MECHANISM OF THIAZOPYR-INDUCED EFFECTS ON THYROID-HORMONE HOMEOSTASISIN MALE SPRAGUE-DAWLEY RATS

Chronic administration of thiazopyr in the diet at dose levels of 1000 and 3000 ppm, but not 100 ppm, has demonstrated an increase in thyroi d follicular cell tumors in male Sprague-Dawley rats. In the studies r eported here we have evaluated the mechanism of thiazopyr-induced thyr oid tumors by studying the effect of thiazopyr on a number of endpoint s that indicate hypothalamic-pituitary-thyroid homeostasis. At a dose level of 3000 ppm, thiazopyr caused a marked depression in circulating levels of T-4 as soon as 7 days after commencement of treatment. Conc urrent with this decrease in T-4 was an increase in TSH levels, an inc rease in thyroid and liver weights, a three- to sixfold increase in he patic T-4-uridine diphosphate glucuronosyl transferase (UDPGT) activit y, and increases in thyroid follicular cell hypertrophy and hyperplasi a. Dose-related changes associated with thiazopyr treatment were signi ficant increases in liver weight, thyroid weight, and hepatic T-4-UDPG T activity at high doses. Increased levels of serum TSH, T-3, and rT(3 ), decreased levels of T-4, and an increased incidence of thyroid foll icular cell hypertrophy and hyperplasia were observed 56 days after th e initiation of 3000 ppm thiazopyr. All the changes, except thyroid we ight, were partially or completely reversible upon removal of thiazopy r from the diet. Increased thyroid T-4 elimination, primarily via incr eased hepatic conjugation by T-4-UDPGT, resulting in decreased serum T -4, appeared to be responsible for the increased TSH levels. The susta ined increase in TSH by thiazopyr appears responsible for the stimulat ion of the thyroid follicular cells resulting in follicular cell hyper trophy, hyperplasia, and ultimately neoplasia. In summary, evidence is presented for a hormonally mediated, threshold-dependent process for the development of thyroid follicular cell tumors from high-dose thiaz opyr administration in male rats. This mechanism is not considered to be relevant to humans, since the thyroid of humans is much less sensit ive to this pathogenic phenomenon than rodents. (C) 1997 Academic Pres s