. Natl. Acad. Sci. USA 75: 74–78.[Abstract/Free Full Text]
  • 67. Vought RL, Brown FA, and Wolff J (1972). Erythrosine: An adventitious source of iodide. J. Clin. Endocrinol. Metab. 34: 747–752.[Abstract/Free Full Text]
  • 68. Watson JW and Sterns EE (1969). Factors influencing distribution of ultrafluid lipiodol (UFL) following intrathyroid injection. Cancer 23: 689–693.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 17, No. 2, 266-293 (1989)
DOI: 10.1177/019262338901700205
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