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

Overview

Journal Environ Health Perspect

Date 2013 Feb 7

PMID 23384675

Citations 36

Authors

Yin Li

Colin J Luh

Katherine A Burns

Yukitomo Arao

Zhongliang Jiang

Christina T Teng

Raymond R Tice

Kenneth S Korach

Affiliations

Soon will be listed here.

Abstract

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 ERα and ERβ. 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 ERα and ERβ via the luciferase reporter assay. Ishikawa cells stably expressing ERα 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 ERα estrogen responsive element (ERE)-mediated responses. Daidzein, genistein, kaempferol, and coumestrol (group 2) activated both ERα and ERβ ERE-mediated activities. Endosulfan and kepone (group 3) weakly activated ERα. Only a few EDCs significantly activated the "tethered" mechanism via ERα or ERβ. 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 ERα and ERβ ERE-mediated activities, similar chemical structure did not correlate with previously reported ligand binding affinities of the EDCs. Using ERα-stable cells, we observed that EDCs differentially induced activity of endogenous ER target genes.

Citing Articles

Maternal deposition of hormones and contaminants shape the gonadal transcriptome in American alligators.

Smaga C, Bock S, Johnson J, Paitz R, Letter A, Deem V Proc Biol Sci. 2025; 292(2039):20242105.

PMID: 39876737 PMC: 11775603. DOI: 10.1098/rspb.2024.2105.

Nongenomic ERα-AMPK Signaling Regulates Sex-Dependent Bcrp Transport Activity at the Blood-Brain Barrier.

Banks D, Lierz S, Cannon R, Korach K Endocrinology. 2024; 165(8).

PMID: 38984714 PMC: 11272090. DOI: 10.1210/endocr/bqae081.

A continuous in silico learning strategy to identify safety liabilities in compounds used in the leather and textile industry.

March-Vila E, Ferretti G, Terricabras E, Ardao I, Manuel Brea J, Varela M Arch Toxicol. 2023; 97(4):1091-1111.

PMID: 36781432 PMC: 10025185. DOI: 10.1007/s00204-023-03459-7.

Phytoestrogens and Health Effects.

Canivenc-Lavier M, Bennetau-Pelissero C Nutrients. 2023; 15(2).

PMID: 36678189 PMC: 9864699. DOI: 10.3390/nu15020317.

Use of Straighteners and Other Hair Products and Incident Uterine Cancer.

Chang C, OBrien K, Keil A, Gaston S, Jackson C, Sandler D J Natl Cancer Inst. 2022; 114(12):1636-1645.

PMID: 36245087 PMC: 9949582. DOI: 10.1093/jnci/djac165.

References

Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G . Mechanisms of estrogen action. Physiol Rev. 2001; 81(4):1535-65. DOI: 10.1152/physrev.2001.81.4.1535. View

Bjornstrom L, Sjoberg M . Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol. 2005; 19(4):833-42. DOI: 10.1210/me.2004-0486. View

Lubahn D, Moyer J, Golding T, Couse J, Korach K, SMITHIES O . Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc Natl Acad Sci U S A. 1993; 90(23):11162-6. PMC: 47942. DOI: 10.1073/pnas.90.23.11162. View

Li Y, Burns K, Arao Y, Luh C, Korach K . Differential estrogenic actions of endocrine-disrupting chemicals bisphenol A, bisphenol AF, and zearalenone through estrogen receptor α and β in vitro. Environ Health Perspect. 2012; 120(7):1029-35. PMC: 3404668. DOI: 10.1289/ehp.1104689. View

Murray T, Lea R, Abramovich D, Haites N, Fowler P . Endocrine disrupting chemicals: effects on human male reproductive health. Early Pregnancy (Cherry Hill). 2001; 5(2):80-112. View

Jakacka M, Ito M, Weiss J, Chien P, Gehm B, Jameson J . Estrogen receptor binding to DNA is not required for its activity through the nonclassical AP1 pathway. J Biol Chem. 2001; 276(17):13615-21. DOI: 10.1074/jbc.M008384200. View

Markaverich B, Webb B, Densmore C, Gregory R . Effects of coumestrol on estrogen receptor function and uterine growth in ovariectomized rats. Environ Health Perspect. 1995; 103(6):574-81. PMC: 1519143. DOI: 10.1289/ehp.95103574. View

Katzenellenbogen B . Mechanisms of action and cross-talk between estrogen receptor and progesterone receptor pathways. J Soc Gynecol Investig. 2000; 7(1 Suppl):S33-7. DOI: 10.1016/s1071-5576(99)00058-1. View

Ying G, Williams B, Kookana R . Environmental fate of alkylphenols and alkylphenol ethoxylates--a review. Environ Int. 2002; 28(3):215-26. DOI: 10.1016/s0160-4120(02)00017-x. View

10.

Kuiper G, Lemmen J, Carlsson B, Corton J, Safe S, van der Saag P . Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 1998; 139(10):4252-63. DOI: 10.1210/endo.139.10.6216. View

11.

Hall J, Korach K . Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis. Mol Carcinog. 2012; 52(9):715-25. PMC: 4287997. DOI: 10.1002/mc.21913. View

12.

Burns K, Li Y, Arao Y, Petrovich R, Korach K . Selective mutations in estrogen receptor alpha D-domain alters nuclear translocation and non-estrogen response element gene regulatory mechanisms. J Biol Chem. 2011; 286(14):12640-9. PMC: 3069464. DOI: 10.1074/jbc.M110.187773. View

13.

Guenther K, Heinke V, Thiele B, Kleist E, Prast H, Raecker T . Endocrine disrupting nonylphenols are ubiquitous in food. Environ Sci Technol. 2002; 36(8):1676-80. DOI: 10.1021/es010199v. View

14.

Welshons W, Nagel S, Vom Saal F . Large effects from small exposures. III. Endocrine mechanisms mediating effects of bisphenol A at levels of human exposure. Endocrinology. 2006; 147(6 Suppl):S56-69. DOI: 10.1210/en.2005-1159. View

15.

Pettersson K, Gustafsson J . Role of estrogen receptor beta in estrogen action. Annu Rev Physiol. 2001; 63:165-92. DOI: 10.1146/annurev.physiol.63.1.165. View

16.

Matsushima A, Liu X, Okada H, Shimohigashi M, Shimohigashi Y . Bisphenol AF is a full agonist for the estrogen receptor ERalpha but a highly specific antagonist for ERbeta. Environ Health Perspect. 2010; 118(9):1267-72. PMC: 2944088. DOI: 10.1289/ehp.0901819. View

17.

Klotz D, Hewitt S, Korach K, DiAugustine R . Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha. Endocrinology. 2000; 141(9):3430-9. DOI: 10.1210/endo.141.9.7649. View

18.

Hall J, McDonnell D . Coregulators in nuclear estrogen receptor action: from concept to therapeutic targeting. Mol Interv. 2006; 5(6):343-57. DOI: 10.1124/mi.5.6.7. View

19.

Hwang C, Kwak H, Lim H, Lee S, Kang Y, Choe T . Isoflavone metabolites and their in vitro dual functions: they can act as an estrogenic agonist or antagonist depending on the estrogen concentration. J Steroid Biochem Mol Biol. 2006; 101(4-5):246-53. DOI: 10.1016/j.jsbmb.2006.06.020. View

20.

Hall J, McDonnell D, Korach K . Allosteric regulation of estrogen receptor structure, function, and coactivator recruitment by different estrogen response elements. Mol Endocrinol. 2002; 16(3):469-86. DOI: 10.1210/mend.16.3.0814. View