Skip to main content

Advertisement

SpringerLink
Log in

Comparative study on estrogen receptor alpha dimerization and transcriptional activity of parabens

  • Original Article
  • Published:
Toxicological Research Aims and scope Submit manuscript

Abstract

Parabens are used as preservatives in various household products, including oral products, cosmetics, and hair/body washes. In recent years, the widespread use of parabens has raised concerns due to the potential health risks associated with their estrogenic effects. In the present study, we evaluated and compared the estrogenic activity of parabens using two cell-based in vitro tests: (1) bioluminescence resonance energy transfer (BRET)-based estrogen receptor alpha (ERα) dimerization using HEK293 cells that were stably transfected with ERα‐fused NanoLuc luciferase (Nluc) and HaloTag (HT) expression vector, and (2) stably transfected transcriptional activation (STTA) assays using ERα-HeLa9903 cells. The following parabens were tested using the BRET‐based ERα dimerization assay and showed estrogenic activity (PC20 values): methyl paraben (MP, 5.98 × 10−5 M), ethyl paraben (EP, 3.29 × 10−5 M), propylparaben (PP, 3.09 × 10−5 M), butyl paraben (BP, 2.58 × 10−5 M), isopropyl paraben (IsoPP, 1.37 × 10−5 M), and isobutyl paraben (IsoBP, 1.43 × 10−5 M). Except MP, all other parabens tested using the STTA assay also showed estrogenic activity: EP, 7.57 × 10−6 M; PP, 1.18 × 10−6 M; BP, 3.02 × 10−7 M; IsoPP, 3.58 × 10−7 M; and IsoBP, 1.80 × 10−7 M. Overall, EP, PP, BP, IsoPP, and IsoBP tested positive for estrogenic activity using both assays. These findings demonstrate that most parabens, albeit not all, induce ERα dimerization and possess estrogenic activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The data could be obtained upon reasonable request to the corresponding author.

References

  1. Engeli RT, Rohrer SR, Vuorinen A, Herdlinger S, Kaserer T, Leugger S, Schuster D, Odermatt A (2017) Interference of paraben compounds with estrogen metabolism by inhibition of 17beta-hydroxysteroid dehydrogenases. Int J Mol Sci 18:2007. https://doi.org/10.3390/ijms18092007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Costa JR, Campos MS, Lima RF, Gomes LS, Marques MR, Taboga SR, Biancardi MF, Brito PVA, Santos FCA (2017) Endocrine-disrupting effects of methylparaben on the adult gerbil prostate. Environ Toxicol 32:1801–1812. https://doi.org/10.1002/tox.22403

    Article  CAS  PubMed  Google Scholar 

  3. Nowak K, Ratajczak-Wrona W, Gorska M, Jablonska E (2018) Parabens and their effects on the endocrine system. Mol Cell Endocrinol 474:238–251. https://doi.org/10.1016/j.mce.2018.03.014

    Article  CAS  PubMed  Google Scholar 

  4. Okubo T, Yokoyama Y, Kano K, Kano I (2001) ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR. Food Chem Toxicol 39:1225–1232. https://doi.org/10.1016/s0278-6915(01)00073-4

    Article  CAS  PubMed  Google Scholar 

  5. Mitra P, Chatterjee S, Paul N, Ghosh S, Das M (2021) An overview of endocrine disrupting chemical paraben and search for an alternative–a review. In: Proceedings of the zoological society, vol 4. Springer, pp 479–493. https://doi.org/10.1007/s12595-021-00418-x

  6. Vo TT, Yoo YM, Choi KC, Jeung EB (2010) Potential estrogenic effect(s) of parabens at the prepubertal stage of a postnatal female rat model. Reprod Toxicol 29:306–316. https://doi.org/10.1016/j.reprotox.2010.01.013

