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Estrogen receptor (ER) ? expression in oligodendrocytes is required for attenuation of clinical disease by an ER? ligand.

ABSTRACT: Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) ? ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ER? ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ER? is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ER?-null mice. Here we investigated the potential role of ER? expression in cells of oligodendrocyte (OL) lineage in ER? ligand-mediated neuroprotection. To this end, we selectively deleted ER? in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ER? CKO on ER? ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ER? CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ER? CKO mice. However, DPN treatment significantly increased brain-derived neurotrophic factor levels in ER? CKO mice. These findings demonstrate that signaling through ER? in OLs is essential for the beneficial myelination effects of the ER? ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.

SUBMITTER: Khalaj AJ

PROVIDER: S-EPMC3839759 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand.

Khalaj Anna J AJ Yoon Jaehee J Nakai Jaspreet J Winchester Zachary Z Moore Spencer M SM Yoo Timothy T Martinez-Torres Leonardo L Kumar Shalini S Itoh Noriko N Tiwari-Woodruff Seema Kaushalya SK

Proceedings of the National Academy of Sciences of the United States of America 20131104 47

Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ERβ ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ERβ is the target molecule of DPN because DPN treatmen ...[more]

PMID: 24191028

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Project description: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.

Dataset Information

Estrogen receptor (ER) ? expression in oligodendrocytes is required for attenuation of clinical disease by an ER? ligand.

Publications

Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand.

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