Mechanism of TCDD-induced oxidative stress, role of estrogen receptor, and modulation by estradiol in liver cells - École Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation ENSBANA Access content directly
Conference Papers Year : 2008

Mechanism of TCDD-induced oxidative stress, role of estrogen receptor, and modulation by estradiol in liver cells

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic member of a large family of halogenated aromatic hydrocarbons present as contaminants in food, mother’s milk and environmental samples. TCDD was classified as a group I 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 rats. There is good evidence for a role of estrogens in the mechanism of TCDD-induced hepatocarcinogenesis in the rat. Estrogens may act as genotoxic procarcinogens. Particularly, the 17ȕ-estradiol (E2) catechol metabolite 4-hydroxyestradiol formed mainly by CYP1B1 can undergo redox cycling and thus generate DNA damaging reactive oxygen species (ROS). As previously seen, induction of CYPs by TCDD led to increased formation of ROS and increased DNA levels of 8-oxo-2’-deoxyguanosine (8-oxo-dG) in rat H4IIE hepatoma cells and in rat primary hepatocytes but not in human HepG2 hepatoma cells. E2 alone increased ROS formation only in hepatocytes while the combination with TCDD had no additive effect. Real-time RT PCR analysis revealed that TCDD induced CYP1B1 mRNA level to a slightly higher extent in rat hepatocytes than in hepatoma cells, while E2 had no clear effect. Since estrogen receptor alpha (ER)Į mRNA was present in hepatocytes but not in hepatoma cells, it can be speculated that the presence of ERĮ may be responsible for the elevated ROS formation after E2 treatment.

Domains

Pharmacology
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Dates and versions

hal-03426732 , version 1 (15-11-2021)

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  • HAL Id : hal-03426732 , version 1

Cite

Manuela Göttel, Marie-Christine Chagnon, Dieter Schrenk. Mechanism of TCDD-induced oxidative stress, role of estrogen receptor, and modulation by estradiol in liver cells. 49. Annual Meeting of the German-Society-for-Experimental-and-Clinical-Pharmacology-and-Toxicology, Mar 2008, Mainz, Germany. pp.88. ⟨hal-03426732⟩

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