Environmental Science and Pollution Research

, Volume 25, Issue 21, pp 21257–21266 | Cite as

Estrogen agonistic/antagonistic activity of brominated parabens

  • Kohei Sasaki
  • Masanori TerasakiEmail author
Short Research and Discussion Article


The estrogen agonistic/antagonistic activity of 16 brominated by-products of parabens was assessed by using a yeast two-hybrid assay transfected with the human estrogen receptor α. Characterization of synthetic compounds including novel brominated parabens was performed using 1H-NMR spectroscopy and high-resolution mass spectrometry. For the agonist assay, five C3–C4 alkylparabens exhibited significant activity (P < 0.05) relative to that of 17β-estradiol, ranging from 3.7 × 10−5 to 7.1 × 10−4. In contrast, none of the brominated alkyl parabens exhibited agonistic activity. In the antagonist assay, 12 brominated alkylparabens and butylparaben exhibited significant antagonistic activity (P < 0.05). Their antagonistic activity relative to 4-hydroxytamoxifen ranged from 0.11 to 2.5. The antagonist activity of C1–C4 alkylparabens increased with the number of bromine substitutions. Benzylparaben exhibited both agonistic and antagonistic activity, and these activities dissipated or were weakened with increased bromination. Thus, increased bromination appeared to attenuate the estrogen agonistic activity of most parabens such that it resulted in increased antagonistic activity, a feature of parabens that had not been previously described.


Personal care products Disinfection by-products Endocrine disruption Agonist Antagonist Yeast two-hybrid assay 


Funding information

This work was supported by the Grant-in-Aid for Scientific Research (B) no. 17H03094 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11356_2018_2600_MOESM1_ESM.docx (197 kb)
ESM 1 (DOCX 197 kb)


