The human body is regularly exposed to simple catechols and small phenols originating from our diet or as a consequence of exposure to various industrial products. Several biological properties have been associated with these compounds such as antioxidant, anti-inflammatory, or antiplatelet activity. Less explored is their potential impact on the endocrine system, in particular through interaction with the alpha isoform of the estrogen receptor (ERα). In this study, human breast cancer cell line MCF-7/S0.5 was employed to investigate the effects on ERα of 22 closely chemically related compounds (15 catechols and 7 phenols and their methoxy derivatives), to which humans are widely exposed. ERα targets genes ESR1 (ERα) and TFF1, both on mRNA and protein level, were chosen to study the effect of the tested compounds on the mentioned receptor. A total of 7 compounds seemed to impact mRNA and protein expression similarly to estradiol (E2). The direct interaction of the most active compounds with the ERα ligand binding domain (LBD) was further tested in cell-free experiments using the recombinant form of the LBD, and 4-chloropyrocatechol was shown to behave like E2 with about 1/3 of the potency of E2. Our results provide evidence that some of these compounds can be considered potential endocrine disruptors interacting with ERα.

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Králové Charles University Hradec Králové Czechia

Zobrazit více v PubMed

Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. (2019) 116:135–70. doi: 10.1016/bs.apcsb.2019.01.001 PubMed DOI PMC

Arnal JF, Fontaine C, Abot A, Valera MC, Laurell H, Gourdy P, et al. . Lessons from the dissection of the activation functions (AF-1 and AF-2) of the estrogen receptor alpha in vivo. Steroids. (2013) 78:576–82. doi: 10.1016/j.steroids.2012.11.011 PubMed DOI

Anbalagan M, Rowan BG. Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer. Mol Cell Endocrinol. (2015) 418:264–72. doi: 10.1016/j.mce.2015.01.016 PubMed DOI

Frigo DE, Bondesson M, Williams C. Nuclear receptors: from molecular mechanisms to therapeutics. Essays Biochem. (2021) 65:847–56. doi: 10.1042/EBC20210020 PubMed DOI PMC

Bourdeau V, Deschenes J, Metivier R, Nagai Y, Nguyen D, Bretschneider N, et al. . Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol. (2004) 18:1411–27. doi: 10.1210/me.2003-0441 PubMed DOI

Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, et al. . Estrogen receptors: how do they signal and what are their targets. Physiol Rev. (2007) 87:905–31. doi: 10.1152/physrev.00026.2006 PubMed DOI

Bocchinfuso WP, Lindzey JK, Hewitt SC, Clark JA, Myers PH, Cooper R, et al. . Induction of mammary gland development in estrogen receptor-alpha knockout mice. Endocrinology. (2000) 141:2982–94. doi: 10.1210/endo.141.8.7609 PubMed DOI

Alva-Gallegos R, Carazo A, Mladenka P. Toxicity overview of endocrine disrupting chemicals interacting in vitro with the oestrogen receptor. Environ Toxicol Pharmacol. (2023) 99:104089. doi: 10.1016/j.etap.2023.104089 PubMed DOI

Diamanti-Kandarakis E BJ, Giudice LC, Hauser R, Prins GS, Soto AM, Zoeller RT, et al. . Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev. (2009) 30:293–342. doi: 10.1210/er.2009-0002 PubMed DOI PMC

Dziewirska E, Hanke W, Jurewicz J. Environmental non-persistent endocrine-disrupting chemicals exposure and reproductive hormones levels in adult men. Int J Occup Med Environ Health. (2018) 31:551–73. doi: 10.13075/ijomeh.1896.01183 PubMed DOI

Encarnacao T, Pais AA, Campos MG, Burrows HD. Endocrine disrupting chemicals: Impact on human health, wildlife and the environment. Sci Prog. (2019) 102:3–42. doi: 10.1177/0036850419826802 PubMed DOI PMC

Monneret C. What is an endocrine disruptor? C R Biol. (2017) 340:403–5. doi: 10.1016/j.crvi.2017.07.004 PubMed DOI

Cladis DP, Weaver CM, Ferruzzi MG. (Poly)phenol toxicity in vivo following oral administration: A targeted narrative review of (poly)phenols from green tea, grape, and anthocyanin-rich extracts. Phytother Res. (2022) 36:323–35. doi: 10.1002/ptr.7323 PubMed DOI

Milheiro J, Filipe-Ribeiro L, Vilela A, Cosme F, Nunes FM. 4-Ethylphenol, 4-ethylguaiacol and 4-ethylcatechol in red wines: Microbial formation, prevention, remediation and overview of analytical approaches. Crit Rev Food Sci Nutr. (2019) 59:1367–91. doi: 10.1080/10408398.2017.1408563 PubMed DOI

Scholtes C, Nizet S, Collin S. Guaiacol and 4-methylphenol as specific markers of torrefied malts. Fate of volatile phenols in special beers through aging. J Agric Food Chem. (2014) 62:9522–8. doi: 10.1021/jf5015654 PubMed DOI

Pimpao RC, Ventura MR, Ferreira RB, Williamson G, Santos CN. Phenolic sulfates as new and highly abundant metabolites in human plasma after ingestion of a mixed berry fruit puree. Br J Nutr. (2015) 113:454–63. doi: 10.1017/S0007114514003511 PubMed DOI

Applova L, Karlickova J, Warncke P, Macakova K, Hrubsa M, Machacek M, et al. . 4-methylcatechol, a flavonoid metabolite with potent antiplatelet effects. Mol Nutr Food Res. (2019) 63:e1900261. doi: 10.1002/mnfr.201900261 PubMed DOI

Duffy SJ, Vita JA. Effects of phenolics on vascular endothelial function. Curr Opin Lipidol. (2003) 14:21–7. doi: 10.1097/01.mol.0000052857.26236.f2 PubMed DOI

