TDCPP mimics thyroid hormones associated with the activation of integrin αvβ3 and ERK1/2

Abstract

Tri(1,3-dichloropropyl) phosphate (TDCPP) potentially damages the thyroid system in humans and animals. However, knowledge of its toxic effects and underlying mechanisms is limited. The present study was conducted to determine the thyroid hormone-disrupting effects of TDCPP and its major metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP) in rat pituitary cell lines (GH3). TDCPP and BDCPP, that mimic the thyroid hormone (TH), promoted GH3 cell proliferation and modulated the progression of the cell cycle at 20 and 200 μmol/L, respectively. Similar to T3, TDCPP and BDCPP also significantly upregulated c-fos and downregulated Tshβ gene expression. Although the binding affinity of these chemicals for thyroid receptor β (TRβ) was not measured, significant competition between these chemicals to bind to the membrane thyroid hormone receptor (integrin αvβ3) was found, suggesting that TDCPP and BDCPP were strongly bound to integrin αvβ3. Results from a molecular docking analysis provided further evidence of strong binding affinities of TDCPP and BDCPP for integrin αvβ3, and the ligand binding site of Arg-Gly-Asp (RGD) was identified. Real-time PCR also supported the supposition that, after binding to integrin αvβ3, TDCPP and BDCPP may induce the activation of the extracellular signal-regulated protein kinase (ERK1/2) signal transduction pathway. Taken together, our data suggest that TDCPP and BDCPP have the ability to mimic THs and that the underlying mechanism might be associated with their interactions with integrin αvβ3 and the activation of the ERK1/2 pathway, providing new insight into the mechanism of TDCPP- and BDCPP-induced cytotoxicity.