Year-end Sale % OFF 
Abstract
Longterm goitrogen administration to rodents is well known to result in multiple proliferative lesions of the thyroid. The regression of these lesions on withdrawal of goitrogen has led to their neoplastic nature being questioned, and they have been regarded as 'nodules' rather than as true tumours. We have induced multiple thyroid lesions by the combined use of high dose radiation as a mutagen, together with goitrogen administration to induce prolonged TSH growth stimulation. G6PD histochemistry was used in heterozygous G6PD deficient female mice to show that all the thyroid lesions induced by this regime were monophenotypic, and therefore monoclonal in origin. The great majority of induced tumours were adenomas, a minority were carcinomas. The number of carcinomas observed was significantly lower in a group of animals from which goitrogen was withdrawn for 4 weeks prior to killing, when compared to animals killed while on goitrogen treatment. Both adenomas and carcinomas, including areas of intravascular tumour, showed morphological features of regression on withdrawal of the goitrogen. There are three key cellular changes which must occur in spontaneous thyroid carcinogenesis--escape from a growth limiting mechanism, acquisition of TSH independent growth and acquisition of invasiveness. In the natural selection of mutations or epimutations during carcinogenesis, prolonged high levels of TSH are likely to remove any selective advantage from mutations that lead to TSH independent growth. Tumours induced by a regime including prolonged goitrogen treatment may therefore develop following two rather than three key stages. They will occur with an increased frequency relative to lesions observed in spontaneous carcinogenesis, but will retain TSH dependency. We speculate that several mechanisms may lead to loss of the growth limiting mechanism, including translocation of an oncogene to the region of a TSH induced promoter. Other carcinogenic regimes may also increase the yield of tumours by creating conditions which reduce the number of essential steps required for carcinogenesis, and may involve translocation to a carcinogen inducible promoter.
Highlights
We have developed a method for assessing the clonal origin of tumours at a cellular level using X-linked enzyme histochemistry. Applying this to thyroid tumours induced by low dose radiation and prolonged goitrogen treatment in the heterozygous glucose-6-phosphate dehydrogenase (G6PD) deficient mouse, we have shown that two types of benign thyroid proliferations can be identified (Thomas et al, 1989)
This study has shown that monoclonal thyroid lesions, both adenomas and carcinomas, induced by a mutagen followed by longterm goitrogen treatment regress when the goitrogen is withdrawn
We have not investigated the reappearance of the malignant phenotype on reintroduction of a high thyroid stimulating hormone (TSH), this has been shown in transplantation experiments (Matovinovic et al, 1970)
Summary
Breeding pairs of the GPDX strain of mice were kindly donated by Dr M.F. Lyon, MRC Harwell, UK. This strain of mouse exhibits erythrocyte G6PD activity 15, 20 and 60% of normal in the homo-, hemi-, and heterozygote respectively (Pretsch et al, 1988) as expected for an X-linked defect. The animals were crossbred with mice of the C3H strain, homozygous for normal levels of G6PD, to produce female heterozygous C3H x GPDX mice. Fifty-six female mice (18 homozygous and 20 heterozygous for deficient G6PD activity, and 18 normal female C3H mice) were given a single intraperitoneal injection of 131I (specific activity 6-20 mCi .tg'-) in 0.1 ml saline at 3 weeks of age. Mice are relatively resistant to the goitrogenic effect of aminotriazole; we have found that a combination of 0.2% aminotriazole and 0.5% sodium perchlorate, sweetened with 0.5% sucrose is both palatable and a consistently effective goitrogen
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
