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Structural and functional profiling of environmental ligands for estrogen receptors.

Delfosse V, Grimaldi M, Cavaillès V, Balaguer P, Bourguet W - Environ. Health Perspect. (2014)

Bottom Line: However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

View Article: PubMed Central - PubMed

Affiliation: Inserm (Institut national de la santé et de la recherche médicale) U1054, Montpellier, France.

ABSTRACT

Background: Individuals are exposed daily to environmental pollutants that may act as endocrine-disrupting chemicals (EDCs), causing a range of developmental, reproductive, metabolic, or neoplastic diseases. With their mostly hydrophobic pocket that serves as a docking site for endogenous and exogenous ligands, nuclear receptors (NRs) can be primary targets of small molecule environmental contaminants. However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.

Objectives: We conducted a correlative analysis of structural and functional data to gain insight into the mechanisms by which 12 members of representative families of pollutants bind to and activate the estrogen receptors ERα and ERβ.

Methods: We used a battery of biochemical, structural, biophysical, and cell-based approaches to characterize the interaction between ERs and their environmental ligands.

Results: Our study revealed that the chemically diverse compounds bound to ERs via varied sets of protein-ligand interactions, reflecting their differential activities, binding affinities, and specificities. We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.

Conclusions: The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

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Related in: MedlinePlus

Chemical structures of the natural agonist E2, the synthetic antagonist OHT, and the various environmental ER ligands used in the present study.
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f1: Chemical structures of the natural agonist E2, the synthetic antagonist OHT, and the various environmental ER ligands used in the present study.

Mentions: Our recent work has shown that approaches combining structural, biophysical, and cell-based techniques are helpful in understanding how environmental compounds that are structurally and chemically divergent from natural ligands can interact with NRs and impact their signaling pathways (Delfosse et al. 2012; le Maire et al. 2009; Riu et al. 2011). In the present study, we used a similar approach to gain insight into the mechanisms by which 12 contaminants interact with ERs and modulate their AFs. The compounds used in this study (Figure 1) were selected on the basis of their structural diversity and because they belong to the most representative families of ER environmental ligands. These are bisphenol A (BPA) and bisphenol C (BPC), both used as plasticizers; the flame retardant tetrachlorobisphenol A (TCBPA); the preservative butylparaben; the surfactant 4-tert-octylphenol (4-OP); the UV filter benzophenone-2 (BP-2); the pesticides 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE, a methoxychlor metabolite), dichlorodiphenyldichloroethylene (DDE, a DDT metabolite), and chlordecone; benzylbutylphthalate (BBP); the phytoestrogen ferutinine; and the growth stimulant α-zearalanol (α-ZA), a double reduction product of the mycoestrogen zearalenone.


Structural and functional profiling of environmental ligands for estrogen receptors.

Delfosse V, Grimaldi M, Cavaillès V, Balaguer P, Bourguet W - Environ. Health Perspect. (2014)

Chemical structures of the natural agonist E2, the synthetic antagonist OHT, and the various environmental ER ligands used in the present study.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256047&req=5

f1: Chemical structures of the natural agonist E2, the synthetic antagonist OHT, and the various environmental ER ligands used in the present study.
Mentions: Our recent work has shown that approaches combining structural, biophysical, and cell-based techniques are helpful in understanding how environmental compounds that are structurally and chemically divergent from natural ligands can interact with NRs and impact their signaling pathways (Delfosse et al. 2012; le Maire et al. 2009; Riu et al. 2011). In the present study, we used a similar approach to gain insight into the mechanisms by which 12 contaminants interact with ERs and modulate their AFs. The compounds used in this study (Figure 1) were selected on the basis of their structural diversity and because they belong to the most representative families of ER environmental ligands. These are bisphenol A (BPA) and bisphenol C (BPC), both used as plasticizers; the flame retardant tetrachlorobisphenol A (TCBPA); the preservative butylparaben; the surfactant 4-tert-octylphenol (4-OP); the UV filter benzophenone-2 (BP-2); the pesticides 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE, a methoxychlor metabolite), dichlorodiphenyldichloroethylene (DDE, a DDT metabolite), and chlordecone; benzylbutylphthalate (BBP); the phytoestrogen ferutinine; and the growth stimulant α-zearalanol (α-ZA), a double reduction product of the mycoestrogen zearalenone.

Bottom Line: However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

View Article: PubMed Central - PubMed

Affiliation: Inserm (Institut national de la santé et de la recherche médicale) U1054, Montpellier, France.

ABSTRACT

Background: Individuals are exposed daily to environmental pollutants that may act as endocrine-disrupting chemicals (EDCs), causing a range of developmental, reproductive, metabolic, or neoplastic diseases. With their mostly hydrophobic pocket that serves as a docking site for endogenous and exogenous ligands, nuclear receptors (NRs) can be primary targets of small molecule environmental contaminants. However, most of these compounds are chemically unrelated to natural hormones, so their binding modes and associated hormonal activities are hardly predictable.

Objectives: We conducted a correlative analysis of structural and functional data to gain insight into the mechanisms by which 12 members of representative families of pollutants bind to and activate the estrogen receptors ERα and ERβ.

Methods: We used a battery of biochemical, structural, biophysical, and cell-based approaches to characterize the interaction between ERs and their environmental ligands.

Results: Our study revealed that the chemically diverse compounds bound to ERs via varied sets of protein-ligand interactions, reflecting their differential activities, binding affinities, and specificities. We observed xenoestrogens binding to both ERs-with affinities ranging from subnanomolar to micromolar values-and acting in a subtype-dependent fashion as full agonists or partial agonists/antagonists by using different combinations of the activation functions 1 and 2 of ERα and ERβ.

Conclusions: The precise characterization of the interactions between major environmental pollutants and two of their primary biological targets provides rational guidelines for the design of safer chemicals, and will increase the accuracy and usefulness of structure-based computational methods, allowing for activity prediction of chemicals in risk assessment.

Show MeSH
Related in: MedlinePlus