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Effects of estradiol on TCDD-induced oxidative stress in hepatoma cells

Abstract : 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was classified as a human carcinogen by the International Agency for Research on Cancer (IARC). Its effects are mediated by the arylhydrocarbon receptor (AhR) that regulates transcription of target genes including cytochromes P450 (CYP) 1A1, 1A2 and 1B1. TCDD acts as a liver carcinogen in female but, to a much lower extent, in male Sprague–Dawley rats. There is good evidence for a role of estrogens in the mechanism of TCDD-induced hepatocarcinogenesis in the rat. Previous studies have shown that TCDD treatment leads to an estrogen-dependent formation of 8-oxo-2′-deoxyguanosine (8-oxo-dG) in female rat liver DNA. It has been postulated that estrogens can act as genotoxic procarcinogens. Particularly, the 17-β-estradiol (E2) catechol metabolite 4-hydroxyestradiol formed by CYPs, can undergo redox cycling and thus generate DNA damaging reactive oxygen species (ROS) and the corresponding quinone may cause DNA damage. We have shown that induction of CYPs by TCDD (1 nM) was able to increase ROS formation in rodent but not in human HepG2 hepatoma cells. Co-incubation of TCDD with E2 (100 nM) did not markedly enhance TCDD-induced ROS formation measured using the 2′,7′-dihydrodichlorofluorescein diacetate (H2DCFDA) fluorescence assay. In addition, real-time RT-PCR analysis following treatment of TCDD and E2 in HepG2 and rat H4IIE hepatoma cells will provide further information on CYP1A1 and CYP1B1 mRNA expression. Utilizing the single-cell gel electrophoresis (Comet) assay we observed no increase in DNA strand breaks in HepG2 and H4IIE cells exposed to TCDD (up to 100 nM) or E2 (1–100 nM) for 20 and 48 h.
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Manuela Goettel, Isabelle Séverin, Marie-Christine Chagnon, Dieter Schrenk. Effects of estradiol on TCDD-induced oxidative stress in hepatoma cells. Toxicology Letters, Elsevier, 2007, 172 (1, Supplément), pp.S229-S230. ⟨10.1016/j.toxlet.2007.05.578⟩. ⟨hal-01981974⟩



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