Ho K, Ferruzzi MG, Wightman JD. Potential health benefits of (poly)phenols derived from fruit and 100% fruit juice. Nutr Rev. (2020) 78:145–74. doi: 10.1093/nutrit/nuz041 PubMed DOI

Hrubsa M, Alva R, Parvin MS, Macakova K, Karlickova J, Fadraersada J, et al. . Comparison of antiplatelet effects of phenol derivatives in humans. Biomolecules. (2022) 12. doi: 10.3390/biom12010117 PubMed DOI PMC

Lin C, Ström A, Vega VB, Kong SL, Yeo AL, Thomsen JS, et al. . Discovery of estrogen receptor a target genes and response elements in breast tumor cells. Genome Biol. (2004) 5. doi: 10.1186/gb-2004-5-9-r66 PubMed DOI PMC

Wang DY, Fulthorpe R, Liss SN, Edwards EA. Identification of estrogen-responsive genes by complementary deoxyribonucleic acid microarray and characterization of a novel early estrogen-induced gene: EEIG1. Mol Endocrinol. (2004) 18:402–11. doi: 10.1210/me.2003-0202 PubMed DOI

Abbasi F, De-la-Torre GE, KalantarHormozi MR, Schmidt TC, Dobaradaran S. A review of endocrine disrupting chemicals migration from food contact materials into beverages. Chemosphere. (2024) 355:141760. doi: 10.1016/j.chemosphere.2024.141760 PubMed DOI

Konecny L, Hrubsa M, Karlickova J, Carazo A, Javorska L, Matousova K, et al. . The effect of 4-methylcatechol on platelets in familial hypercholesterolemic patients treated with lipid apheresis and/or proprotein convertase subtilisin kexin 9 monoclonal antibodies. Nutrients. (2023) 15. doi: 10.3390/nu15081842 PubMed DOI PMC

Feliciano RP, Boeres A, Massacessi L, Istas G, Ventura MR, Nunes Dos Santos C, et al. . Identification and quantification of novel cranberry-derived plasma and urinary (poly)phenols. Arch Biochem Biophys. (2016) 599:31–41. doi: 10.1016/j.abb.2016.01.014 PubMed DOI

Fernandes I, Faria A, Azevedo J, Soares S, Calhau C, De Freitas V, et al. . Influence of anthocyanins, derivative pigments and other catechol and pyrogallol-type phenolics on breast cancer cell proliferation. J Agric Food Chem. (2010) 58:3785–92. doi: 10.1021/jf903714z PubMed DOI

Li C, Li W, Chen S, Kang Z, Sun L, Li H, et al. . 4-Methylcatechol-induced cell damage in TM4 Sertoli cells. Cell Biol Int. (2015) 39:770–4. doi: 10.1002/cbin.10420 PubMed DOI

Li CJ, Jiang YW, Chen SX, Li HJ, Chen L, Liu YT, et al. . 4-Methylcatechol inhibits cell growth and testosterone production in TM3 Leydig cells by reducing mitochondrial activity. Andrologia. (2017) 49. doi: 10.1111/and.12581 PubMed DOI

Borrás M, Hardy L, Lempereur F, el Khissiin A, Legros N, Gol-Winkler R, et al. . Estradiol-induced down-regulation of estrogen receptor. Effect of various modulators of protein synthesis and expression. J Steroid Biochem Mol Biol. (1994) 48:325–36. doi: 10.1016/0960-0760(94)90072-8 PubMed DOI

Brzezinski A, Debi A. Phytoestrogens: the ‘‘natural’’ selective estrogen receptor modulators? Eur J Obstetrics Gynecology Reprod Biol. (1999) 85: 47–51. doi: 10.1016/s0301-2115(98)00281-4 PubMed DOI

Thent ZC, Froemming GRA, Ismail ABM, Fuad S, Muid S. Phytoestrogens by inhibiting the non-classical oestrogen receptor, overcome the adverse effect of bisphenol A on hFOB 1.19 cells. Iran J Basic Med Sci. (2020) 23:1155–63. doi: 10.22038/ijbms.2020.45296.10545 PubMed DOI PMC

Yang J, Wen L, Jiang Y, Yang B. Natural estrogen receptor modulators and their heterologous biosynthesis. Trends Endocrinol Metab. (2019) 30:66–76. doi: 10.1016/j.tem.2018.11.002 PubMed DOI

Yu L, Rios E, Castro L, Liu J, Yan Y, Dixon D. Genistein: dual role in women’s health. Nutrients. (2021) 13. doi: 10.3390/nu13093048 PubMed DOI PMC

Jiang Q, Payton-Stewart F, Elliott S, Driver J, Rhodes LV, Zhang Q, et al. . Effects of 7-O substitutions on estrogenic and anti-estrogenic activities of daidzein analogues in MCF-7 breast cancer cells. J Med Chem. (2010) 53:6153–63. doi: 10.1021/jm100610w PubMed DOI PMC

Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag PT, et al. . Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor b. Endocrinology. (1998) 139:4252–63. doi: 10.1210/endo.139.10.6216 PubMed DOI

Comşa Ş, Cimpean AM, Marius R. The story of MCF 7 breast cancer cell line: 40 years of experience in research. Anticancer Res. (2015) 35:3147–54. PubMed

European Chemical A, European Food Safety Authority with the technical support of the Joint Research C. Andersson N, Arena M, Auteri D, Barmaz S, et al. . Guidance for the identification of endocrine disruptors in the context of Regulations (EU) No 528/2012 and (EC) No 1107/2009. EFSA J. (2018) 16:e05311. doi: 10.2903/j.efsa.2018.5311 PubMed DOI PMC