Academic journal article Environmental Health Perspectives

Endocrine-Disrupting Chemicals (EDCs): In Vitro Mechanism of Estrogenic Activation and Differential Effects on ER Target Genes

Academic journal article Environmental Health Perspectives

Endocrine-Disrupting Chemicals (EDCs): In Vitro Mechanism of Estrogenic Activation and Differential Effects on ER Target Genes

Article excerpt

BACKGROUND: Endocrine-disrupting chemicals (EDCs) influence the activity of estrogen receptors (ERs) and alter the function of the endocrine system. However, the diversity of EDC effects and mechanisms of action are poorly understood.

OBJECTIVES: We examined the agonistic activity of EDCs through ER[alpha] and ER[beta]. We also investigated the effects of EDCs on ER-mediated target genes.

METHODS: HepG2 and HeLa cells were used to determine the agonistic activity of EDCs on ER[alpha] and ER[beta] via the luciferase reporter assay. Ishikawa cells stably expressing ER[alpha] were used to determine changes in endogenous ER target gene expression by EDCs.

RESULTS: Twelve EDCs were categorized into three groups on the basis of product class and similarity of chemical structure. As shown by luciferase reporter analysis, the EDCs act as ER agonists in a cell type- and promoter-specific manner. Bisphenol A, bisphenol AF, and 2-2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (group 1) strongly activated ERB estrogen responsive element (ERE)-mediated responses. Daidzein, genistein, kaempferol, and coumestrol (group 2) activated both ER[alpha] and ER[beta] ERE-mediated activities. Endosulfan and kepone (group 3) weakly activated ER[alpha]. Only a few EDCs significantly activated the "tethered" mechanism via ER[alpha] or ER[beta]. Results of real-time polymerase chain reaction indicated that bisphenol A and bisphenol AF consistently activated endogenous ER target genes, but the activities of other EDCs on changes of ER target gene expression were compound specific.

CONCLUSION: Although EDCs with similar chemical structures (in the same group) tended to have comparable ER[alpha] and ER[beta] ERE-mediated activities, similar chemical structure did not correlate with previously reported ligand binding affinities of the EDCs. Using ER[alpha]-stable cells, we observed that EDCs differentially induced activity of endogenous ER target genes.

KEY WORDS: [E.sub.2], EDCs, ER[alpha], ER[beta], ERE, ER target genes. Environ Health Perspect 121:459-466 (2013). http://dx.doi.org/10.1289/ehp.1205951 [Online 5 February 2013]

Many natural and synthetic chemicals have been reported to disrupt the normal function of the endocrine system (Henley and Korach 2010). These compounds, classified as endocrine-disrupting chemicals (EDCs), interfere with hormone biosynthesis, metabolism, or action, which can result in deviation from normal homeostatic control and can alter normal development and reproduction (Diamanti-Kandarakis et al. 2009). Many known EDCs influence the activity of the estrogen receptors (ERs) and alter their function in in vitro and in vivo model systems (Diamanti-Kandarakis et al. 2009). Estrogens play an essential role in the growth, differentiation, and homeostasis of a number of target tissues, including reproductive tracts (both male and female), mammary glands, bone, brain, and liver (Katzenellenbogen 1996; Katzenellenbogen et al. 1997; Lubahn et al. 1993; McDonnell and Norris 2002; Nilsson et al. 2001; Pettersson and Gustafsson 2001). The biological effects of estrogen ([E.sub.2]) are mediated through two ERs, ER[alpha] and ER[beta], which belong to the nuclear receptor super-family of ligand-inducible transcription factors (Hall and McDonnell 2005). There are two major mechanisms of ER-mediated transcriptional gene regulations. In the classical mechanism, ERs directly bind to estrogen responsive elements (EREs) located in the promoter region of target genes. The non-classical mechanism is the "tethered" mechanism, which involves the ERs regulating gene expression by associating with other transcription factors such as c-Jun and c-Fos, which bind the DNA but not with direct ER-DNA binding (Bjornstrom and Sjoberg 2005; Hall and McDonnell 2005; O'Lone et al. 2004).

Estrogens regulate a large number of target genes through the ER. PR (progesterone receptor) and pS2 are the well-known ER target genes (Berry et al. …

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