Estrogen receptor-dependent and independent roles of benzo[a]pyrene in Ishikawa cells

in Journal of Endocrinology
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  • 1 Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Philadelphia, Philadelphia, Pennsylvania, USA
  • 2 Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Philadelphia, Philadelphia, Pennsylvania, USA

Correspondence should be addressed to T M Penning: penning@upenn.edu
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Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants generated from the incomplete combustion of organic material. PAHs have been studied as genotoxicants, but some also act via non-genotoxic mechanisms in estrogen-dependent malignancies, such as breast cancer. PAHs require metabolic activation to electrophilic metabolites to exert their genotoxicity but non-genotoxic properties may also contribute to their carcinogenicity. The role of PAHs in endometrial cancer, a cancer associated with unopposed estrogen action is unknown. We assessed the metabolism of the representative PAH, benzo[a]pyrene (B[a]P), to estrogenic compounds in Ishikawa human endometrial cells in the presence and absence of cytochrome P450 induction. Using stable-isotope dilution high-performance liquid chromatography and APCI tandem mass spectrometry in the selected reaction monitoring mode, we analyzed B[a]P metabolism in Ishikawa cells. Estrogenic activity of B[a]P metabolites was determined by the endogenous estrogen inducible alkaline phosphatase reporter gene and an exogenous estrogen response element (ERE) luciferase reporter gene construct. We also assessed whether PAHs can induce a proliferative phenotype via estrogen receptor (ER)- and non-ER-regulated pathways. We demonstrate that B[a]P can be metabolized in human endometrial cells into 3-OH-B[a]P and B[a]P-7,8-dione in sufficient amounts to activate ERs. We also show that only B[a]P-7,8-dione induces endometrial cell proliferation at concentrations lower than required to activate the ER; instead non-genomic signaling by the EGF receptor (EGFR) and activation of the mitogen-activated protein kinase (MAPK) pathway was responsible. This work indicates that human endometrial cells can metabolize PAHs into estrogenic metabolites, which may induce cell proliferation through non-ER-regulated pathways.

 

      Society for Endocrinology

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  • Abdelrahim M, Ariazi E, Kim K, Khan S, Barhoumi R, Burghardt R, Liu SX, Hill D, Finnell R, Wlodarczyk B, et al. 2006 3-Methylcholanthrene and other aryl hydrocarbon receptor agonists directly activate estrogen receptor alpha. Cancer Research 66 24592467. (https://doi.org/10.1158/0008-5472.CAN-05-3132)

    • Search Google Scholar
    • Export Citation
  • Andrysik Z, Vondracek J, Machala M, Krcmar P, Svihalkova-Sindlerova L, Kranz A, Weiss C, Faust D, Kozubik A & Dietrich C 2007 The aryl hydrocarbon receptor-dependent deregulation of cell cycle control induced by polycyclic aromatic hydrocarbons in rat liver epithelial cells. Mutation Research 615 8797. (https://doi.org/10.1016/j.mrfmmm.2006.10.004)

    • Search Google Scholar
    • Export Citation
  • Arcaro KF, O’Keefe PW, Yang Y, Clayton W & Gierthy JF 1999 Antiestrogenicity of environmental polycyclic aromatic hydrocarbons in human breast cancer cells. Toxicology 133 115127. (https://doi.org/10.1016/s0300-483x(99)00018-9)

    • Search Google Scholar
    • Export Citation
  • Armstrong B, Hutchinson E, Unwin J & Fletcher T 2004 Lung cancer risk after exposure to polycyclic aromatic hydrocarbons: a review and meta-analysis. Environmental Health Perspectives 112 97097 8. (https://doi.org/10.1289/ehp.6895)

    • Search Google Scholar
    • Export Citation
  • Borek-Dohalska L, Klusonova Z, Holecova J, Martinkova M, Barta F, Dracinska H, Cajthaml T & Stiborova M 2016 Exposure of rats to exogenous endocrine disruptors 17alpha-ethinylestradiol and benzo(a) pyrene and an estrogenic hormone estradiol induces expression of cytochromes P450 involved in their metabolism. Neuro Endocrinology Letters 37 8494.

