Shen O et al. (2011), Thyroid disruption by Di-n-butyl phthalate (DBP...

XB-ART-43194

PLoS One 2011 Apr 22;64:e19159. doi: 10.1371/journal.pone.0019159.

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Thyroid disruption by Di-n-butyl phthalate (DBP) and mono-n-butyl phthalate (MBP) in Xenopus laevis.

Shen O , Wu W , Du G , Liu R , Yu L , Sun H , Han X , Jiang Y , Shi W , Hu W , Song L , Xia Y , Wang S , Wang X .

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BACKGROUND: Di-n-butyl phthalate (DBP), a chemical widely used in many consumer products, is estrogenic and capable of producing seriously reproductive and developmental effects in laboratory animals. However, recent in vitro studies have shown that DBP and mono-n-butyl phthalate (MBP), the major metabolite of DBP, possessed thyroid hormone receptor (TR) antagonist activity. It is therefore important to consider DBP and MBP that may interfere with thyroid hormone system. METHODOLOGY/PRINCIPAL FINDINGS: Nieuwkoop and Faber stage 51 Xenopus laevis were exposed to DBP and MBP (2, 10 or 15 mg/L) separately for 21 days. The two test chemicals decelerated spontaneous metamorphosis in X. laevis at concentrations of 10 and 15 mg/L. Moreover, MBP seemed to possess stronger activity. The effects of DBP and MBP on inducing changes of expression of selected thyroid hormone response genes: thyroid hormone receptor-beta (TRβ), retinoid X receptor gamma (RXRγ), alpha and beta subunits of thyroid-stimulating hormone (TSHα and TSHβ) were detected by qPCR at all concentrations of the compounds. Using mammalian two-hybrid assay in vitro, we found that DBP and MBP enhanced the interactions between co-repressor SMRT (silencing mediator for retinoid and thyroid hormone receptors) and TR in a dose-dependent manner, and MBP displayed more markedly. In addition, MBP at low concentrations (2 and 10 mg/L) caused aberrant methylation of TRβ in head tissue. CONCLUSIONS: The current findings highlight potential disruption of thyroid signalling by DBP and MBP and provide data for human risk assessment.

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Species referenced: Xenopus laevis
Genes referenced: dbp mbp ncor2

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	Figure 1. Chemical structures of DBP and MBP.
	Figure 2. Effects of DBP and MBP exposure on mRNA expression of TRβ (panel A), RXRγ (panel B), TSHα (panel C) and TSHβ (panel D) in head of tadpoles exposed day 21.Treatment with 0.005% DMSO served as a solvent control. Exposure of tadpoles was initiated at stage 51, and head tissue was sampled when control tadpoles reached stage 57. TRβ, RXRγ, TSHα and TSHβ values were normalized by gapdh values, and results were expressed relative to the control. Data are shown as mean ± standard deviations (SD) (n = 3 tadpoles per treatment group). Asterisks denote significant differences from controls (P<0.05).
	Figure 3. Effects of DBP and MBP exposure on mRNA expression of TRβ (panel A), RXRγ (panel B), TSHα (panel C) and TSHβ (panel D) in head tissue of tadpoles reached stage 57.Treatment with 0.005% DMSO served as a solvent control. TRβ, RXRγ, TSHα and TSHβ values were normalized by gapdh values, and results were expressed relative to the control. Data are shown as mean ± SD (n = 3 tadpoles per treatment group). Asterisks denote significant differences from controls (P<0.05).
	Figure 4. The effects of DBP and MBP on the interaction between TR and SMRT.Cells were treated with increasing concentrations of DBP (10−5 M = 2.78 mg/L) and MBP (10−5 M = 2.22 mg/L) alone or with 1 nM T3 (6.51×10−4 mg/L) respectively. Data are shown as mean ± SD of three independent experiments, and the activities are presented as fold of solvent control. *P<0.05 compared with solvent control. #P<0.05 compared with 1 nM T3.

References [+] :

Bock, BiQ Analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing. 2005, Pubmed