Abstract
BackgroundDi-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.ConclusionsThe current findings highlight potential disruption of thyroid signalling by DBP and MBP and provide data for human risk assessment.
Highlights
Di-n-butyl phthalate (DBP) are high production volume plasticizers present in food products such as butter and infant formula, as well as in a variety of cosmetics [1,2,3]
Gene Expression Analysis When determined in head tissues of tadpoles exposed day 21, the expression of thyroid hormone receptor-beta (TRb) and retinoid X receptor gamma (RXRc) were significantly increased in tadpoles exposed to T3, while no significant differences was detected in expression of TSHa and TSHb between control and T3 treatment groups (Figure 2)
The TRb mRNA levels were downregulated significantly in all the 2, 10 and 15 mg/L DBP/mono-n-butyl phthalate (MBP) treated groups compared with the control group (Figure 2A)
Summary
Di-n-butyl phthalate (DBP) are high production volume plasticizers present in food products such as butter and infant formula, as well as in a variety of cosmetics [1,2,3]. Given its ability to intercalate into the ecosystem, it is not surprising that DBP and its major metabolite, mono-n-butyl phthalate (MBP), have been identified in tissues from several human subpopulations [4,5,6]. Recent work from our laboratory showed that the reproductive system was damaged severely by DBP, resulting in the developmental condition of hypospadiac male offspring [7]. Comparing to DBP, the metabolite MBP has been proved to be a more potent antagonist [8]. 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. 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 important to consider DBP and MBP that may interfere with thyroid hormone system
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