    • Search Google Scholar
    • Export Citation
  • Brandenberger AW, Lebovic DI, Tee MK, Ryan IP, Tseng JF, Jaffe RB & Taylor RN 1999 Oestrogen receptor (ER)-α and ER-β isoforms in normal endometrial and endometriosis-derived stromal cells. Molecular Human Reproduction 5 651655. (https://doi.org/10.1093/molehr/5.7.651)

    • Search Google Scholar
    • Export Citation
  • Burczynski ME, Lin HK & Penning TM 1999 Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (AOHs), electrophiles & oxidative stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase. Cancer Research 59 607614.

    • Search Google Scholar
    • Export Citation
  • Burdick AD, Davis JW, Liu KJ, Hudson LG, Shi H, Monske ML & Burchiel SW 2003 Benzo(a)pyrene quinones increase cell proliferation, generate reactive oxygen species, and transactivate the epidermal growth factor receptor in breast epithelial cells. Cancer Research 63 782578 33.

    • Search Google Scholar
    • Export Citation
  • Charles GD, Bartels MJ, Zacharewski TR, Gollapudi BB, Freshour NL & Carney EW 2000 Activity of benzo[a]pyrene and its hydroxylated metabolites in an estrogen receptor-alpha reporter gene assay. Toxicological Sciences 55 320326. (https://doi.org/10.1093/toxsci/55.2.320)

    • Search Google Scholar
    • Export Citation
  • Fertuck KC, Kumar S, Sikka HC, Matthews jb & Zacharewski TR 2001 Interaction of PAH-related compounds with the alpha and beta isoforms of the estrogen receptor. Toxicology Letters 121 167177. (https://doi.org/10.1016/s0378-4274(01)00344-7)

    • Search Google Scholar
    • Export Citation
  • Furuya Y, Kohno N, Fujiwara Y & Saitoh Y 1989 Mechanisms of estrogen action on the proliferation of MCF-7 human breast cancer cells in an improved culture medium. Cancer Research 49 6670667 4.

    • Search Google Scholar
    • Export Citation
  • Fussell KC, Udasin RG, Smith PJ, Gallo MA & Laskin JD 2011 Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells. Carcinogenesis 32 128512 93. (https://doi.org/10.1093/carcin/bgr109)

    • Search Google Scholar
    • Export Citation
  • Gammon MD, Santella RM, Neugut AI, Eng SM, Teitelbaum SL, Paykin A, Levin B, Terry MB, Young TL, Wang LW, et al. 2002 Environmental toxins and breast cancer on Long Island. I. Polycyclic aromatic hydrocarbon DNA adducts. Cancer Epidemiology, Biomarkers and Prevention 11 6776 85.

    • Search Google Scholar
    • Export Citation
  • Gozgit JM, Nestor KM, Fasco MJ, Pentecost BT & Arcaro KF 2004 Differential action of polycyclic aromatic hydrocarbons on endogenous estrogen-responsive genes and on a transfected estrogen-responsive reporter in MCF-7 cells. Toxicology and Applied Pharmacology 196 5867. (https://doi.org/10.1016/j.taap.2003.12.003)

    • Search Google Scholar
    • Export Citation
  • Hayakawa K, Bekki K, Yoshita M, Tachikawa C, Kameda T, Tang N, Toriba A & Hosoi S 2011 Estrogenic/antiestrogenic activities of quinoid polycyclic aromatic hydrocarbons. Journal of Health Science 57 274280. (https://doi.org/10.1248/jhs.57.274)

    • Search Google Scholar
    • Export Citation
  • Hirose T, Morito K, Kizu R, Toriba A, Hayakawa K, Ogawa S, Inoue S, Muramatsu M & Masamune Y 2001 Estrogenic/antiestrogenic activities of benzo[a]pyrene monohydroxy derivatives. Journal of Health Science 47 552558. (https://doi.org/10.1248/jhs.47.552)

