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Environ Health Perspect
2011 Sep 01;1199:1227-32. doi: 10.1289/ehp.1003328.
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Peroxisome proliferator-activated receptor γ is a target for halogenated analogs of bisphenol A.
Riu A
,
Grimaldi M
,
le Maire A
,
Bey G
,
Phillips K
,
Boulahtouf A
,
Perdu E
,
Zalko D
,
Bourguet W
,
Balaguer P
.
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BACKGROUND: The occurrence of halogenated analogs of the xenoestrogen bisphenol A (BPA) has been recently demonstrated both in environmental and human samples. These analogs include brominated [e.g., tetrabromobisphenol A (TBBPA)] and chlorinated [e.g., tetrachlorobisphenol A (TCBPA)] bisphenols, which are both flame retardants. Because of their structural homology with BPA, such chemicals are candidate endocrine disruptors. However, their possible target(s) within the nuclear hormone receptor superfamily has remained unknown.
OBJECTIVES: We investigated whether BPA and its halogenated analogs could be ligands of estrogen receptors (ERs) and peroxisome proliferator-activated receptors (PPARs) and act as endocrine-disrupting chemicals.
METHODS: We studied the activity of compounds using reporter cell lines expressing ERs and PPARs. We measured the binding affinities to PPARγ by competitive binding assays with [3H]-rosiglitazone and investigated the impact of TBBPA and TCBPA on adipocyte differentiation using NIH3T3-L1 cells. Finally, we determined the binding mode of halogenated BPAs to PPARγ by X-ray crystallography.
RESULTS: We observed that TBBPA and TCBPA are human, zebrafish, and Xenopus PPARγ ligands and determined the mechanism by which these chemicals bind to and activate PPARγ. We also found evidence that activation of ERα, ERβ, and PPARγ depends on the degree of halogenation in BPA analogs. We observed that the bulkier brominated BPA analogs, the greater their capability to activate PPARγ and the weaker their estrogenic potential.
CONCLUSIONS: Our results strongly suggest that polyhalogenated bisphenols could function as obesogens by acting as agonists to disrupt physiological functions regulated by human or animal PPARγ.
Figure 2. Results of luciferase assays showing dose–response curves for BPA and its halogenated analogs (TBBPA and/or TCBPA; A–G), and lower brominated analogs (monoBBPA, diBBPA, and triBBPA; D–F), as well as MEHP, PFOA, and PFOS (G), in HGELN‑ERα (A,D), HGELN‑ERβ (B,E), and HGELN‑PPARγ (C,F,G) cells. Results are expressed as a percentage of luciferase activity measured per well (mean ± SEM; n = 4) relative to the value obtained with 10 nM E2 (HGELN‑ERα and ERβ; A,B,D,E) and 100 nM rosiglitazone (Rosi; HGELN‑PPARγ; C,F,G).
Figure 3. Competitive inhibition of [3H]-rosiglitazone (Rosi) binding in HGELN‑PPARγ cells incubated with different concentrations (0.001–30 μM) of Rosi, TBBPA, and TCBPA in the presence of 3 nM [3H]‑Rosi. Values are the mean ± SD from four separate experiments.
Figure 4. TBBPA and TCBPA induce adipogenesis through PPARγ. Two-day postconfluent 3T3L1 cells were treated for 8 days with 10 μg/mL insulin with vehicle (0.1% DMSO) or the ligands as indicated. Rosi, rosiglitazone. (A) Entire wells imaged after Oil Red O staining. (B) Quantitative real-time PCR of PPARγ and adipocyte-specific fatty acid–binding protein AP2 expression levels in postconfluent 3T3-L1 cells treated with the ligands for 24 hr. Data were normalized to 18S or 36B4 controls and plotted as average fold induction ± SE (n = 3 per treatment).
Figure 5. Effect of halogenated BPAs on activation of human, zebrafish, and Xenopus PPARγ. HeLa cells transiently transfected with (GALRE)5-βglobin-luciferase and pSG5-GAL4-PPARγ (human and zebrafish) or (PPRE)3-TK-luciferase and pSG5-PPARγ (Xenopus laevis) plasmids were incubated with 10 μM TBBPA, 10 μM TCBPA, 10 μM MEHP, or 1 μM rosiglitazone (Rosi) to assess their agonist potential on PPARγ. Values are the mean ± SD of three separate experiments.
Figure 6. Crystal structures of PPARγ LBD in complex with TBBPA and TCBPA. (A) Overall structure of the TBBPA-bound PPARγ LBD. The polypeptide backbone is illustrated as a green ribbon, and TBBPA is shown in stick representation with each atom type: carbon, yellow; oxygen, red; bromine, black. (B) Superimposition of the co-crystal structure of TBBPA-bound PPARγ LBD on the structure with rosiglitazone (PDB code 2PRG; Nolte et al. 1998). Carbon atoms are shown in green in the TBBPA complex and in magenta in the rosiglitazone structure. (C) TBBPA (carbon, green; oxygen, red; bromine, black), TCBPA (carbon, cyan; oxygen, red; chlorine, green), and rosiglitazone (carbon, magenta; oxygen, red; nitrogen, blue; sulfur, yellow) as they appear in their respective LBP. (D,E,F) PPARγ residues in contact with TBBPA cycle A (D), cycle B (E), and the linker region (F). Key interactions are highlighted as black dashed lines; water molecules are shown as red spheres.
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