Significance of AHR nuclear translocation sequence in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cPLA2α activation and hydronephrosis

• Published in: Archives of toxicology 2019-05, Vol.93 (5), p.1255-1264
• Main Authors: Fujisawa, Nozomi, Yoshioka, Wataru, Yanagisawa, Hiroyuki, Tohyama, Chiharu
• Format: Article
• Language: English
• Subjects: Aromatic compounds; Biomedical and Life Sciences; Biomedicine; Body weight; Cell activation; Dioxins; Environmental Health; Gene expression; Gene regulation; Genes; Macrophages; Mice; Molecular Toxicology; Nuclear transport; Occupational Medicine/Industrial Medicine; Oral administration; Peritoneum; Pharmacology/Toxicology; Phenotypes; Phospholipase; Phospholipase A2; TCDD; Toxicity; Transcription; Translocation
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-019-02414-9

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 2 α (cPLA 2 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 nls/nls mice as a model in which AHR was mutated to lack nuclear translocation sequence (NLS), and AHR d/− mice as the corresponding control. Using this model, we studied TCDD-induced alterations in cPLA 2 α activation and related factors because of the pivotal roles of cPLA 2 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 nls/nls group. An ex vivo experiment using peritoneal macrophages exposed to 100 nM TCDD resulted in rapid activation of cPLA 2 α, an indicator of the nongenomic action, only in the control group but not in the AHR nls/nls group. These results indicated that an NLS is required for the AHR’s genomic and nongenomic actions.