Peroxysome Proliferator-Activated Receptor gamma is a Target for Halogenated Analogues of Bisphenol-A
- Authors
- Riu, A., Grimaldi, M., le Maire, A., Bey, G., Phillips, K., Boulahtouf, A., Perdu, E., Zalko, D., Bourguet, W., and Balaguer, P.
- ID
- ZDB-PUB-110524-10
- Date
- 2011
- Source
- Environmental health perspectives 119(9): 1227-32 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding, Competitive
- Cell Line
- Chlorophenols/pharmacology*
- Crystallography, X-Ray
- Endocrine Disruptors/pharmacology
- Estrogen Receptor alpha/genetics
- Estrogen Receptor alpha/metabolism*
- Estrogen Receptor beta/genetics
- Estrogen Receptor beta/metabolism*
- Estrogens, Non-Steroidal/pharmacology*
- Flame Retardants/pharmacology*
- Humans
- Ligands
- PPAR alpha/genetics
- PPAR alpha/metabolism*
- PPAR delta/genetics
- PPAR delta/metabolism
- PPAR gamma/genetics
- PPAR gamma/metabolism
- Polybrominated Biphenyls/pharmacology*
- Xenopus/genetics
- Xenopus/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 21561829 Full text @ Environ. Health Perspect.
- CTD
- 21561829
BACKGROUND:
The occurrence of halogenated analogues of the xeno-estrogen bisphenol-A (BPA) has been recently demonstrated both in environmental and human samples. These include brominated (e.g. tetrabromobisphenol-A; TBBPA) as well as chlorinated (e.g. tetrachlorobisphenol-A; TCBPA) bisphenols which are both flame retardants. Due to their structural homology with BPA, such chemicals are candidate endocrine disruptors. However, their possible target(s) within the nuclear hormone receptor (NHRs) superfamily has remained unknown.
OBJECTIVES:
We investigated whether BPA and halogenated analogues could be ligands of estrogen (ERs) and peroxysome proliferator-activated (PPARs) receptors and act as endocrine disrupting chemicals (EDCs).
METHODS:
The activity of compounds was studied using reporter cell lines expressing ERs and PPARs. The binding affinities to PPARγ were measured by competitive binding assays with [3H]-rosiglitazone. We also investigated the impact of TBBPA and TCBPA on adipocyte differentiation using NIH3T3-L1 cells. Finally, the binding mode of halogenated BPAs to PPARγ was determined by X-ray crystallography.
RESULTS:
Two major outcomes of this study are the demonstration that TBBPA and TCBPA are human, zebrafish and xenopus PPARγ ligands and the discovery of the mechanism by which these chemicals bind to and activate PPARγ. We also provide evidence that activation of ERα, ERβ and PPARγ depends on the halogenation degree of BPA analogues. The bulkier brominated BPA analogues, the greater their capability to activate PPARγ and the weaker their estrogenic potential.
CONCLUSIONS:
Our results strongly suggest that poly-halogenated bisphenols could function as obesogens by acting as agonists able to disrupt physiological functions regulated by human or animal PPARγ.