    Article  CAS  PubMed  Google Scholar 

  7. Chuffa LG, Lupi-Junior LA, Costa AB, Amorim JP, Seiva FR (2017) The role of sex hormones and steroid receptors on female reproductive cancers. Steroids 118:93–108. https://doi.org/10.1016/j.steroids.2016.12.011

    Article  CAS  PubMed  Google Scholar 

  8. Oishi S (2001) Effects of butylparaben on the male reproductive system in rats. Toxicol Ind Health 17:31–39. https://doi.org/10.1191/0748233701th093oa

    Article  CAS  PubMed  Google Scholar 

  9. Oishi S (2004) Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food Chem Toxicol 42:1845–1849. https://doi.org/10.1016/j.fct.2004.06.015

    Article  CAS  PubMed  Google Scholar 

  10. Beekhuijzen M, Rijk JCW, Meijer M, de Raaf MA, Pelgrom S (2019) A critical evaluation of thyroid hormone measurements in OECD test guideline studies: is there any added value? Reprod Toxicol 88:56–66. https://doi.org/10.1016/j.reprotox.2019.07.014

    Article  CAS  PubMed  Google Scholar 

  11. Lee HS, Park EJ, Han S, Oh GY, Kim MH, Kang HS, Suh JH, Oh JH, Lee KS, Hwang MS, Moon G, Hong JH, Hwang IG (2016) In vitro OECD test methods applied to screen the estrogenic effect of chemicals, used in Korea. Food Chem Toxicol 95:121–127. https://doi.org/10.1016/j.fct.2016.06.014

    Article  CAS  PubMed  Google Scholar 

  12. OECD (2021) Test No. 455: Performance-based test guideline for stably transfected transactivation in vitro assays to detect estrogen receptor agonists and antagonists. https://doi.org/10.1787/9789264265295-en

  13. Lee SH, Seo H, Seo H, Lazari M, D’Agostino M, Byrd N, Yoon KS, Lee HS, Park Y (2022) An in vitro dimerization assay for the adverse outcome pathway approach in risk assessment of human estrogen receptor alpha-mediated endocrine-disrupting chemicals. Chemosphere 290:133267. https://doi.org/10.1016/j.chemosphere.2021.133267

    Article  CAS  PubMed  Google Scholar 

  14. OECD (2015) Test No. 493: Performance-based test guideline for human recombinant estrogen receptor (hrER) in vitro assays to detect chemicals with ER binding affinity. https://doi.org/10.1787/9789264242623-en

  15. Union P (2009) Regulation (EC) no 1223/2009 of the european parliament and of the council. Off J Eur Union L 342:59

    Google Scholar 

  16. Authority E (2004) Opinion of the scientific panel on food additives, flavourings, processing aids and materials in contact with food (AFC) related to para hydroxybenzoates (E 214–219). EFSA J 2:83. https://doi.org/10.2903/j.efsa.2004.83

    Article  Google Scholar 

  17. Lim S (2020) The associations between personal care products use and urinary concentrations of phthalates, parabens, and triclosan in various age groups: the Korean National Environmental Health Survey cycle 3 2015–2017. Sci Total Environ 742:140640. https://doi.org/10.1016/j.scitotenv.2020.140640

    Article  CAS  PubMed  Google Scholar 

  18. Liao C, Chen L, Kannan K (2013) Occurrence of parabens in foodstuffs from China and its implications for human dietary exposure. Environ Int 57–58:68–74. https://doi.org/10.1016/j.envint.2013.04.001

    Article  CAS  PubMed  Google Scholar 

  19. Ma WL, Zhao X, Lin ZY, Mohammed MO, Zhang ZF, Liu LY, Song WW, Li YF (2016) A survey of parabens in commercial pharmaceuticals from China and its implications for human exposure. Environ Int 95:30–35. https://doi.org/10.1016/j.envint.2016.07.013

