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Significance of AHR nuclear translocation sequence in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cPLA 2 α activation and hydronephrosis.

Authors :
Fujisawa N
Yoshioka W
Yanagisawa H
Tohyama C
Source :
Archives of toxicology [Arch Toxicol] 2019 May; Vol. 93 (5), pp. 1255-1264. Date of Electronic Publication: 2019 Feb 21.
Publication Year :
2019

Abstract

The aryl hydrocarbon receptor (AHR) plays a major role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity phenotypes. TCDD bound to AHR elicits both genomic action in which target genes are transcriptionally upregulated and nongenomic action in which cytosolic phospholipase A <subscript>2</subscript> α (cPLA <subscript>2</subscript> α) is rapidly activated. However, how either of these actions, separately or in combination, induces toxicity phenotypes is largely unknown. In this study, we used AHR <superscript>nls/nls</superscript> mice as a model in which AHR was mutated to lack nuclear translocation sequence (NLS), and AHR <superscript>d/-</superscript> mice as the corresponding control. Using this model, we studied TCDD-induced alterations in cPLA <subscript>2</subscript> α activation and related factors because of the pivotal roles of cPLA <subscript>2</subscript> α both in AHR's nongenomic action and in regulation of causative genes of TCDD-induced hydronephrosis. Dams were orally administered TCDD at a dose of 300 µg/kg body weight on postnatal day 1, and pups subsequently exposed to TCDD via milk were examined for gene expression on PND 7 and for histological changes on PND 14. The activation of the AHR genomic action and hydronephrosis onset were observed in the control group but not in the AHR <superscript>nls/nls</superscript> group. An ex vivo experiment using peritoneal macrophages exposed to 100 nM TCDD resulted in rapid activation of cPLA <subscript>2</subscript> α, an indicator of the nongenomic action, only in the control group but not in the AHR <superscript>nls/nls</superscript> group. These results indicated that an NLS is required for the AHR's genomic and nongenomic actions.

Details

Language :
English
ISSN :
1432-0738
Volume :
93
Issue :
5
Database :
MEDLINE
Journal :
Archives of toxicology
Publication Type :
Academic Journal
Accession number :
30790002
Full Text :
https://doi.org/10.1007/s00204-019-02414-9