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Mechanism of thiazopyr-induced effects on thyroid hormone homeostasis in male Sprague-Dawley rats.
Toxicol Appl Pharmacol. 1997 Jan; 142(1):133-42.TA

Abstract

Chronic administration of thiazopyr in the diet at dose levels of 1000 and 3000 ppm, but not 100 ppm, has demonstrated an increase in thyroid follicular cell tumors in male Sprague-Dawley rats. In the studies reported here we have evaluated the mechanism of thiazopyr-induced thyroid tumors by studying the effect of thiazopyr on a number of endpoints that indicate hypothalamic-pituitary-thyroid homeostasis. At a dose level of 3000 ppm, thiazopyr caused a marked depression in circulating levels of T4 as soon as 7 days after commencement of treatment. Concurrent with this decrease in T4 was an increase in TSH levels, an increase in thyroid and liver weights, a three- to sixfold increase in hepatic T4-uridine diphosphate glucuronosyl transferase (UDPGT) activity, and increases in thyroid follicular cell hypertrophy and hyperplasia. Dose-related changes associated with thiazopyr treatment were significant increases in liver weight, thyroid weight, and hepatic T4-UDPGT activity at high doses. Increased levels of serum TSH, T3, and rT3, decreased levels of T4, and an increased incidence of thyroid follicular cell hypertrophy and hyperplasia were observed 56 days after the initiation of 3000 ppm thiazopyr. All the changes, except thyroid weight, were partially or completely reversible upon removal of thiazopyr from the diet. Increased thyroid T4 elimination, primarily via increased hepatic conjugation by T4-UDPGT, resulting in decreased serum T4, appeared to be responsible for the increased TSH levels. The sustained increase in TSH by thiazopyr appears responsible for the stimulation of the thyroid follicular cells resulting in follicular cell hypertrophy, 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 thiazopyr administration in male rats. This mechanism is not considered to be relevant to humans, since the thyroid of humans is much less sensitive to this pathogenic phenomenon than rodents.

Authors+Show Affiliations

Monsanto Company, St. Louis, Missouri 63167, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9007042

Citation

Hotz, K J., et al. "Mechanism of Thiazopyr-induced Effects On Thyroid Hormone Homeostasis in Male Sprague-Dawley Rats." Toxicology and Applied Pharmacology, vol. 142, no. 1, 1997, pp. 133-42.
Hotz KJ, Wilson AG, Thake DC, et al. Mechanism of thiazopyr-induced effects on thyroid hormone homeostasis in male Sprague-Dawley rats. Toxicol Appl Pharmacol. 1997;142(1):133-42.
Hotz, K. J., Wilson, A. G., Thake, D. C., Roloff, M. V., Capen, C. C., Kronenberg, J. M., & Brewster, D. W. (1997). Mechanism of thiazopyr-induced effects on thyroid hormone homeostasis in male Sprague-Dawley rats. Toxicology and Applied Pharmacology, 142(1), 133-42.
Hotz KJ, et al. Mechanism of Thiazopyr-induced Effects On Thyroid Hormone Homeostasis in Male Sprague-Dawley Rats. Toxicol Appl Pharmacol. 1997;142(1):133-42. PubMed PMID: 9007042.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of thiazopyr-induced effects on thyroid hormone homeostasis in male Sprague-Dawley rats. AU - Hotz,K J, AU - Wilson,A G, AU - Thake,D C, AU - Roloff,M V, AU - Capen,C C, AU - Kronenberg,J M, AU - Brewster,D W, PY - 1997/1/1/pubmed PY - 1997/1/1/medline PY - 1997/1/1/entrez SP - 133 EP - 42 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 142 IS - 1 N2 - Chronic administration of thiazopyr in the diet at dose levels of 1000 and 3000 ppm, but not 100 ppm, has demonstrated an increase in thyroid follicular cell tumors in male Sprague-Dawley rats. In the studies reported here we have evaluated the mechanism of thiazopyr-induced thyroid tumors by studying the effect of thiazopyr on a number of endpoints that indicate hypothalamic-pituitary-thyroid homeostasis. At a dose level of 3000 ppm, thiazopyr caused a marked depression in circulating levels of T4 as soon as 7 days after commencement of treatment. Concurrent with this decrease in T4 was an increase in TSH levels, an increase in thyroid and liver weights, a three- to sixfold increase in hepatic T4-uridine diphosphate glucuronosyl transferase (UDPGT) activity, and increases in thyroid follicular cell hypertrophy and hyperplasia. Dose-related changes associated with thiazopyr treatment were significant increases in liver weight, thyroid weight, and hepatic T4-UDPGT activity at high doses. Increased levels of serum TSH, T3, and rT3, decreased levels of T4, and an increased incidence of thyroid follicular cell hypertrophy and hyperplasia were observed 56 days after the initiation of 3000 ppm thiazopyr. All the changes, except thyroid weight, were partially or completely reversible upon removal of thiazopyr from the diet. Increased thyroid T4 elimination, primarily via increased hepatic conjugation by T4-UDPGT, resulting in decreased serum T4, appeared to be responsible for the increased TSH levels. The sustained increase in TSH by thiazopyr appears responsible for the stimulation of the thyroid follicular cells resulting in follicular cell hypertrophy, 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 thiazopyr administration in male rats. This mechanism is not considered to be relevant to humans, since the thyroid of humans is much less sensitive to this pathogenic phenomenon than rodents. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/9007042/Mechanism_of_thiazopyr_induced_effects_on_thyroid_hormone_homeostasis_in_male_Sprague_Dawley_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(96)98032-1 DB - PRIME DP - Unbound Medicine ER -