title: Time course observation of thyroid proliferative lesions and serum levels of related hormones in rats treated with kojic acid after DHPN initiation.
abstract: Time course changes in thyroid proliferative lesions as well as related hormone levels in the blood of male F344 rats given N-bis(2-hydroxypropyl)nitrosamine (DHPN: 2800 mg/kg body weight, single s.c. injection) as an initiation treatment followed by pulverized basal diet containing 0% (Group 2), 2% (Group 3) or 4% (Group 4) kojic acid (KA) were examined at Weeks 1, 2, 4, 8 and 12. As an untreated control group (Group 1), rats were given basal diet for 13 weeks and examined in the same manner. Serum T3/T4 levels in the DHPN + 2% KA and DHPN + 4% KA groups were significantly reduced as compared with the DHPN-alone group at each time point. Serum TSH levels in both DHPN + KA groups were significantly increased at each time point in a treatment period-dependent manner from Weeks 1 to 12, and the extent of elevation was more remarkable in the DHPN + 4% KA group. At Week 2, there were no statistically significant intergroup differences in liver T4-UDP-GT activities on a milligram microsomal protein basis. Histopathologically, no thyroid proliferative lesions were observed in the untreated control group or the DHPN-alone group. However, diffuse follicular cell hypertrophy and decreased colloid in the thyroid were apparent in all rats of the DHPN + KA groups at each time point. In addition, focal follicular cell hyperplasias and adenomas of the thyroid were observed at high incidence in the DHPN + 2% KA group from Week 4 and in the DHPN + 4% KA group from Week 8. Multiplicities of focal follicular cell hyperplasias and adenomas of the thyroid in the DHPN + 2% KA group were significantly greater than those in the DHPN + 4% KA group at Week 8. In the pituitary, an increase in the number of TSH producing cells with expanded cytoplasm was apparent from Weeks 4 to 12 in both DHPN + KA groups. These results strongly suggest that thyroid proliferative lesions were induced by KA administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resulting from depression of serum T3 and T4.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tamura
authors.forename: K
authors.initials: K
authors.lastname: Mitsumori
authors.forename: H
authors.initials: H
authors.lastname: Onodera
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Funakoshi
authors.forename: K
authors.initials: K
authors.lastname: Yasuhara
authors.forename: K
authors.initials: K
authors.lastname: Takegawa
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Hirose
mesh_terms: D000236:Adenoma / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003043:Cocarcinogenesis; D014453:Glucuronosyltransferase / Q000378:metabolism; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009183:Mycotoxins / Q000633:toxicity*; D009602:Nitrosamines / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D011753:Pyrones / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000187:drug effects* / Q000473:pathology; D013963:Thyroid Hormones / Q000097:blood*; D013964:Thyroid Neoplasms / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D013972:Thyrotropin / Q000097:blood*; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D009183:Mycotoxins; D009602:Nitrosamines; D011753:Pyrones; D013963:Thyroid Hormones; D014284:Triiodothyronine; C012457:diisopropanolnitrosamine; C011890:kojic acid; D013972:Thyrotropin; D014453:Glucuronosyltransferase; D013974:Thyroxine