    Article  CAS  PubMed  Google Scholar 

  20. Fransway AF, Fransway PJ, Belsito DV, Yiannias JA (2019) Paraben toxicology. Dermatitis 30:32–45. https://doi.org/10.1097/DER.0000000000000428

    Article  CAS  PubMed  Google Scholar 

  21. Nowak K, Jablonska E, Garley M, Iwaniuk A, Radziwon P, Wolczynski S, Ratajczak-Wrona W (2022) Investigation of estrogen-like effects of parabens on human neutrophils. Environ Res 214:113893. https://doi.org/10.1016/j.envres.2022.113893

    Article  CAS  PubMed  Google Scholar 

  22. Prusakiewicz JJ, Harville HM, Zhang Y, Ackermann C, Voorman RL (2007) Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects. Toxicology 232:248–256. https://doi.org/10.1016/j.tox.2007.01.010

    Article  CAS  PubMed  Google Scholar 

  23. Vo TT, Jeung EB (2009) An evaluation of estrogenic activity of parabens using uterine calbindin-d9k gene in an immature rat model. Toxicol Sci 112:68–77. https://doi.org/10.1093/toxsci/kfp176

    Article  CAS  PubMed  Google Scholar 

  24. Aker AM, Watkins DJ, Johns LE, Ferguson KK, Soldin OP, Del Anzalota LV, Alshawabkeh AN, Cordero JF, Meeker JD (2016) Phenols and parabens in relation to reproductive and thyroid hormones in pregnant women. Environ Res 151:30–37. https://doi.org/10.1016/j.envres.2016.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim S, Carson KA, Chien AL (2021) Methyl paraben may increase risk of pruritus in African Americans whereas Triclosan is inversely associated with pruritus and eczema. Dermatitis 32:124–130. https://doi.org/10.1097/DER.0000000000000495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Matwiejczuk N, Galicka A, Zareba I, Brzoska MM (2020) The protective effect of rosmarinic acid against unfavorable influence of methylparaben and propylparaben on collagen in human skin fibroblasts. Nutrients 12:1282. https://doi.org/10.3390/nu12051282

    Article  PubMed  PubMed Central  Google Scholar 

  27. Handa O, Kokura S, Adachi S, Takagi T, Naito Y, Tanigawa T, Yoshida N, Yoshikawa T (2006) Methylparaben potentiates UV-induced damage of skin keratinocytes. Toxicology 227:62–72. https://doi.org/10.1016/j.tox.2006.07.018

    Article  CAS  PubMed  Google Scholar 

  28. Yasar P, Ayaz G, User SD, Gupur G, Muyan M (2017) Molecular mechanism of estrogen-estrogen receptor signaling. Reprod Med Biol 16:4–20. https://doi.org/10.1002/rmb2.12006

    Article  CAS  PubMed  Google Scholar 

  29. Negi A, Kesari KK, Voisin-Chiret AS (2022) Estrogen receptor-alpha targeting: PROTACs, SNIPERs, Peptide-PROTACs, antibody conjugated PROTACs and SNIPERs. Pharmaceutics 14:2523. https://doi.org/10.3390/pharmaceutics14112523

    Article  PubMed  PubMed Central  Google Scholar 

  30. Seo H, Seo H, Lee HY, Lee SH, Park Y (2023) Comprehensive analysis of cellular estrogen signaling in representative estrogen receptor ligands. Chem Biol Interact 369:110303. https://doi.org/10.1016/j.cbi.2022.110303

    Article  CAS  PubMed  Google Scholar 

  31. Borgna JL, Rochefort H (1980) High-affinity binding to the estrogen receptor of [3H]4-hydroxytamoxifen, an active antiestrogen metabolite. Mol Cell Endocrinol 20:71–85. https://doi.org/10.1016/0303-7207(80)90095-7

    Article  CAS  PubMed  Google Scholar 

  32. Katzenellenbogen BS, Katzenellenbogen JA (2000) Estrogen receptor transcription and transactivation: estrogen receptor alpha and estrogen receptor beta: regulation by selective estrogen receptor modulators and importance in breast cancer. Breast Cancer Res 2:335–344. https://doi.org/10.1186/bcr78

