Ch. Sewall et al., ALTERATIONS IN THYROID-FUNCTION IN FEMALE SPRAGUE-DAWLEY RATS FOLLOWING CHRONIC TREATMENT WITH 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN, Toxicology and applied pharmacology, 132(2), 1995, pp. 237-244
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multisite carcinogen.
Although the hepatocarcinogenic actions of TCDD have received the most
attention, it has been demonstrated in several rodent carcinogenicity
bioassays that TCDD causes a dose-related increase in thyroid follicu
lar cell adenomas and carcinomas. The purpose of the present experimen
t was to investigate the dose-response relationship for thyroid functi
on alterations in female Sprague-Dawley rats following chronic treatme
nt with TCDD. TCDD was administered via oral gavage biweekly for 30 we
eks at average daily equivalent doses of 0.1-125 ng/kg/day, thereby mo
re than encompassing the dose range historically used in previous TCDD
rodent bioassays. The endpoints examined include serum levels of thyr
oxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TS
H). In addition, the induction of the dioxin-responsive genes UDP-gluc
uronosyltransferase-1 (UGT1) and cytochrome P450 1A1 (CYP1A1) in liver
were measured using reverse-transcriptase-polymerase chain reaction (
RT-PCR). In agreement with previous hypotheses, TCDD appears to alter
thyroid function via a secondary mechanism, namely increased excretion
of T4-glucuronide resulting from TCDD induction of UGT1. The observed
follicular cell hyperplasia and hypertrophy are consistent with the o
bserved elevated TSH levels and may represent the early stages in the
progression of thyroid carcinogenesis. Therefore, TCDD induces alterat
ions in thyroid hormone function, probably as a result of chronic pert
urbations of liver-pituitary-thyroid axis. (C) 1995 Academic Press, In
c.