    • Search Google Scholar
    • Export Citation
  • Huang CY, Chen CA, Chen YL, Chiang CJ, Hsu TH, Lin MC, Lai MS, Chen CJ, You SL & Cheng WF 2012 Nationwide surveillance in uterine cancer: survival analysis and the importance of birth cohort: 30-year population-based registry in Taiwan. PLoS ONE 7 e51372. (https://doi.org/10.1371/journal.pone.0051372)

    • Search Google Scholar
    • Export Citation
  • Iannaccone PM, Fahl WE & Stols L 1984 Reproductive toxicity associated with endometrial cell mediated metabolism of benzo[a]pyrene: a combined in vitro, in vivo approach. Carcinogenesis 5 143714 42. (https://doi.org/10.1093/carcin/5.11.1437)

    • Search Google Scholar
    • Export Citation
  • Koeber R, Niessner R & Bayona JM 1997 Comparison of liquid chromatography-mass spectrometry interfaces for the analysis of polar metabolites of benz[a]pyrene. Fresenius’ Journal of Analytical Chemistry 359 267273. (https://doi.org/10.1007/s002160050571)

    • Search Google Scholar
    • Export Citation
  • Korsh J, Shen A, Aliano K & Davenport T 2015 Polycyclic aromatic hydrocarbons and breast cancer: a review of the literature. Breast Care 10 31631 8. (https://doi.org/10.1159/000436956)

    • Search Google Scholar
    • Export Citation
  • Kriek E, Van schooten FJ, Hillebrand MJ, Van Leeuwen FE, Den Engelse L, De Looff AJ & Dijkmans AP 1993 DNA adducts as a measure of lung cancer risk in humans exposed to polycyclic aromatic hydrocarbons. Environmental Health Perspectives 99 7175. (https://doi.org/10.1289/ehp.939971)

    • Search Google Scholar
    • Export Citation
  • Kummer V, Maskova J, Zraly Z, Neca J, Simeckova P, Vondracek J & Machala M 2008 Estrogenic activity of environmental polycyclic aromatic hydrocarbons in uterus of immature Wistar rats. Toxicology Letters 180 212221. (https://doi.org/10.1016/j.toxlet.2008.06.862)

    • Search Google Scholar
    • Export Citation
  • Lam MM, Engwall M, Denison MS & Larsson M 2018 Methylated polycyclic aromatic hydrocarbons and/or their metabolites are important contributors to the overall estrogenic activity of polycyclic aromatic hydrocarbon-contaminated soils. Environmental Toxicology and Chemistry 37 385397. (https://doi.org/10.1002/etc.3958)

    • Search Google Scholar
    • Export Citation
  • Liao XH, Lu DL, Wang N, Liu LY, Wang Y, Li YQ, Yan TB, Sun XG, Hu P & Zhang TC 2014 Estrogen receptor alpha mediates proliferation of breast cancer MCF-7 cells via a p21/PCNA/E2F1-dependent pathway. FEBS Journal 281 9279 42. (https://doi.org/10.1111/febs.12658)

    • Search Google Scholar
    • Export Citation
  • Littlefield BA, Gurpide E, Markiewicz L, Mckinley B & Hochberg RB 1990 A simple and sensitive microtiter plate estrogen bioassay based on stimulation of alkaline phosphatase in Ishikawa cells: estrogenic action of delta 5 adrenal steroids. Endocrinology 127 275727 62. (https://doi.org/10.1210/endo-127-6-2757)

    • Search Google Scholar
    • Export Citation
  • Lu D, Harvey RG, Blair IA & Penning TM 2011 Quantitation of benzo[a]pyrene metabolic profiles in human bronchoalveolar (H358) cells by stable isotope dilution liquid chromatography-atmospheric pressure chemical ionization mass spectrometry. Chemical Research in Toxicology 24 19051 91 4. (https://doi.org/10.1021/tx2002614)

    • Search Google Scholar
    • Export Citation
  • Morris JJ & Seifter E 1992 The role of aromatic hydrocarbons in the genesis of breast cancer. Medical Hypotheses 38 1771 84. (https://doi.org/10.1016/0306-9877(92)90090-y)

    • Search Google Scholar
    • Export Citation
  • Penning TM 2014 Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons. Chemical Research in Toxicology 27 19011917. (https://doi.org/10.1021/tx500298n)

