Interaction of PAH-related compounds with the α and β isoforms of the estrogen receptor

Fertuck, Kirsten C.; Kumar, Subodh; Sikka, Harish C.; Matthews, Jason; Zacharewski, Timothy R.

doi:10.1016/s0378-4274(01)00344-7

Cited by 114 publications

(63 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Shown are means and S.E. from three independent experiments, and ‫ء‬ indicates significant decrease in the presence of ICI at p Ͻ 0.05. have also been reported to have ER isoform-specific interactions with a preference for ER␤ (Fertuck et al, 2001). In this study, we demonstrate that 3-MC and BaP have similar properties.…”

Section: Discussionsupporting

confidence: 70%

3-Methylcholanthrene Displays Dual Effects on Estrogen Receptor (ER) α and ERβ Signaling in a Cell-Type Specific Fashion

Swedenborg

Rüegg²,

Hillenweck³

et al. 2007

Mol Pharmacol

View full text Add to dashboard Cite

The biological effects of 17␤-estradiol (E 2 ) are mediated by the two estrogen receptor (ER) isoforms ER␣ and ER␤. These receptors are ligand-inducible transcription factors that belong to the nuclear receptor superfamily. These receptors are also targets for a broad range of natural and synthetic compounds that induce ER activity, including dietary compounds, pharmaceuticals, and various types of environmental pollutants such as bisphenols and polychlorinated hydroxy-biphenyls. Here, we study the effect of the combustion byproduct 3-methylcholanthrene (3-MC) on ER␣ and ER␤. 3-MC is a compound identified previously as an activator of the aryl hydrocarbon receptor (AhR). Activation of AhR is traditionally associated with an inhibition of the E 2 signaling network. In this study, we demonstrate that 3-MC is a cell-specific activator or inhibitor of E 2 signaling pathways. We show that 3-MC acts as a repressor in some cells, presumably via the AhR, whereas it is a potent activator of ER activity in other cells. It is interesting that we demonstrate that the estrogenic effects of 3-MC are dependent on the ability of cells to metabolize parental 3-MC to alternative compounds. In summary, our results suggest that exposure to AhR ligands like 3-MC can lead to either activation or repression of E 2 signaling, depending on the cellular context.Eukaryotic cells respond and adapt to changes in their environment by altering their enzymatic activities. This can be accomplished in part by increasing or decreasing the transcription rate of genes encoding relevant proteins. A critical point for cells is to correctly decipher the environmental changes that occur. To meet this challenge, eukaryotic cells have developed receptor proteins with the ability to distinguish between different environmental cues. However, the intensive use of chemicals in today's modern society has introduced a plethora of manmade compounds into the environment that possess abilities to interfere with receptormediated signaling pathways, a phenomenon known as endocrine disruption.The two estrogen receptor isoforms, ER␣ and ER␤, regulate the cellular response to estrogens, which are involved in the regulation of a wide range of physiological functions, including cell growth and proliferation, regulation of the cardiovascular system, and maintaining of bone homeostasis. Besides the endogenous hormones, a broad range of natural and synthetic compounds induces ER activity. For example, dietary substances like isoflavonoids and coumestans activate the ERs and so do various types of environmental pollutants such as bisphenol A and polychlorinated hydroxybiphenyls.The ERs belong to the nuclear receptor (NR) superfamily and share a conserved structural arrangement with other members of the family. NRs carry a centrally located, highly conserved DNA binding domain that mediates both dimerization and specific DNA binding. The DNA binding domain

show abstract

Section: Discussionsupporting

confidence: 70%

3-Methylcholanthrene Displays Dual Effects on Estrogen Receptor (ER) α and ERβ Signaling in a Cell-Type Specific Fashion

Swedenborg

Rüegg²,

Hillenweck³

et al. 2007

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…The CYP1A is usually induced by the production of AhR and increasing binding activity of AhR-Arnt and Xenobiotics Responsive Elements (XRE). 25) Differently from this AhR relating reaction, phorbol-12-myristate-13-acetate (PMA) is not an AhR agonist (therefore, it does not cause XREbinding of AhR-Arnt), but it does enhance CYP1A1 expression in human hepatocellular carcinoma cells (HepG2)-derived cells. 26,27) This phenomenon also involves AhR-related modulation via another signaling pathway and is unrelated to the increase of AhR expression or the XRE-binding activity of AhR-Arnt.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Toxic Activities of Polycyclic Aromatic Hydrocarbon Derivatives Using In Vitro Bioassays

