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Cited by 1,307Estrogen and related hormone effectsEffects and risks of endocrine disrupting chemicalsPhytoestrogen effects and research

Phenol red in tissue culture media is a weak estrogen: implications concerning the study of estrogen-responsive cells in culture.

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Berthois, Y, Katzenellenbogen, J A, Katzenellenbogen, B S·1986·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.83.8.2496PMC PMC323325
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Abstract

Although much attention has been paid to the removal of hormones from sera and to the development of serum-free media for studies on hormone-responsive cells in culture, little consideration has been given to the possibility that the media components themselves may have hormonal activity. We have found that phenol red, which bears a structural resemblance to some nonsteroidal estrogens and which is used ubiquitously as a pH indicator in tissue culture media, has significant estrogenic activity at the concentrations (15-45 microM) at which it is found in tissue culture media. Phenol red binds to the estrogen receptor of MCF-7 human breast cancer cells with an affinity 0.001% that of estradiol (Kd = 2 X 10(-5) M). It stimulates the proliferation of estrogen receptor-positive MCF-7 breast cancer cells in a dose-dependent manner but has no effect on the growth of estrogen receptor-negative MDA-MB-231 breast cancer cells. At the concentrations present in tissue culture media, phenol red causes partial estrogenic stimulation, increasing cell number to 200% and progesterone receptor content to 300% of that found for cells grown in phenol red-free media, thereby reducing the degree to which exogenous estrogen is able to stimulate responses. The antiestrogens tamoxifen and hydroxytamoxifen inhibit cell proliferation below the control level only when cells are grown in the presence of phenol red; in the absence of phenol red, the antiestrogens do not suppress growth. The estrogenic activity of phenol red should be considered in any studies that utilize estrogen-responsive cells in culture.

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  • Estrogen receptors are found on most cell types and exposure of male cells to estrogenic media (e.g., phenol red) can lead to estrogen-receptor-dependent influences on cell proliferation, differentiation, and metabolism.

    “Estrogen receptors are found on most cell types and exposure of male cells to estrogenic media (e.g. phenol red structurally resembles some nonsteroidal estrogens) can lead to estrogen-receptor-dependent influences on cell proliferation, differentiation, and metabolism (Berthois et al., 1986; Farzaneh and Zarghi, 2016).”

    From In Vitro research Reproducibility: Keeping up High Standards (2019) · cites this paper as Berthois et al., 1986

    The Results and Discussion report that phenol red is estrogenic and stimulates proliferation in estrogen-receptor-positive MCF-7 cells, but not in receptor-negative MDA-MB-231 cells. The paper does not establish that estrogen receptors occur on most cell types, nor does its evidence about breast cancer cell lines establish effects in male cells or on differentiation and metabolism. (LLM, conf=0.88)

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  • pH indicators may affect the phenotype and functionality of specific cell types and may interfere with downstream assay readouts; phenol red is known to have some endocrine disrupting effects.

    “On the other hand, pH indicators may affect the phenotype and functionality of specific cell types and may interfere with downstream assay readouts, e.g., phenol red is known to have some endocrine disrupting effects (Berthois et al., 1986).”

    From Guidance document on Good cell and tissue culture practice 2.0 (GCCP 2.0) (2021) · cites this paper as Berthois et al., 1986

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Research works printed but not linked: 4

  1. [2]Sirbasku, D. A. & Leland, F. E. (1982) in Biochemical Actions of Hormones, ed. Litwack, G. (Academic, New York), Vol. 9, pp. 115-140.
  2. [18]Reiner, G. C. A., Nardulli, A., Norman, M. J., Mangel, W. F. & Katzenellenbogen, B. S. (1984) Proc. Am. Assoc. Cancer Res. 75, abstr. 806, p. 204.
  3. [27]Brown, A. M. C., Jeltsch, J. M., Robert, M. & Chambon, P. (1984) Proc. Natl. Acad. Sci. USA 81, 6344–6348.
  4. [30]Faye, J. C., Jozan, S., Redeuilh, G., Baulieu, E. E. & Bayard, F. (1983) Proc. Natl. Acad. Sci. USA 80, 3158–3162.

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Authors
Berthois, Y., Katzenellenbogen, J. A., & Katzenellenbogen, B. S.
Affiliations
University of Illinois Urbana-Champaign (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
1986-04
Volume
83
Issue
8
Pages
2496-2500
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.83.8.2496
PMC
PMC323325
OpenAlex
W2059153388
Cited by
1,307
References
0
Citations by year
2026: 31 · 2025: 27 · 2024: 25 · 2023: 41 · 2022: 18 · 2021: 27 · 2020: 20 · 2019: 23 · 2018: 26 · 2017: 23 · 2016: 39 · 2015: 31 · 2014: 25 · 2013: 33 · 2012: 36
FWCI
46.30
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01am015556-15, 5RO1 CA)
  • National Cancer Institute (R01CA018119)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Phytoestrogen effects and research
Keywords
phenol red, tissue culture media, estrogenic activity, estrogen receptor binding, MCF-7 cells, breast cancer cell proliferation, progesterone receptor, tamoxifen, 4-hydroxytamoxifen
MeSH terms
Binding, Competitive, Breast Neoplasms, Cell Cycle, Cell Line, Culture Media, Dose-Response Relationship, Drug, Humans, Phenolphthaleins, Phenolsulfonphthalein, Receptors, Estrogen, Receptors, Progesterone, Tamoxifen

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