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Auto-induction mechanism of aryl hydrocarbon receptor 2 (AHR2) gene by TCDD-activated AHR1 and AHR2 in the red seabream (Pagrus major)

  • Molecular Toxicology
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Abstract

The toxic effects of dioxins and related compounds (DRCs) are mediated by the aryl hydrocarbon receptor (AHR). Our previous study identified AHR1 and AHR2 genes from the red seabream (Pagrus major). Moreover, we found that AHR2 mRNA levels were notably elevated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in the early life stage of red seabream embryos, while AHR1 mRNA level was not altered. In this study, to investigate the regulatory mechanism of these AHR transcripts, we cloned and characterized 5′-flanking regions of AHR1 and AHR2 genes. Both of the 5′-flanking regions in these AHR genes contained three potential xenobiotic-responsive elements (XREs). To assess whether the 5′-flanking region is transactivated by rsAHR1 and rsAHR2 proteins, we measured the transactivation potency of the luciferase reporter plasmids containing the 5′-flanking regions by AHR1 and AHR2 proteins that were transiently co-expressed in COS-7. Only reporter plasmid (pGL4-rsAHR2-3XREs) that contained three putative XRE sites in the 5′-flanking region of AHR2 gene showed a clear TCDD dose-dependent transactivation by AHR1 and AHR2 proteins. TCDD-EC50 values for the rsAHR2-derived XRE transactivation were 1.3 and 1.4 nM for AHR1 and AHR2, respectively. These results suggest that the putative XREs of AHR2 gene have a function for AHR1- and AHR2-mediated transactivation, supporting our in ovo observation of an induction of AHR2 mRNA levels by TCDD exposure. Mutations in XREs of AHR2 gene led to a decrease in luciferase induction. Electrophoretic mobility shift assay showed that XRE1, the closest XRE from the start codon in AHR2 gene, is mainly responsible for the binding with TCDD-activated AHR. This suggests that TCDD-activated AHR1 and AHR2 up-regulate the AHR2 mRNA levels and this auto-induced AHR2 may amplify the signal transduction of its downstream targets including CYP1A in the red seabream.

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology to E.-Y. Kim. (2013R1A1A2A10010043, 2012K2A2A4021504). This study was also supported by Grants-in-Aid for Scientific Research (S) (26220103) from Japan Society of the Promotion of Science (JSPS). This research was supported in part by a grant (to MSD) from the National Institute of Environmental Health Sciences (R01ES07685) and the California Agricultural Experiment Station.

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  1. Department of Life and Nanopharmaceutical Science, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Korea

    Su-Min Bak & Eun-Young Kim

  2. Department of Biology, Kyung Hee University, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Korea

    Su-Min Bak & Eun-Young Kim

  3. Laboratory of Environmental Toxicology, Center for Marine Environmental Studies, Ehime University, Bunkyo-cho 2-5, Matsuyama, 790-8577, Japan

    Midori Iida & Hisato Iwata

  4. Department of Environmental Toxicology, University of California, Davis, CA, 95616, USA

    Anatoly A. Soshilov & Michael S. Denison

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  1. Su-Min Bak
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Bak, SM., Iida, M., Soshilov, A.A. et al. Auto-induction mechanism of aryl hydrocarbon receptor 2 (AHR2) gene by TCDD-activated AHR1 and AHR2 in the red seabream (Pagrus major). Arch Toxicol 91, 301–312 (2017). https://doi.org/10.1007/s00204-016-1732-9

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