Styrene Trimer May Increase Thyroid Hormone Levels via Down-Regulation of the Aryl Hydrocarbon Receptor (AhR) Target Gene UDP-Glucuronosyltransferase

Background: Styrene trimers (STs) are polystyrene-container-eluted materials that are sometimes detected in packaged foods. Although the possible endocrine-disrupting effects of STs, such as estrogenic activities, have been reported, their potential thyroid toxicity, such as that caused by the related endocrine disruptor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has not been studied in detail. Objective: Using wild-type and aryl hydrocarbon receptor (Ahr)-null mice, we investigated whether 2,4,6-triphenyl-1-hexene (ST-1), an isomer of STs, influences thyroxia $({\rm T}_{4})$ levels in the same manner as TCDD, which induces UDP-glucuronosyltransferase (UGT) via the AhR, resulting in a decrease in ${\rm T}_{4}$ levels in the plasma of mice. Methods: Both wild-type and Ahr-null mice (five mice per group) were treated for 4 days by gavage with ST-1 (0, 32, or 64 μmol/kg). Results: High-dose (64 μmol/kg) ST-1 decreased the expression of AhR, cytochrome P450 (CYP) 1A1/2, UGT1A1/A6, and CYP2B10 mRNAs and the enzyme activity for CYP1A and UGT1A only in the wild-type mice. This dose decreased AhR DNA binding, but paradoxically increased AhR translocation to the nucleus. In contrast, a high dose of ST-1 increased ${\rm T}_{4}$ levels in the plasma in wild-type mice but did not influence ${\rm T}_{4}$ levels in AhR-null mice. Conclusions: Although ST-1 treatment might cause an increase in AhR levels in the nucleus by inhibiting AhR export, this chemical down-regulated AhR mRNA, thus leading to down-regulation of AhR target genes and an increase in plasma ${\rm T}_{4}$ levels.