Bekki

Takigami

Suzuki

et al. 2009

JOURNAL OF HEALTH SCIENCE

View full text Add to dashboard Cite

Several polycyclic aromatic hydrocarbons and nitrated polycyclic aromatic hydrocarbons (PAHs/NPAHs) such as benzo [a]pyrene and 1-nitropyrene are mutagens and/or carcinogens. These compounds secondarily generate PAH hydroxides, ketones, and quinones through atmospheric and metabolic reactions. The health effects of these compounds is now an important social concern. For example, lung cancer, bronchitis, whistling and so on. In this work, we evaluated toxicities of 25 PAH derivatives (hydroxides, ketones and quinones) in terms of aryl hydrocarbon receptor (AhR) binding and thyroid hormone-related endpoints using three in vitro bioassays: dioxinresponsive chemical-activated luciferase gene expression (DR-CALUX), thyroid receptor β chemical-activated luciferase gene expression (TRβ-CALUX), and competitive human transthyretin-binding (TTR-binding) assays. Eleven of the 25 PAH derivatives had AhR agonist activity, six had AhR antagonist activity and seven had TRpotentiation activity in the TR-CALUX. Furthermore, PAH quinones and hydroxides had strong TTR-binding activity. 3,4-Dihydrobenz[a]anthracen-1(2 H)-one had the strongest agonist activity (EC 20 : 0.4 µM) as determined by DR-CALUX. PAH ketones showed stronger activity than the control and significant difference by statistical analysis. Benzo[c]phenanthrene-[1,4]-quinone was the most TTR-active compound (IC 50 : 2.5 µM). Both PAH ketones and quinones, which have functional groups with low polarity, had significant activities in all tested assays. These in vitro results suggest that PAH derivatives might have various toxic activities in animals. For estimating the health effects and accessing the environmental risks of PAHs, further studies on the toxicity mechanisms are necessary.

show abstract

“…Higher levels of PAH-DNA adducts have been detected in the breast tissue of cancer patients compared with that of controls (143). In addition to binding DNA, certain PAHs and/or their metabolites bind the ER (182)(183)(184)(185)(186). It has been suggested that by binding ERs, PAHs may accumulate in the nucleus of cells, resulting in increased rates of mutagenesis (183).…”

Section: Steroidal Hormone Function and Chemical Mixturesmentioning

confidence: 99%

“…Results from a number of studies suggest that metabolism of environmental chemicals may produce more potent estrogens/antiestrogens (186,195). Also, most assays measure the estrogenic activity of a compound on basis of binding to ER and activation of transcription.…”

Section: Steroidal Hormone Function and Chemical Mixturesmentioning

confidence: 99%

Understanding the human health effects of chemical mixtures.

Carpenter

Arcaro

Spink

2002

Environ Health Perspect

330

198

View full text Add to dashboard Cite

Most research on the effects of chemicals on biologic systems is conducted on one chemical at a time. However, in the real world people are exposed to mixtures, not single chemicals. Although various substances may have totally independent actions, in many cases two substances may act at the same site in ways that can be either additive or nonadditive. Many even more complex interactions may occur if two chemicals act at different but related targets. In the extreme case there may be synergistic effects, in which case the effects of two substances together are greater than the sum of either effect alone. In reality, most persons are exposed to many chemicals, not just one or two, and therefore the effects of a chemical mixture are extremely complex and may differ for each mixture depending on the chemical composition. This complexity is a major reason why mixtures have not been well studied. In this review we attempt to illustrate some of the principles and approaches that can be used to study effects of mixtures. By the nature of the state of the science, this discussion is more a presentation of what we do not know than of what we do know about mixtures. We approach the study of mixtures at three levels, using specific examples. First, we discuss several human diseases in relation to a variety of environmental agents believed to influence the development and progression of the disease. We present results of selected cellular and animal studies in which simple mixtures have been investigated. Finally, we discuss some of the effects of mixtures at a molecular level.

show abstract

Interaction of PAH-related compounds with the α and β isoforms of the estrogen receptor

Cited by 114 publications

References 48 publications

3-Methylcholanthrene Displays Dual Effects on Estrogen Receptor (ER) α and ERβ Signaling in a Cell-Type Specific Fashion

3-Methylcholanthrene Displays Dual Effects on Estrogen Receptor (ER) α and ERβ Signaling in a Cell-Type Specific Fashion

Evaluation of Toxic Activities of Polycyclic Aromatic Hydrocarbon Derivatives Using In Vitro Bioassays

Understanding the human health effects of chemical mixtures.

Contact Info

Product

Resources

About