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Peroxisome proliferator-activated receptor ? is a target for halogenated analogs of bisphenol A.

ABSTRACT: 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 PPAR? 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 PPAR? by X-ray crystallography. RESULTS: We observed that TBBPA and TCBPA are human, zebrafish, and Xenopus PPAR? ligands and determined the mechanism by which these chemicals bind to and activate PPAR?. We also found evidence that activation of ER?, ER?, and PPAR? depends on the degree of halogenation in BPA analogs. We observed that the bulkier brominated BPA analogs, the greater their capability to activate PPAR? 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 PPAR?.

SUBMITTER: Riu A

PROVIDER: S-EPMC3230400 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor γ is a target for halogenated analogs of bisphenol A.

Riu Anne A Grimaldi Marina M le Maire Albane A Bey Gilbert G Phillips Kevin K Boulahtouf Abdelhay A Perdu Elisabeth E Zalko Daniel D Bourguet William W Balaguer Patrick P

Environmental health perspectives 20110511 9

<h4>Background</h4>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 rec ...[more]

PMID: 21561829

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Project description:BackgroundDespite the use of combination antiretroviral therapy for the treatment of HIV-1 infection, cognitive impairments remain prevalent due to persistent viral replication and associated brain inflammation. Primary cellular targets of HIV-1 in the brain are macrophages, microglia, and to a certain extent astrocytes which in response to infection release inflammatory markers, viral proteins [i.e., glycoprotein 120 (gp120)] and exhibit impaired glutamate uptake. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. Compelling evidence suggests that PPAR? exerts anti-inflammatory properties in neurological disorders. The goal of this study was to examine the role of PPAR? in the context of HIV-1ADA gp120-induced inflammation in vitro, in primary cultures of rat astrocytes and microglia, and in vivo, in a rodent model of HIV-1ADA gp120-associated brain inflammation.MethodsPrimary mixed cultures of rat astrocytes and microglia were treated with PPAR? agonists (rosiglitazone or pioglitazone) and exposed to HIV-1ADA gp120. Inflammatory cytokines and indicator of oxidative stress response (TNF?, IL-1?, iNOS) were measured using qPCR, and glutamate transporter (GLT-1) was quantified by immunoblotting. In vivo, rats were administered an intracerebroventricular injection of HIV-1ADA gp120 and an intraperitoneal injection of PPAR? agonist (rosiglitazone) or co-administration with PPAR? antagonist (GW9662). qPCR and immunoblotting analyses were applied to measure inflammatory markers, GLT-1 and PPAR?.ResultsIn primary mixed cultures of rat astrocytes and microglia, HIV-1ADA gp120 exposure resulted in a significant elevation of inflammatory markers and a decrease in GLT-1 expression which were significantly attenuated with rosiglitazone or pioglitazone treatment. Similarly, in vivo, treatment with rosiglitazone reversed the gp120-mediated inflammatory response and downregulation of GLT-1. Furthermore, we demonstrated that the anti-inflammatory effects of PPAR? agonist rosiglitazone were mediated through inhibition of NF-?B.ConclusionOur data demonstrate that gp120 can induce an inflammatory response and decrease expression of GLT-1 in the brain in vitro and in vivo. We have also successfully shown that these effects can be reversed by treatment with PPAR? agonists, rosiglitazone or pioglitazone. Together our data suggest that targeting PPAR? signaling may provide an option for preventing/treating HIV-associated brain inflammation.

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Peroxisome proliferator-activated receptor ? is a target for halogenated analogs of bisphenol A.

Publications

Peroxisome proliferator-activated receptor γ is a target for halogenated analogs of bisphenol A.

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