Toxicology of Industrial Compounds

264 ENDOCRINE TOXICOLOGY OF THE THYROID
studies where rats were given carcinogens such as N-methyl-N-nitrosourea
(MNU) and then phenobarbital, or put on an iodine deficient diet. These
treatments cause an early and increased incidence of thyroid follicular
lesions and tumour formation (Hiasa et al., 1982; Oshima and Ward, 1984).
The duration of exposure to high circulating TSH concentrations is also
important in that intermittent administration of chemical goitrogens with
TSH ‘normalisation’ does not appear to lead to follicular neoplasias.
An elaborate series of studies have shown that a sustained elevation of
serum TSH in the rat leads to three phases of thyroid growth (Figure 19.6):
(1) a phase of rapid growth lasting 1–2 months, followed by (2) a plateau
phase of 3–6 months (growth desensitising mechanism (GDM) limiting
epithelial cell mitotic response), followed eventually (3) by the appearance
of multiple follicular cell tumours (loss of GDM; see Wynford-Thomas et
al., 1982; Stringer et al., 1985; Smith et al., 1986). The reversibility of TSHinduced
thyroid focal hyperplasia will evidently depend, therefore, on the
stage during these ‘timed’ cellular changes in the first 6 months at which
the TSH stimulus is withdrawn. Once the GDM is non-operative
reversibility is not possible.
Tumour progression seems to occur by a multi-stage process involving
clonal ‘expansion’ and naturally occuring clones of cells have been
demonstrated with high intrinsic proliferation potential in the mouse
thyroid gland (Smeds et al., 1987), perhaps helping to explain the focal
nature of hyperplastic and neoplastic lesions. The loss of a GDM within
the follicular cells appears to be accompanied by an altered dependence or
sensitivity to certain growth factors as well as the possible loss of an antioncogene
which limits the follicular cells’s growth response to TSH. For
example, the growth of normal cultured human thyroid cells requires TSH
and insulin-like growth factor 1 (IGF1) in combination, whereas cells from
adenomatous tissue in vitro proliferate in response to either TSH or IGF
independently (Williams et al., 1987). This is due to the acquisition of
autocrine production of IGF 1 by the tumour cells themselves (see Thomas
and Williams, 1991). Since the differentiation and growth of thyrocytes
under TSH is regulated by cyclic-AMP-dependent mechanisms
(Figure 19.2), tissue hyperplasia and hyperthyroidism might be expected to
result when activation of the adenyl cyclase-cAMP cascade becomes
unregulated. This can occur, for example, when somatic mutations impair
the GTPase activity of G-protein coupled reactors, which may thus behave
as proto-oncogenes. Such a mechanism is probably responsible for the
development of a minority of monoclonal hyperfunctioning thyroid
adenomas (Parma et al., 1993) (these also result in a silencing of normal
thyroid function in extra-adenomatous tissue). Other non-genotoxic
factors, such as agents affecting patterns of DNA methylation when
coupled with a growth stimulus, should also be given consideration when