Research Article Advance Publication
Genistein Disrupts Glucocorticoid Receptor Signaling in Human Uterine Endometrial Ishikawa Cells
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Citation: Whirledge S, Senbanjo LT, Cidlowski JA. Genistein Disrupts Glucocorticoid Receptor Signaling in Human Uterine Endometrial Ishikawa Cells. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1408437.
Received: 18 March 2013
Accepted: 15 August 2014
Advance Publication: 19 August 2014
Background: The link between environmental estrogen exposure and defects in the female reproductive tract is well established. The phytoestrogen genistein is able to modulate uterine estrogen receptor (ER) activity and dietary exposure is associated with uterine pathologies. Regulation of stress and immune functions by the glucocorticoid receptor (GR) is also an integral part of maintaining reproductive tract function and disruption of GR signaling by genistein may also have a role in the adverse effects of genistein.
Objective: We evaluated the transcriptional response to genistein in Ishikawa cells and investigated the effects of genistein on GR-mediated target genes.
Methods: Ishikawa cells were used as a model system to identify novel targets of genistein and the synthetic glucocorticoid dexamethasone through whole genome microarray analysis. Common gene targets were defined and response patterns verified by quantitative real-time reverse transcription-PCR. The mechanism of transcriptional antagonism was determined for select genes.
Results: Genistein regulates numerous genes in Ishikawa cells independently of estradiol, and the response to co-administration of genistein and dexamethasone is unique compared to estradiol and dexamethasone. Furthermore, genistein alters glucocorticoid regulation of GR-target genes. In a select set of genes, co-regulation by dexamethasone and genistein was found to require both GR and ERα signaling, respectively.
Conclusions: Using Ishikawa cells, we observed that exposure to genistein results in distinct changes in gene expression and unique differences in the glucocorticoid receptor transcriptome.
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