Abstract
Pentabromophenol (PBP), a brominated flame retardant (BFR), is widely used in various consumer products. BFRs exert adverse health effects such as neurotoxic and endocrine-disrupting effects. In this study, we found that PBP suppressed TGF-β response by accelerating the turnover rate of TGF-β receptors. PBP suppressed TGF-β-mediated cell migration, PAI-1 promoter-driven reporter gene activation, and Smad2/3 phosphorylation in various cell types. Furthermore, PBP abolished TGF-β-mediated repression of E-cadherin expression, in addition to the induction of vimentin expression and N-cadherin and fibronectin upregulation, thus blocking TGF-β-induced epithelial–mesenchymal transition in A549 and NMuMG cells. However, this inhibition was not observed with other congeners such as tribromophenol and triiodophenol. TGF-β superfamily members play key roles in regulating various biological processes including cell proliferation and migration as well as cancer development and progression. The results of this in vitro study provide a basis for studies on the detailed relationship between PBP and modulation of TGF-β signalling. Because PBP is similar to other BFRs such as polybrominated diphenyl ethers (PBDEs), additional laboratory and mechanistic studies should be performed to examine BFRs as potential risk factors for tumorigenesis and other TGF-β-related diseases.
Highlights
Brominated flame retardant (BFR) phenols include pentabromophenol (PBP), 2,4,6-tribromophenol (TBP), 2,4-dibromophenol, and tetrabrominated bisphenol (TBBP)
Acute toxicity of PBP was determined by measuring G6PDH leakage, and the IC50 of PBP on NMuMG cells and A549 cells are more than 30 μM (Figure S1)
This study investigated the ability of PBP to induce the internalisation and turnover of TβRII; inhibit the migration of cells; and affect the expression of TGF-β-regulated proteins such as PAI-1, fibronectin, N-cadherin, vimentin, and E-cadherin
Summary
Brominated flame retardant (BFR) phenols include pentabromophenol (PBP), 2,4,6-tribromophenol (TBP), 2,4-dibromophenol, and tetrabrominated bisphenol (TBBP). We determined that PBP suppressed transforming growth factor-beta (TGF-β) signalling by accelerating TGF-βreceptor degradation through caveolae-mediated endocytosis. Our and other previous studies have demonstrated that cellular responses to TGF-βare determined by TGF-βpartitioning between clathrin- and caveolae-mediated endocytic pathways[16,17,18,19,20,21,22]. On the basis of the results of studies that have implicated the role of PBP in TGF-βreceptor endocytosis and rapid degradation, we hypothesized that PBP displaces TGF-βreceptors on the cell surface and facilitates their accumulation in lipid-raft membrane domains and caveolin-positive vesicles, leading to proteasome-mediated degradation and subsequent reduced TGF-βsignalling. The present study emphasizes the potential ecotoxic and endocrine-disrupting effects of PBP in TGF-β-related diseases
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