Dataset Information

Differential action of monohydroxylated polycyclic aromatic hydrocarbons with estrogen receptors ? and ?.

ABSTRACT: Polycyclic aromatic hydrocarbons (PAHs) are a diverse group of widespread environmental pollutants, some of which have been found to be estrogenic or antiestrogenic. Recent data have shown that hydroxylated PAH metabolites may be responsible for the estrogenic effects of some PAHs. The purpose of this study was to investigate the effects of several PAHs, as well as their monohydroxylated metabolites, on estrogen receptors (ERs), ER? and ER?. Three parent PAHs and their monohydroxylated metabolites were each evaluated using transcriptional reporter assays in isogenic stable cell lines to measure receptor activation, competitive binding assays to determine ligand binding, and bioluminescence resonance energy transfer assays to assess dimerization. Finally, the estrogenic effects of the hydroxylated metabolites were confirmed by quantitative real-time PCR of estrogen-responsive target genes. Although the parent PAHs did not induce ER? or ER? transcriptional activity, all of the monohydroxylated PAHs (1-OH naphthanol, 9-OH phenanthrene, 1-OH pyrene) selectively induced ER? transcriptional activity at the concentrations tested, while not activating ER?. Additionally, the monohydroxylated PAHs were able to competively bind ER?, induce ER? homodimers, and regulate ER? target genes. Although monohydroxylated PAHs appeared to have weak agonist activity to ER?, our results showed that they can elicit a biologically active response from ER? in human breast cancer cells and potentially interfere with ER? signaling pathways.

SUBMITTER: Sievers CK

PROVIDER: S-EPMC3595519 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Differential action of monohydroxylated polycyclic aromatic hydrocarbons with estrogen receptors α and β.

Sievers Chelsie K CK Shanle Erin K EK Bradfield Christopher A CA Xu Wei W

Toxicological sciences : an official journal of the Society of Toxicology 20120918 2

Polycyclic aromatic hydrocarbons (PAHs) are a diverse group of widespread environmental pollutants, some of which have been found to be estrogenic or antiestrogenic. Recent data have shown that hydroxylated PAH metabolites may be responsible for the estrogenic effects of some PAHs. The purpose of this study was to investigate the effects of several PAHs, as well as their monohydroxylated metabolites, on estrogen receptors (ERs), ERα and ERβ. Three parent PAHs and their monohydroxylated metabolit ...[more]

PMID: 22989670

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Project description:Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the Aryl Hydrocarbon Receptor (AHR) in a structurally-dependent manner, and induce toxicity via both AHR-dependent and -independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at a concentration that induces developmental malformations by 120 hours post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burden was analyzed at these time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the smallest number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure and may provide a path for unraveling the toxicity of complex PAH mixtures. Gene expression was measured in zebrafish embryos after exposure to PAHs. Embryos were batch-exposed in groups of 40 to 25 μM BAA, 25 μM DBT, 25 μM PYR or 1% DMSO vehicle control starting at 6 hpf and collected at 24 or 48 hpf. Four independent biological replicates were prepared for each treatment. The reference was a pool of zebrafish embryos exposed to DMSO control until 24 and 48 hpf.

Dataset Information

Differential action of monohydroxylated polycyclic aromatic hydrocarbons with estrogen receptors ? and ?.

Publications

Differential action of monohydroxylated polycyclic aromatic hydrocarbons with estrogen receptors α and β.

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