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  • Title: One-way inhibiting cross-talk between arylhydrocarbon receptor (AhR) and estrogen receptor (ER) signaling in primary cultures of rainbow trout hepatocytes.
    Author: Gräns J, Wassmur B, Celander MC.
    Journal: Aquat Toxicol; 2010 Nov 01; 100(3):263-70. PubMed ID: 20739074.
    Abstract:
    The aryl hydrocarbon receptor (AhR) and the estrogen receptor (ER) are ligand-activated transcription factors, both of which can be activated by environmental pollutants. The AhR regulates cytochrome P450 1A (CYP1A) expression and can be induced by aromatic hydrocarbons. The ER regulates vitellogenin (VTG) expression and can be induced by estrogenic substances. Both receptor responses are established biomarkers used to assess the effects of pollutants in the aquatic environment. The receptors can also be affected in situations of mixed exposure. Cross-talk between these receptor pathways has been suggested, although there are conflicting data in the literature. We investigated cross-talk between ER-VTG and AhR-CYP1A signaling pathways in primary cultures of rainbow trout hepatocytes, using quantitative PCR (qPCR) for mRNA analyses and studies of CYP1A catalytic function and protein expression. The model agonists β-naphthoflavone (BNF) and 17α-ethinylestradiol (EE(2)) were used for AhR and ER activation, respectively. Combined exposure to BNF and EE(2) reduced the EE(2)-mediated induction of VTG mRNA levels by about 40%, but had no effect on the BNF-mediated CYP1A mRNA levels, indicative of a one-way inhibiting AhR-ER cross-talk. However, basal levels of CYP1A mRNA were reduced 40% upon exposure to EE(2) alone, implying different cross-talk mechanism between basal and induced CYP1A mRNA levels. The mammalian ER antagonist fulvestrant (ICI) is commonly described as an absolute ER antagonist. However, ICI failed to reverse the ER activation caused by EE(2) in the present study. The CYP1A-mediated ethoxyresorufin-O-deethylase (EROD) activity was reduced by 80% in cells co-treated with BNF and EE(2), compared to cells exposed to BNF alone. In vitro inhibiting studies suggests that this reduction was a result of inhibition of the CYP1A catalyst by EE(2) since EE(2) acted as a potent inhibitor (IC(50): 4.6μM) of the EROD activity. In addition, ICI also acted as a potent inhibitor of the EROD enzyme (IC(50): 0.6μM). Taken together, our data supports a one-way inhibiting AhR-ER cross-talk in rainbow trout hepatocytes exposed to a mixture of BNF and EE(2).
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