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Cited by 87Estrogen and related hormone effectsPharmacogenetics and Drug MetabolismEffects and risks of endocrine disrupting chemicals

Diluted Mainstream Cigarette Smoke Condensates Activate Estrogen Receptor and Aryl Hydrocarbon Receptor-Mediated Gene Transcription

Meek, Murray D., Finch, Gregory L.·1999·Environmental Research
DOI 10.1006/enrs.1998.3872
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Abstract

Background Epidemiological data indicate that in females cigarette smoking exerts antiestrogenic effects that manifest clinically in an increased incidence of osteoporosis, earlier menopause, increased spot bleeding, and decreased risk of endometrial cancer for female smokers. The molecular mechanism of this effect is unclear; however, decreased serum estrogen levels in female smokers have been correlated with increased concentrations of the metabolite 2-hydroxyestrogen in females who smoke. Induction of estrogen metabolizing enzymes, CYP1A1 and 1A2, is one mechanism by which increased 2-hydroxyestrogen concentrations may occur. It has also been suggested that the estrogen receptor (ER) may contribute to this anti-estrogenic effect by binding to antagonist(s) in cigarette smoke.Methods Gel retardation analysis was employed to determine if diluted mainstream cigarette smoke condensates (DMCSCs) could activate the aryl hydrocarbon receptor (AhR). AhR-regulated ethoxyresorufin-O-deethylase (EROD) activity and dioxin response element (DRE)-mediated luciferase induction were assessed in Hepa1c1c7 mouse hepatoma cells. A competitive ligand binding assay was utilized to determine if DMCSCs could bind to the ER. ER-dependent luciferase activity was assessed in MCF-7 cells.Results In gel retardation assays, DMCSCs induced a protein-DNA complex when incubated with a radiolabeled wild-type DRE oligonucleotide. The complex was effectively competed by excess unlabeled DRE but not by excess unlabeled mutant DRE. In Hepa1c1c7 mouse hepatoma cells transiently transfected with a DRE-regulated luciferase reporter gene, pGudluc1.1, treatment with DMCSCs resulted in a 23- and 25-fold increase in luciferase activity (P<0.01) and an 8.5- and 10.5-fold (P<0.01) induction in EROD activity, respectively. DMCSCs completely displaced bound tritiated E2 from the ER in a dose-dependent manner and induced ER-regulated luciferase activity significantly 6-fold (P<0.01), representing 86% of the maximal induction observed with E2.Conclusions DMCSCs can bind to and transcriptionally activate the AhR and ER nuclear receptors and cause induction of DRE- and ER-regulated genes. Further study is required to identify the specific compound(s) responsible for these activities.

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  • Another proposed effect of smoking is 2-hydroxylation of estradiol, resulting in 2-hydroxyestrogens that have minimal estrogenic activity and are immediately removed from circulation.

    “Another proposed effect of smoking is the 2-hydroxylation of estradiol, resulting in 2-hydroxyestrogens, which have minimal estrogenic activity and which are immediately removed from circulation [39].”

    From Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic (2021) · cites this paper as [39]

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Authors
Meek, M. D., & Finch, G. L.
Affiliations
  • Western University (CA)
  • Lovelace Respiratory Research Institute (US)
Corresponding author
Meek, Murray D.
Venue
Environmental Research
Publisher
Elsevier BV
Published
1999-01
Volume
80
Issue
1
Pages
9-17
ISSN
0013-9351 (ISSN-L)
DOI
10.1006/enrs.1998.3872
OpenAlex
W2011610137
Cited by
87
References
42
Citations by year
2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 1 · 2020: 3 · 2019: 3 · 2018: 2 · 2017: 7 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 2 · 2012: 5
FWCI
2.11
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Environmental Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
University of California, Los Angeles
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
Keywords
cigarette smoke condensate, aryl hydrocarbon receptor, estrogen receptor, gene transcription, CYP1A1, CYP1A2, dioxin response element, ethoxyresorufin-O-deethylase, antiestrogens, women smokers, osteoporosis
MeSH terms
Animals, Breast Neoplasms, Enzyme Induction, Female, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Experimental, Luciferases, Receptors, Estrogen, Smoking, Tobacco Smoke Pollution, Transcription, Genetic, Tumor Cells, Cultured, Uterus, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Air Pollution, Indoor, Rats, Sprague-Dawley, Receptors, Aryl Hydrocarbon, Cytochrome P-450 CYP1A1, Mice, Rats

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