Alterations in thyroid function in female Sprague-Dawley rats following chronic treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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 follicular cell adenomas and carcinomas. The purpose of the present experiment was to investigate the dose-response relationship for thyroid function alterations in female Sprague-Dawley rats following chronic treatment with TCDD. TCDD was administered via oral gavage biweekly for 30 weeks at average daily equivalent doses of 0.1-125 ng/kg/day, thereby more than encompassing the dose range historically used in previous TCDD rodent bioassays. The endpoints examined include serum levels of thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH). In addition, the induction of the dioxin-responsive genes UDP-glucuronosyltransferase-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 observed elevated TSH levels and may represent the early stages in the progression of thyroid carcinogenesis. Therefore, TCDD induces alterations in thyroid hormone function, probably as a result of chronic perturbations of liver-pituitary-thyroid axis.
Sewall
C H
CH
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Flagler
N
N
Vanden Heuvel
J P
JP
Clark
G C
GC
Tritscher
A M
AM
Maronpot
R M
RM
Lucier
G W
GW
D000818:Animals; D013956:Antithyroid Agents / Q000378:metabolism; D001483:Base Sequence; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004790:Enzyme Induction / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D008969:Molecular Sequence Data; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D013963:Thyroid Hormones / Q000096:biosynthesis*; D013972:Thyrotropin / Q000096:biosynthesis*; D013974:Thyroxine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014284:Triiodothyronine / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D013956:Antithyroid Agents; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D013963:Thyroid Hormones; D014284:Triiodothyronine; D013972:Thyrotropin; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D013974:Thyroxine