Dataset Information

Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism.

ABSTRACT: Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women's health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 ?g/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in "normal" vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast cancer patients should avoid red clover and isoflavone based BDSs when making choices for menopausal symptom relief.

SUBMITTER: Dunlap TL

PROVIDER: S-EPMC5698877 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism.

Dunlap Tareisha L TL Howell Caitlin E CE Mukand Nita N Chen Shao-Nong SN Pauli Guido F GF Dietz Birgit M BM Bolton Judy L JL

Chemical research in toxicology 20171019 11

Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the ...[more]

PMID: 28985473

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Project description:Atmospheric particulate matter (PM) is a complex component of air pollution and the leading environmental risk factor for death worldwide. PM is formed from a combination of primary sources that emit PM directly into the atmosphere and secondary sources that emit gaseous precursors which oxidize in the atmosphere to form PM and composed of both inorganic and organic components. Currently, all PM is regulated by total mass. This regulatory strategy does not consider individual chemical constituents and assumes all PM is equally toxic. The chemically-extracted organic fraction (OF) of PM retains most organic constituents such as polycyclic aromatic hydrocarbons (PAHs) and excludes inorganics. PAHs are ubiquitous environmental toxicants and known aryl hydrocarbon receptor (AHR) ligands. This study addressed the role of individual components, specifically PAHs, of PM and how differences in chemical composition of real-world samples drive differential responses. This study tested the hypothesis that real-world extracts containing different combinations and concentrations of PAHs activate the AHR and enhance T helper (Th)17 differentiation to different degrees based on specific PAHs present in each sample, and not simply the mass of PM. The ability of the real-world OF, with different PAH compositions, to enhance Th17 differentiation and activate the AHR was tested in vitro. Cumulatively, the results identified PAHs as possible candidate components of PM contributing to increased inflammation and demonstrated that the sum concentration of PAHs does not determine the extent to which each PM activates the AHR and enhances Th17 differentiation suggesting individual components of each PM, and interactions of those components with others in the mixture, contribute to the inflammatory response. This demonstrates that not all PM are the same and suggests that when regulating PM based on its ability to cause human pathology, a strategy based on PM mass may not reduce pathologic potential of exposures.

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Dataset Information

Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism.

Publications

Red Clover Aryl Hydrocarbon Receptor (AhR) and Estrogen Receptor (ER) Agonists Enhance Genotoxic Estrogen Metabolism.

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