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Mcclain MR Mechanist Fundamental and Molecular Mechanisms of Mutagenesis ELSEVIER Mutation Research 333 (I 995) 13 I - I41 Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment R. Michael McClain Abstract There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms. disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposi- tion. There are important species differences in thyroid gland physiology between rodents and humans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia. secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves’ disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans. Kqwords: Thyroid neoplasm: Chemical involvement 1. Introduction other aspects of thyroid gland function is a receptor mediated process. Many chemicals stimulate thyroid gland growth Small organic molecules are not known to be as a compensatory response to altered thyroid func- direct TSH receptor agonists or antagonists; how- tion. This response is mediated via thyroid-stimulat- ever, various antibodies found in autoimmune dis- ing hormone (TSH) released by the pituitary in ease such as Graves’ disease can directly stimulate response to decreased circulating levels of thyroid or inhibit the TSH receptor. Chemicals can, how- hormone. The plasma membrane surface of the fol- ever, modulate the TSH response by effects on com- licular cell has receptors for TSH and other growth ponents of the TSH receptor responsible for autoreg- factors. The effect of TSH on cell proliferation and ulation of follicular cell function and thereby in- Elsevier Science B.V. SSDI 0027.5107(95)00139-S 132 R.M. M&lain / Muration Research 333 (lYY51 1316142 crease or decrease the response of the follicular cell pathogenic factor responsible for thyroid tumor pro- to TSH. duction. That excessive secretion of endogenous TSH alone (in the absence of any chemical treatment) will produce a high incidence of thyroid tumors has been 2. Altered thyroid gland function and thyroid clearly established by experiments in which rats neoplasia were fed diets deficient in iodine (Axelrad and Leblond, 1955: Bielschowsky, 1953; Isler et al., An understanding of the mechanisms of chemical 1958: Leblond et al.. 1957) or in which TSH-secret- induction of thyroid neoplasia was obtained during ing pituitary tumors were transplanted into mice with experimentation in the 40s and 50s as a result of normal thyroids (Furth, 1954). Iodine deficient diets interest in thyroid cancer during this period. It was are goitrogenic and result in an increased TSH secre- recognized that two basic mechanisms were involved tion with concomitant high incidence of thyroid tu- in thyroid carcinogenesis. the first of which involves mors. These effects can be reversed by iodine sup- chemicals that exert a direct carcinogenic effect on plementation. thyroid hormone replacement, or hy- the thyroid gland. Thyroid tumors have been pro- pophysectomy. Goitrogenic substances or regimens duced by a variety of direct-acting carcinogenic sub- are also powerful promoters of thyroid gland neopla- stances such as the polycyclic hydrocarbons sia after the administration of direct acting carcino- (Esmarch. 1942; Gnatyshak, 1957). 2-acetylaminof- genic substances (Bielschowsky, 1944; Hiasa et al., luorene (Cox et al.. 1947). dichlorobenzidine (Pliss. 1982b; Morris, 1955). 1959). and a variety of nitrosamines. The second basic mechanism was the production of thyroid tu- mors by a variety of regimens that result in a hor- 3. Thyroid hormone synthesis mone imbalance. Kennedy and Purves, 1941 found thyroid adenomas in rats fed a diet containing bras- The functional unit of the thyroid gland is the sica seeds. a naturally occurring goitrogen. Subse- follicle which consists of an area of colloid, the quently, numerous studies have demonstrated that storage form of thyroid hormone. surrounded by a treatment with a variety of anti-thyroid substances single layer of follicular epithelium. The thyroid (thiourea, thiouracil and their derivatives, and 3- gland is unique among the endocrine glands in that amino-l,3,4-triazole) will result in a high incidence hormone synthesis and storage are essentially extra- of thyroid tumors in rats (Napalkov, 1976). Other cellular processes that occur at the apical surface of substances exerting anti-thyroid effects in rats such the cell membrane. Thyroid hormone synthesis in- as some sulfonamides will also produce thyroid tu- volves the active transport of iodine into the cell and mors (Swarm et al.. 1973). a peroxidase mediated iodination and coupling of A consistent mechanism, widely accepted by many tyrosine residues on thyroglobulin to form thyroid investigators, to explain the pathogenesis of thyroid hormone which is stored as colloid until released tumors induced in rats treated with anti-thyroid drugs into the circulation (Degroot and Niepomniszcze, has been described (Furth. 1959, 1968). Anti-thyroid 1977: Ekholm. 198 1). The thyroid follicle and the drugs initially produce a hormonal imbalance by follicular cell are highly organized and polarized interfering with thyroid hormone production. AS a structures. Thyroid hormone synthesis involves reac- result, a sustained increase in the synthesis and tive biochemical processes, and the organization of secretion of TSH occurs via the negative feedback its structure and function serves to protect the cell system of the pituitary gland to stimulate thyroid from accidental iodination and cytotoxicity from oxi- function. Increased TSH stimulation produces a vari- dation products. The thyroid peroxidases appear to ety of morphological and functional changes in the be active only at the apical surface of the cell follicular cell including follicular cell hypertrophy. membrane. hyperplasia, and ultimately neoplasia. The sustained Thyroid hormone release involves pinocytosis of excessive level of TSH is considered to be the colloid by microvilli and digestion by lysosomes to R.M. McClain/ Mutution Research 333 (19%) 131-142 133 release TJ and T, which are secreted into plasma and pituitary are released in response to decreased circu- bound to plasma proteins for transport to peripheral lating levels of thyroid hormone. Another important tissues. The most important aspect of the metabolism aspect in the control of thyroid function is autoregu- of thyroid hormone is monodeiodination to form T,. lation (Vanderlan and Caplan, 1954; Halmi and Spir- the physiologically active form of thyroid hormone. tos, 1954; Bray, 1968) via a modulation of the T, is also metabolized by glucuronidation and T, is receptor response to TSH. The TSH receptor has an predominantly sulfated and both are excreted in urine extracellular component which undergoes a confor- and bile (Robbins. 198 1). mational change after binding to TSH. The catalytic unit of the receptor (adenylcyclase) produces cyclic AMP (C-AMP) which functions as a second messen- 4. Regulation of thyroid function ger and mediates all the intracellular effects of TSH including the various differentiated functions of the Thyroid gland function is controlled by the hypo- follicular cell and cell proliferation (Kahn et al., thalamus and pituitary and is regulated via a negative 1985). The adenylcyclase activity of the TSH recep- feedback process in which thyrotropin-releasing fac- tor is subject to autoregulation and is controlled by a tor (TRH) from the hypothalamus and TSH from the class of iodolipids that attenuates the formation of Fig. I. Photomicrograph (33 X ) of a thyroid gland from a control rat (A) and a control cynomolgus monkey (B). Note the ‘active’ appearance of the rat thyroid gland which consists of microfollicles with cuboidal follicular epithelium and small amounts of colloid. In contrast. the monkey thyroid gland consists of large follicles containing abundant colloid and surrounded by flattened follicular epithelium. C-AMP (Pisarev. 1985; Pisarev et al., 19881. When (Pisarev, 1985) or chemicals that can either supply the iodolipids are low as a result of either iodine iodine or perhaps
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