TIME-COURSE OBSERVATION OF THYROID PROLIFERATIVE LESIONS AND SERUM TSH LEVELS IN RATS TREATED WITH THIOUREA AFTER DHPN INITIATION

Time course changes in serum TSH and quantitative data for thyroid pro liferative lesions in male F344 rats administered N-bis(2-hydroxypropy l)nitrosamine (DHPN: 2000 mg/kg body weight, single s.c. injection) fo llowed by 0.1% thiourea (TU), were assessed at weeks 1, 2, 4, 8, 12 an d 16 of treatment. The serum T4 level in the TU group was markedly dec reased at week 1 and remained significantly lowered throughout the exp eriment. Serum TSH levels, in contrast, were elevated up to a peak at around week 4 with a return to the normal range at week 12. Thyroid we ights in the TU group were increased significantly in a treatment peri od-dependent manner. Histopathologically, marked hypertrophy of thyroi d follicular cells occurred at the early stage of TU treatment. Prolif erative lesions, such as hyperplasia and adenomas, occurred from weeks 2 and 4, respectively, and increased with the later treatment period. The cell proliferative activity of follicular cells, assessed by BrdU incorporation, was high until week 2, but then returned to normal. Th e initially appearing hyperplasias and adenomas were characterized by marked proliferation but this also greatly decreased at later stages w hen TSH was no longer elevated. The results of our study thus suggest that a high serum TSH level plays an important role in the early phase of thyroid tumorigenesis and 8 weeks treatment with test substances i s sufficient for detection of thyroid tumor promoter potential in two- stage thyroid carcinogenesis models.