    • Search Google Scholar
    • Export Citation
  • Plagens-Rotman K, Zak E & Pieta B 2016 Odds ratio analysis in women with endometrial cancer. Przeglad Menopauzalny 15 121 9. (https://doi.org/10.5114/pm.2016.58767)

    • Search Google Scholar
    • Export Citation
  • Plíšková M, Vondracek J, Vojtesek B, Kozubik A & Machala M 2005 Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events. Toxicological Sciences 83 246256. (https://doi.org/10.1093/toxsci/kfi040)

    • Search Google Scholar
    • Export Citation
  • Poland A, Grover E & Kende AS 1976 Stereospecific, high affinity binding of 2,3,7.8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. Journal of Biological Chemistry 251 49364 94 6.

    • Search Google Scholar
    • Export Citation
  • Ran C, Xu D, Dai Q, Penning TM, Blair IA & Harvey RG 2008 Synthesis of (13)C2-benzo[a]pyrene and its 7,8-dihydrodiol and 7,8-dione implicated as carcinogenic metabolites. Tetrahedron Letters 49 45314533. (https://doi.org/10.1016/j.tetlet.2008.05.033)

    • Search Google Scholar
    • Export Citation
  • Rempel MA, Hester B, Deharo H, Hong H, Wang Y & Schlenk D 2009 Effects of 17beta-estradiol, and its metabolite, 4-hydroxyestradiol on fertilization, embryo development and oxidative DNA damage in sand dollar (Dendraster excentricus) sperm. Science of the Total Environment 407 220922 15. (https://doi.org/10.1016/j.scitotenv.2008.12.054)

    • Search Google Scholar
    • Export Citation
  • Rodriguez AC, Blanchard Z, Maurer KA & Gertz J 2019 Estrogen signaling in endometrial cancer: a key oncogenic pathway with several open questions. Hormones and Cancer 10 5163. (https://doi.org/10.1007/s12672-019-0358-9)

    • Search Google Scholar
    • Export Citation
  • Rodríguez-Fragoso L, Melendez K, Hudson LG, Lauer FT & Burchiel SW 2009 EGF-receptor phosphorylation and downstream signaling are activated by benzo[a]pyrene 3,6-quinone and benzo[a]pyrene 1,6-quinone in human mammary epithelial cells. Toxicology and Applied Pharmacology 235 321328. (https://doi.org/10.1016/j.taap.2008.12.022)

    • Search Google Scholar
    • Export Citation
  • Rundle A, Tang D, Hibshoosh H, Estabrook A, Schnabel F, Cao W, Grumet S & Perera FP 2000 The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer. Carcinogenesis 21 1281128 9. (https://doi.org/10.1093/carcin/21.7.1281)

    • Search Google Scholar
    • Export Citation
  • Rutledge FN 1976 ARS presidential address: estrogen therapy: a causal role in endometrial cancer? American Journal of Roentgenology 127 89789 9. (https://doi.org/10.2214/ajr.127.6.897)

    • Search Google Scholar
    • Export Citation
  • Sanderson JT, Slobbe L, Lansbergen GW, Safe S & Van den Berg M 2001 2,3,7,8-Tetrachlorodibenzo-p-dioxin and diindolylmethanes differentially induce cytochrome P450 1A1, 1B1, and 19 in H295R human adrenocortical carcinoma cells. Toxicological Sciences 61 404 8. (https://doi.org/10.1093/toxsci/61.1.40)

    • Search Google Scholar
    • Export Citation
  • Santodonato J 1997 Review of the estrogenic and antiestrogenic activity of polycyclic aromatic hydrocarbons: relationship to carcinogenicity. Chemosphere 34 835848. (https://doi.org/10.1016/s0045-6535(97)00012-x)

    • Search Google Scholar
    • Export Citation
  • Schaufler K, Haslmayer P, Jager W, Pec M & Thalhammer T 2002 The environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin induces cytochrome P450 activity in high passage PC 3 and DU 145 human prostate cancer cell lines. International Journal of Molecular Medicine 9 41141 6. (https://doi.org/10.3892/ijmm.9.4.411)