  1. Błędzka D, Gromadzińska J, Wąsowicz W (2014) Parabens. From environmental studies to human health. Environ Int 67:27–42. CrossRefGoogle Scholar
  2. Byford JR, Shaw LE, Drew MG, Pope GS, Sauer MJ, Darbre PD (2002) Oestrogenic activity of parabens in MCF7 human breast cancer cells. J Steroid Biochem Mol Biol 80:49–60. CrossRefGoogle Scholar
  3. Canosa P, Rodríguez I, Rubí E, Negreira N, Cela R (2006) Formation of halogenated by-products of parabens in chlorinated water. Anal Chim Acta 575:106–113. CrossRefGoogle Scholar
  4. Darbre PD, Harvey PW (2008) Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J Appl Toxicol 28:561–578. CrossRefGoogle Scholar
  5. Flores A, Hill EM (2008) Formation of estrogenic brominated ethinylestradiol in drinking water: implications for aquatic toxicity testing. Chemosphere 73:1115–1120. CrossRefGoogle Scholar
  6. García-Reyero N, Requena V, Petrovic M, Fischer B, Hansen PD, Díaz A, Ventura F, Barceló D, Piña B (2004) Estrogenic potential of halogenated derivatives of nonylphenol ethoxylates and carboxylates. Environ Toxicol Chem 23:705–711. CrossRefGoogle Scholar
  7. Golden R, Gandy J, Vollmer G (2005) A review of the endocrine activity of parabens and implications for potential risks to human health. Crit Rev Toxicol 35:435–458. CrossRefGoogle Scholar
  8. González-Marinõ I, Quintana JB, Rodríguez I, Cela R (2011) Evaluation of the occurrence and biodegradation of parabens and halogenated by-products in wastewater by accurate-mass liquid chromatography-quadrupole-time-of-flight-mass spectrometry (LC-QTOF-MS). Water Res 45:6770–6780. CrossRefGoogle Scholar
  9. Hill EM, Smith MD (2006) Identification and steroid receptor activity of products formed from the bromination of technical nonylphenol. Chemosphere 64:1761–1768. CrossRefGoogle Scholar
  10. Kawagoshi Y, Tsukagoshi Y, Fukunaga I (2002) Determination of estrogenic activity in landfill leachate by simplified yeast two-hybrid assay. J Environ Monit 4:1040–1046. CrossRefGoogle Scholar
  11. Kitamura S, Shinohara S, Iwase E, Sugihara K, Uramaru N, Shigematsu H, Fujimoto N, Ohta S (2008) Affinity for thyroid hormone and estrogen receptors of hydroxylated polybrominated diphenyl ethers. J Health Sci 54:607–614. CrossRefGoogle Scholar
  12. Kolle SN, Kamp HG, Huener HA, Knickel J, Verlohner A, Woitkowiak C, Landsiedel R, van Ravenzwaay B (2010) In house validation of recombinant yeast estrogen and androgen receptor agonist and antagonist screening assays. Toxicol in Vitro 24:2030–2040. CrossRefGoogle Scholar
  13. Kuruto-Niwa R, Nozawa R, Miyakoshi T, Shiozawa T, Terao Y (2005) Estrogenic activity of alkylphenols, bisphenol S, and their chlorinated derivatives using a GFP expression system. Environ Toxicol Pharmacol 19:121–130. CrossRefGoogle Scholar
  14. Kusk KO, Krüger T, Long M, Taxvig C, Lykkesfeldt AE, Frederiksen H, Andersson AM, Andersen HR, Hansen KM, Nellemann C, Bonefeld-Jørgensen EC (2011) Endocrine potency of wastewater: contents of endocrine disrupting chemicals and effects measured by in vivo and in vitro assays. Environ Toxicol Chem 30:413–426. CrossRefGoogle Scholar
  15. Li X, Gao Y, Guo LH, Jiang G (2013) Structure-dependent activities of hydroxylated polybrominated diphenyl ethers on human estrogen receptor. Toxicology 309:15–22. CrossRefGoogle Scholar
  16. Meerts IATM, Letcher RJ, Hoving S, Marsh G, Bergman A, Lemmen JG, Van Der Burg B, Brouwer A (2001) In vitro estrogenicity of polybrominated diphenyl ethers, hydroxylated PBDEs, and polybrominated bisphenol A compounds. Environ Health Perspect 109:399–407. CrossRefGoogle Scholar
  17. Mikula P, Dobsikova R, Svobodova Z, Jarovsky J (2006) Evaluation of xenoestrogenic potential of propylparaben in zebrafish (Danio rerio). Neuro Endocrinol Lett 27:104–107Google Scholar
  18. Miller D, Wheals BB, Beresford N, Sumpter JP (2001) Estrogenic activity of phenolic additives determined by an in vitro yeast bioassay. Environ Health Perspect 109:133–138. CrossRefGoogle Scholar
  19. Nakamura H, Shiozawa T, Terao Y, Shiraishi F, Fukazawa H (2006) By-products produced by the reaction of estrogens with hypochlorous acid and their estrogen activities. J Health Sci 52:124–131. CrossRefGoogle Scholar
  20. Olsen CM, Meussen-Elholm ET, Holme JA, Hongslo JK (2002) Brominated phenols: characterization of estrogen-like activity in the human breast cancer cell-line MCF-7. Toxicol Lett 129:55–63. CrossRefGoogle Scholar
  21. Rivas Ibáñez G, Bittner M, Toušová Z, Campos-Mañas MC, Agüera A, Casas López JL, Sánchez Pérez JA, Hilscherová K (2017) Does micropollutant removal by solar photo-Fenton reduce ecotoxicity in municipal wastewater ? A comprehensive study at pilot scale open reactors. J Chem Technol Biotechnol 92:2114–2122. CrossRefGoogle Scholar
  22. Routledge EJ, Parker J, Odum J, Ashby J, Sumpter JP (1998) Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol Appl Pharmacol 153:12–19. CrossRefGoogle Scholar
  23. Shaw J, de Catanzaro D (2009) Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice. Reprod Toxicol 28:26–31. CrossRefGoogle Scholar
  24. Soni MG, Carabin IG, Burdock GA (2005) Safety assessment of esters of p-hydroxybenzoic acid (parabens). Food Chem Toxicol 43:985–1015. CrossRefGoogle Scholar
  25. Terasaki M, Kamata R, Shiraishi F, Makino M (2009) Evaluation of estrogenic activity of paraben and their chlorinated derivatives by using the yeast two-hybrid assay the enzyme-linked immunosorbent assay. Environ Toxicol Chem 28:204–208. CrossRefGoogle Scholar
  26. Terasaki M, Takemura Y, Makino M (2012) Paraben-chlorinated derivatives in river waters. Environ Chem Lett 10:401–406. CrossRefGoogle Scholar
  27. Terasaki M, Yasuda M, Makino M, Shimoi K (2015) Aryl hydrocarbon receptor potency of chlorinated parabens in the aquatic environment. Environ Sci Water Res Technol 1:375–382. CrossRefGoogle Scholar
  28. Terasaki M, Wada T, Nagashima S, Makino M, Yasukawa H (2016) In vitro transformation of chlorinated parabens by the liver S9 fraction: kinetics, metabolite identification, and aryl hydrocarbon receptor agonist activity. Chem Pharm Bull 64:650–654. CrossRefGoogle Scholar
  29. U.S. Environmental Protection Agency (2012) EPI Suite™-Estimation Program, version 4.11, Washington, D.C.: U.S. Environmental Protection Agency. Available from:
  30. van Meeuwen JA, van SO, Piersma AH, de Jong PC, van den BM (2008) Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics. Toxicol Appl Pharmacol 230:372–382CrossRefGoogle Scholar
  31. Vanparys C, Maras M, Lenjou M, Robbens J, Van Bockstaele D, Blust R, De Coen W (2006) Flow cytometric cell cycle analysis allows for rapid screening of estrogenicity in MCF-7 breast cancer cells. Toxicol in Vitro 20:1238–1248. CrossRefGoogle Scholar
  32. Zhang Z, Sun L, Hu Y, Jiao J, Hu J (2013) Inverse antagonist activities of parabens on human oestrogen-related receptor γ (ERRγ): in vitro and in silico studies. Toxicol Appl Pharmacol 270:16–22. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Environmental Sciences, Faculty of Humanities and Social SciencesIwate UniversityMoriokaJapan

Personalised recommendations