The Estrogenicity of Bisphenol A-Related Diphenylalkanes with Various Substituents at the Central Carbon and the Hydroxy Groups

SummaryA wide variety of environmental contaminants exert estrogenic actions in wildlife, laboratory animals, and in human beings through binding to nuclear estrogen receptors (ERs). Here, the mechanism(s) of bisphenol A (BPA) to induce cell proliferation and the occurrence of its bioremediation by treatment with laccase are reported. BPA, highly present in natural world and considered as a model of environmental estrogen action complexity, promotes human cancer cell proliferation via ERa-dependent signal transduction pathways. Similar to 17b-estradiol, BPA increases the phosphorylation of both extracellular regulated kinase and AKT. Specific inhibitors of these kinase completely block the BPA effect on cancer cell proliferation. Notably, high BPA concentrations (i.e., 0.1 and 1 mM) are cytotoxic even in ERa-devoid cancer cells, indicating that an ERa-independent mechanism participates to BPA-induced cytotoxicity. On the other hand, BPA oxidation by laccase impairs the binding of this environmental estrogen to ERa loosing at all ERa-dependent effect on cancer cell proliferation. Moreover, the laccase-catalyzed oxidation of BPA reduces the BPA cytotoxic effect. Thus, laccase appears to impair BPA action(s), representing an invaluable bioremediation enzyme.2008 IUBMB IUBMB Life, 60(12): 843-852, 2008

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“…This BPA concentration is compatible with the maximum estrogenic activity observed in MCF-7 cells (43,44).…”

Section: Discussionsupporting

confidence: 82%

Expression of Concern: Laccase treatment impairs bisphenol A‐induced cancer cell proliferation affecting estrogen receptor α‐dependent rapid signals

et al. 2008

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“…The longer the side chain, the greater the binding affinity for the ER (35). Common pharmacophore identification indicated that the optimal structural superposition between bisphenol A and E 2 is one in which the two benzene rings of bisphenol A are positioned over the A and C rings of E 2 , with the bridge carbon overlaying the B ring ( Figure 9).…”

Section: Resultsmentioning

confidence: 99%

Structure−Activity Relationships for a Large Diverse Set of Natural, Synthetic, and Environmental Estrogens

Fang

Tong

Shi

et al. 2001

Chem. Res. Toxicol.

420

357

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Understanding structural requirements for a chemical to exhibit estrogen receptor (ER) binding has been important in various fields. This knowledge has been directly and indirectly applied to design drugs for human estrogen replacement therapy, and to identify estrogenic endocrine disruptors. This paper reports structure-activity relationships (SARs) based on a total of 230 chemicals, including both natural and xenoestrogens. Activities were generated using a validated ER competitive binding assay, which covers a 10 6 -fold range. This study is focused on identification of structural commonalities among diverse ER ligands. It provides an overall picture of how xenoestrogens structurally resemble endogenous 17 -estradiol (E 2 ) and the synthetic estrogen diethylstilbestrol (DES). On the basis of SAR analysis, five distinguishing criteria were found to be essential for xenoestrogen activity, using E 2 as a template: (1) H-bonding ability of the phenolic ring mimicking the 3-OH, (2) H-bond donor mimicking the17 -OH and O-O distance between 3-and 17 -OH, (3) precise steric hydrophobic centers mimicking steric 7R-and 11 -substituents, (4) hydrophobicity, and (5) a ring structure. The 3-position H-bonding ability of phenols is a significant requirement for ER binding. This contributes as both a H-bond donor and acceptor, although predominantly as a donor. However, the 17 -OH contributes as a H-bond donor only. The precise space (the size and orientation) of steric hydrophobic bulk groups is as important as a 17 -OH. Where a direct comparison can be made, strong estrogens tend to be more hydrophobic. A rigid ring structure favors ER binding. The knowledge derived from this study is rationalized into a set of hierarchical rules that will be useful in guidance for identification of potential estrogens.

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“…7 Particular public interests have also been focused on the potential health impact and exposure risk assessments on these estrogenic xenobiotics. 8 However, despite their extensive usage in industry and commercial applications, there is still a lack of knowledge about the release patterns and environmental occurrence of some of the BPs, which is essential to better estimate potential exposure routes to human. Current monitoring studies mostly focus on a small fraction of BP analogues, mainly on BPA which is the dominant BP and is utilized as a monomer in the production of polycarbonate plastics and epoxy resins.…”

Section: ■ Introductionmentioning

confidence: 99%

Distribution and Preliminary Exposure Assessment of Bisphenol AF (BPAF) in Various Environmental Matrices around a Manufacturing Plant in China

Song

Ruan

Wang

et al. 2012

Environ. Sci. Technol.

170

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Increasing attention has been paid to bisphenol A and bisphenol (BP) analogues due to high production volumes, wide usage and potential adverse effects. Bisphenol AF (BPAF) is considered a new bisphenol analogue which is used as raw material in plastic industry, but little is known about its occurrence in the environment and the potential associated risk. In this work, BPAF levels and environmental distribution were reported in samples collected around a manufacturing plant and a preliminary exposure risk assessment to local residents was conducted. BPAF was detected in most of the samples, with levels in river ranging between

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The Estrogenicity of Bisphenol A-Related Diphenylalkanes with Various Substituents at the Central Carbon and the Hydroxy Groups

Cited by 57 publications

References 23 publications

Expression of Concern: Laccase treatment impairs bisphenol A‐induced cancer cell proliferation affecting estrogen receptor α‐dependent rapid signals

Expression of Concern: Laccase treatment impairs bisphenol A‐induced cancer cell proliferation affecting estrogen receptor α‐dependent rapid signals

Structure−Activity Relationships for a Large Diverse Set of Natural, Synthetic, and Environmental Estrogens

Distribution and Preliminary Exposure Assessment of Bisphenol AF (BPAF) in Various Environmental Matrices around a Manufacturing Plant in China

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