    Article  CAS  PubMed  Google Scholar 

  33. 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. https://doi.org/10.1016/s0960-0760(01)00174-1

    Article  CAS  PubMed  Google Scholar 

  34. Watanabe Y, Kojima H, Takeuchi S, Uramaru N, Ohta S, Kitamura S (2013) Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor alpha and beta and androgen receptor. Food Chem Toxicol 57:227–234. https://doi.org/10.1016/j.fct.2013.03.036

    Article  CAS  PubMed  Google Scholar 

  35. 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. https://doi.org/10.1006/taap.1998.8544

    Article  CAS  PubMed  Google Scholar 

  36. Blair RM, Fang H, Branham WS, Hass BS, Dial SL, Moland CL, Tong W, Shi L, Perkins R, Sheehan DM (2000) The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol Sci 54:138–153. https://doi.org/10.1093/toxsci/54.1.138

    Article  CAS  PubMed  Google Scholar 

  37. Guadarrama P, Fomine S, Salcedo R, Martinez A (2008) Construction of simplified models to simulate estrogenic disruptions by esters of 4-hydroxy benzoic acid (parabens). Biophys Chem 137:1–6. https://doi.org/10.1016/j.bpc.2008.06.001

    Article  CAS  PubMed  Google Scholar 

  38. Guo Y, Wang L, Kannan K (2014) Phthalates and parabens in personal care products from China: concentrations and human exposure. Arch Environ Contam Toxicol 66:113–119. https://doi.org/10.1007/s00244-013-9937-x

    Article  CAS  PubMed  Google Scholar 

  39. Kang HS, Kyung MS, Ko A, Park JH, Hwang MS, Kwon JE, Suh JH, Lee HS, Moon GI, Hong JH, Hwang IG (2016) Urinary concentrations of parabens and their association with demographic factors: a population-based cross-sectional study. Environ Res 146:245–251. https://doi.org/10.1016/j.envres.2015.12.032

    Article  CAS  PubMed  Google Scholar 

  40. Calafat AM, Ye X, Wong LY, Bishop AM, Needham LL (2010) Urinary concentrations of four parabens in the U.S. population: NHANES 2005–2006. Environ Health Perspect 118:679–685. https://doi.org/10.1289/ehp.0901560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by “Cooperative Research Program of Center for Companion Animal Research (project no. PJ01398403), Rural Development Administration, Republic of Korea.

Author information

Authors and Affiliations

  1. Department of Food Science and Biotechnology, Gachon University, Seongnam, 13120, Republic of Korea

    Jong-Yeon Kim & Hae‐Jeung Lee

  2. Department of Food Science and Biotechnology, Dongguk University, Goyang, 10326, Republic of Korea

    Yooheon Park & Seok-Hee Lee

  3. Department of Food and Nutrition, Gachon University, Seongnam, Gyeonggi‐do, 13120, Republic of Korea

    Eun‐Jung Park & Hae‐Jeung Lee

  4. Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam, 13120, Republic of Korea

    Eun‐Jung Park & Hae‐Jeung Lee

  5. Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, 21999, Republic of Korea

    Hae‐Jeung Lee

  6. Gachon University Gil Medical Center, Incheon, 21565, Republic of Korea

    Hae‐Jeung Lee

Authors
  1. Jong-Yeon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yooheon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seok-Hee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eun‐Jung Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hae‐Jeung Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Eun‐Jung Park or Hae‐Jeung Lee.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, JY., Park, Y., Lee, SH. et al. Comparative study on estrogen receptor alpha dimerization and transcriptional activity of parabens. Toxicol Res. 40, 153–161 (2024). https://doi.org/10.1007/s43188-023-00212-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43188-023-00212-1

Keywords

Search

Navigation