Cross-talk between endocrine-disrupting chemicals and cytokine signaling through estrogen receptors

Abstract

STAT3 mainly acts as a signal transducer of IL-6 family cytokines and transcriptionally activates specific target genes. STAT3 has also been demonstrated to mediate cellular transformation and is found in numerous cancers. Endocrine-Disrupting Chemicals (EDCs) are a diverse group of chemicals that bind to estrogen receptors (ERs), mimic estrogenic actions, and may have adverse effects on human health. In our previous study, we demonstrated that estrogens suppressed the STAT3-mediated transcription activity through ERs. In this study, we examined the effects of EDCs on STAT3-mediated signaling through ERs. Surprisingly, some of EDCs enhanced STAT3-mediated transcription activity through ERs. This finding strongly suggests that EDCs may play an important role in the endocrine functions by mimicking cytokine activity by stimulating STAT3 actions through ERs.

DUSP22/LMW-DSP2 regulates estrogen receptor-α-mediated signaling through dephosphorylation of Ser-118

“…The cells were harvested and assayed for the LUC activity using the Dual-Luciferase Reporter Assay System (Promega, Madison, WI, USA) according to the manufacturer's instructions. Human embryonic kidney carcinoma cell line, 293T, was maintained in DMEM containing 10% FCS and transfected by the standard calcium precipitation protocol (Sekine et al, 2004). The cells were harvested 36 h after transfection and lysed in 50 ml of Reporter Lysis Buffer (Promega) and assayed for LUC and b-galactosidase activities according to the manufacturer's instructions.…”

Stat3 is a candidate epigenetic biomarker of perinatal Bisphenol A exposure associated with murine hepatic tumors with implications for human health

“…18 In fact, the classical sexual dimorphism in HCC incidence is thought to be due to the anti-inflammatory influence of endogenous estrogen via suppression of IL-6 production in an ERa-dependent manner. 23 BPA has been shown to increase expression of both IL-6 and STAT3 via both ERa and ERb in human hepatoma Hep3b cells. 23 In order to identify short, defined regions for quantitative DNA methylation analysis within these candidate genes, we mined existing whole genome next generation sequencing DNA methylation data sets for windows that exhibited lability in DNA methylation profiles following perinatal BPA exposure in both mice 24 and humans (unpublished data, in review) (MethylPlex technology, Rubicon Genomics, Ann Arbor, MI).…”

“…23 BPA has been shown to increase expression of both IL-6 and STAT3 via both ERa and ERb in human hepatoma Hep3b cells. 23 In order to identify short, defined regions for quantitative DNA methylation analysis within these candidate genes, we mined existing whole genome next generation sequencing DNA methylation data sets for windows that exhibited lability in DNA methylation profiles following perinatal BPA exposure in both mice 24 and humans (unpublished data, in review) (MethylPlex technology, Rubicon Genomics, Ann Arbor, MI). This approach allowed us to combine a traditional candidate gene approach, suitable for highly quantitative bisulfite sequencing on the Sequenom EpiTYPER MassARRAY platform, with epigenome-wide assessments of regions of altered methylation associated with early life BPA exposure, to identify candidate biomarkers linked to both exposure and disease.…”

Stimulation of transactivation of the largemouth bass estrogen receptors alpha, beta-a, and beta-b by methoxychlor and its mono- and bis-demethylated metabolites in HepG2 cells

“…MXC, and its demethylated metabolites, monohydroxymethoxychlor (OH-MXC) and 2,2-bis (p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), have been shown to cause ER-mediated signaling disruption in rodents [5][6][7], frogs [8], and various fish species [9,10]. These effects are thought to occur both through direct interaction with the ERs or indirectly by altering enzymes such as CYP3A, involved in the metabolism of endogenous E 2 [11], or through changes in steroid biosynthesis [12,13] possibly through ER-independent pathways [14,15]. Understanding how the ERs are directly affected has been studied through analysis of E 2 displacement from the ERs by these compounds [16], and through transfection assays using ERs from human [17,18], rat [17], and a rainbow trout chimera [16].…”