Hormonal disregulation mechanism in the rat thyroid tumor induced by diniconazole.
To assess the toxicological significance of thyroidal tumor observed slightly in a long-term rat study with diniconazole, (E)-1-(2,4-dichlorophenyl)- 4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol, a 3-month subacute feeding study was conducted in male Crj: CD (SD) rats by administering diniconazole in diet at concentrations of 0, 100, 1,000, or 2,000 ppm. Examinations mainly for thyroid functions were performed at Weeks 2, 4 and 13. Measurement of serum hormone levels revealed continuous decreases in serum thyroxine (T4) and free T4 levels at and above 1,000 ppm and increase in serum thyroid stimulating hormone (TSH) level at 2,000 ppm concurrently with liver weight and hepatic UDP-glucuronyltransferase (UDP-GT) increases at and above 1,000 ppm. No changes were observed in serum triiodothyronine (T3) and free T3 levels. Increase in thyroid uptake of 125I and organification of 125I in the thyroid at 2,000 ppm and thyroid follicular cell hyperplasia at and above 1,000 ppm were also observed. However, no compound-related changes were observed in autopsy and organ weight in the thyroid. Based on the above results, diniconazole induces increases in the hepatic UDP-GT activity and the thyroid hormone excretion from the liver. The increased excretion of thyroid hormones causes decrease in serum T4 and free T4 levels, triggering the feedback mechanism of the pituitary gland, promotion of TSH release from the pituitary gland and increase in serum TSH level. The increased serum TSH level probably leads to increased 125I uptake of thyroid and thyroid follicular cell hyperplasia. Thus, the thyroid tumorigenesis in rats treated with diniconazole is due to the secondary overstimulant effect on the thyroid by increased serum TSH level. The toxicological significance in humans is extremely low and it is unlikely that diniconazole would increase thyroid tumor in humans even if diniconazole were to alter normal thyroid hormone level in humans.
Hosokawa
S
S
Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan.
Nakamura
J
J
Ito
S
S
Murakami
M
M
Ineyama
M
M
Yoshioka
K
K
Yamada
T
T
Seki
T
T
Matsuo
M
M
Yamada
H
H
D000818:Animals; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D013960:Thyroid Function Tests; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000097:blood*; D014230:Triazoles / Q000633:toxicity*; D014284:Triiodothyronine / Q000097:blood
D014230:Triazoles; D014284:Triiodothyronine; D013972:Thyrotropin; D014453:Glucuronosyltransferase; D013974:Thyroxine; C049346:diniconazole