INVESTIGATION ON MECHANISMS OF THYROXINE SUPPRESSIVE EFFECTS OF DIOXINS USING KNOCKOUT MICE

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Thyroxine (T4) suppressive effects of dioxins or PCBs were well documented. Several possible mechanisms such as enhanced biliary excretion of T4-glucuronide and competitive binding to transthyretin (TTR), a major T4 binding protein, are proposed. To investigate the mechanisms of T4 suppressive effects of dioxins or PCBs, arylhydrocarbon receptor (AhR)-null mice (AhR-/-) and TTR-null mice (TTR-/-) were employed.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and PCB126 significantly reduced the serum total T4 (TT4) level concomitant induction of hepatic UGT-1 mRNA and CYP1A1 mRNA in AhR+/-, TTR+/+ and TTR-/-mice but not in AhR1/1 mice. PCB77 and PCB153 significantly reduced the serum TT4 level both in wild type and TTR-/-mice but the reduction in TTR-/-mice was much less compared to TCDD. As PCB77 is easily metabolized to form a hydroxylated metabolite which has high affinity to TTR, PCB77 is thought to reduce TT4 via competitive binding to TTR. TCDD and PCB126 suggested to reduce TT4 by an enhanced biliary excretion of T4-glucuronide mediated by the AhR. PCB153 is thought to reduce serum TT4 level via factors other than AhR and TTR since PCB 153 do not induce hepatic CYP1A1 and is hardly hydroxylated to bind to TTR.