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Styrene trimer may increase thyroid hormone levels via down-regulation of the aryl hydrocarbon receptor (AhR) target gene UDP-glucuronosyltransferase - PubMed

Styrene trimer may increase thyroid hormone levels via down-regulation of the aryl hydrocarbon receptor (AhR) target gene UDP-glucuronosyltransferase

Yukie Yanagiba et al. Environ Health Perspect. 2008 Jun.

Abstract

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 thyroxin (T(4)) levels in the same manner as TCDD, which induces UDP-glucuronosyltransferase (UGT) via the AhR, resulting in a decrease in 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 micromol/kg).

Results: High-dose (64 micromol/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 T(4) levels in the plasma in wild-type mice but did not influence 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 T(4) levels.

Keywords: UDP-glucuronosyltransferase; aryl hydrocarbon receptor; cytochrome P450 1A; styrene trimer; thyroid hormone.

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Figures

Figure 1
Figure 1

Chemical structure of ST-1.

Figure 2
Figure 2

Real-time quantitative PCR analyses of liver CYP1A1 (A) and CYP1A2 (B) mRNA and microsomal CYP1A enzyme activity (EROD; C) in wild-type and AhR-null control ST-1–exposed mice. Values represent mean ± SD (n = 5). *Significantly different from the corresponding control (p < 0.05).

Figure 3
Figure 3

Real-time quantitative PCR analyses of liver UGT1A1 (A) and UGT1A6 (B) mRNA levels, and microsomal UGT enzyme activity (C) in wild-type and AhR-null control and ST-1–exposed mice. Values represent mean ± SD (n = 5). *Significantly different from the corresponding control (p < 0.05).

Figure 4
Figure 4

Effects of ST-1 treatments on expression of CAR (A) and CYP2B10 (B) mRNA levels in the livers of wild-type and AhR-null mice. Values represent mean ± SD (n = 5). *Significantly different from the corresponding control (p < 0.05).

Figure 5
Figure 5

Real-time quantitative PCR analysis of AhR mRNA in the liver (A) and immunoblot analysis AhR protein in the cytosol (B) and nuclear (C) fractions of control, 3MC-, and ST-1–exposed wild-type mice. Liver samples from 3MC-treated mice were used to determine the induction of AhR and AhR-target genes. Values represent mean ± SD (n = 5). *Significantly different from the corresponding control by Dunnett’s test (p < 0.05).

Figure 6
Figure 6

Electrophoresis mobility shift assay of AhR–XRE complex in liver nuclear fraction of control, 3MC-treated, and ST-1–treated wild-type mice (A) and quantification of the assay by densitometric analysis (B), with the mean strength of the control group assigned a value of 1.0. Values represent the mean ± SD (n = 5). *Significantly different from the correspondng control by Dunnett’s test (p < 0.05).

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