    • Search Google Scholar
    • Export Citation
  • Shen J, Liao Y, Hopper JL, Goldberg M, Santella RM & terry MB 2017 Dependence of cancer risk from environmental exposures on underlying genetic susceptibility: an illustration with polycyclic aromatic hydrocarbons and breast cancer. British Journal of Cancer 116 12291233. (https://doi.org/10.1038/bjc.2017.81)

    • Search Google Scholar
    • Export Citation
  • Shimada T & Fujii-Kuriyama Y 2004 Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and 1B1. Cancer Science 95 16. (https://doi.org/10.1111/j.1349-7006.2004.tb03162.x)

    • Search Google Scholar
    • Export Citation
  • Siegel RL, Miller KD & Jemal A 2019 Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 69 734. (https://doi.org/10.3322/caac.21551)

    • Search Google Scholar
    • Export Citation
  • Sjogren M, Ehrenberg L & Rannug U 1996 Relevance of different biological assays in assessing initiating and promoting properties of polycyclic aromatic hydrocarbons with respect to carcinogenic potency. Mutation Research 358 97112. (https://doi.org/10.1016/0027-5107(96)00175-3)

    • Search Google Scholar
    • Export Citation
  • Song MK, Park YK & Ryu JC 2013 Polycyclic aromatic hydrocarbon (PAH)-mediated upregulation of hepatic microRNA-181 family promotes cancer cell migration by targeting MAPK phosphatase-5, regulating the activation of p38 MAPK. Toxicology and Applied Pharmacology 273 13013 9. (https://doi.org/10.1016/j.taap.2013.08.016)

    • Search Google Scholar
    • Export Citation
  • Soto am & Sonnenschein C 1985 The role of estrogens on the proliferation of human breast tumor cells (MCF-7). Journal of Steroid Biochemistry 23 8794. (https://doi.org/10.1016/0022-4731(85)90265-1)

    • Search Google Scholar
    • Export Citation
  • Tu BB, Lin SL, Yan LY, Wang ZY, Sun QY & Qiao J 2011 ER-alpha36, a novel variant of estrogen receptor alpha, is involved in EGFR-related carcinogenesis in endometrial cancer. American Journal of Obstetrics and Gynecology 205 227.e1227.e 6. (https://doi.org/10.1016/j.ajog.2011.04.015)

    • Search Google Scholar
    • Export Citation
  • Wang Z, Wijewickrama GT, Peng KW, Dietz BM, Yuan L, Van Breemen RB, Bolton JL & Thatcher GR 2009 Estrogen receptor {alpha} enhances the rate of oxidative DNA damage by targeting an equine estrogen catechol metabolite to the nucleus. Journal of Biological Chemistry 284 863386 42. (https://doi.org/10.1074/jbc.M807860200)

    • Search Google Scholar
    • Export Citation
  • Wang Z, Chandrasena ER, Yuan Y, Peng KW, van Breemen RB, Thatcher GR & Bolton JL 2010 Redox cycling of catechol estrogens generating apurinic/apyrimidinic sites and 8-oxo-deoxyguanosine via reactive oxygen species differentiates equine and human estrogens. Chemical Research in Toxicology 23 136513 73. (https://doi.org/10.1021/tx1001282)

    • Search Google Scholar
    • Export Citation
  • Weng MS, Chang JH, Hung WY, Yang YC & Chien MH 2018 The interplay of reactive oxygen species and the epidermal growth factor receptor in tumor progression and drug resistance. Journal of Experimental and Clinical Cancer Research 37 61. (https://doi.org/10.1186/s13046-018-0728-0)

    • Search Google Scholar
    • Export Citation
  • Zhou L, Cai B, Bao W, He YY, Chen XY, Yang YX, Liu XL & Wan XP 2011 Crosstalk between estrogen receptor and mitogen-activated protein kinase signaling in the development and progression of endometrial cancer. International Journal of Gynecological Cancer 21 135713 65. (https://doi.org/10.1097/IGC.0b013e3182216ac9)

    • Search Google Scholar
    • Export Citation