A mouse strain less responsive to dioxin-induced prostaglandin E2 synthesis is resistant to the onset of neonatal hydronephrosis.

Abstract

Dioxin is a ubiquitous environmental pollutant that induces toxicity when bound to the aryl hydrocarbon receptor (AhR). Significant differences in susceptibility of mouse strains to dioxin toxicity are largely accounted for by the dissociation constant of binding to dioxins of AhR subtypes encoded by different alleles. We showed that cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), components of a prostanoid synthesis pathway, play essential roles in the onset of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hydronephrosis of neonatal mice. Although C57BL/6J and BALB/cA mice harbor AhR receptors highly responsive to TCDD, they were found by chance to differ significantly in the incidence of TCDD-induced hydronephrosis. Therefore, the goal of the present study was to determine the molecular basis of this difference in susceptibility to TCDD toxicity. For this purpose, we administered C57BL/6J and BALB/cA dams' TCDD at an oral dose of 15 or 80 μg/kg on postnatal day (PND) 1 to expose pups to TCDD via lactation, and the pups' kidneys were collected on PND 7. The incidence of hydronephrosis in C57BL/6J pups (64%) was greater than in BALB/cA pups (0%, p < 0.05), despite similarly increased levels of COX-2 mRNA. The incidence of hydronephrosis in these mouse strains paralleled the levels of renal mPGES-1 mRNA and early growth response 1 (Egr-1) that modulates mPGES-1 gene expression, as well as PGE2 concentrations in urine. Although these mouse strains possess AhR alleles tightly bound to TCDD, their difference in incidence and severity of hydronephrosis can be explained, in part, by differences in the expression of mPGES-1 and Egr-1.

• Authors: Keiko Aida-Yasuoka, Wataru Yoshioka, Tatsuya Kawaguchi, Seiichiroh Ohsako, Chiharu Tohyama
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 141 Issue 2 Pg. 465-74 (Oct 2014) ISSN: 1096-0929 [Electronic] United States
• PMID: 25015655 (Publication Type: Comparative Study, Journal Article)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Ahr protein, mouse
• Basic Helix-Loop-Helix Transcription Factors
• Early Growth Response Protein 1
• Egr1 protein, mouse
• Polychlorinated Dibenzodioxins
• RNA, Messenger
• Receptors, Aryl Hydrocarbon
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Intramolecular Oxidoreductases
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Dinoprostone

Topics

• Animals
• Animals, Newborn
• Basic Helix-Loop-Helix Transcription Factors (agonists, metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Dinoprostone (biosynthesis)
• Dose-Response Relationship, Drug
• Early Growth Response Protein 1 (genetics, metabolism)
• Female
• Gene Expression Regulation, Enzymologic (drug effects)
• Hydronephrosis (chemically induced, genetics, metabolism, pathology)
• Intramolecular Oxidoreductases (genetics, metabolism)
• Kidney (drug effects, metabolism, pathology)
• Lactation
• Maternal Exposure
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Polychlorinated Dibenzodioxins (toxicity)
• Prostaglandin-E Synthases
• RNA, Messenger (metabolism)
• Receptors, Aryl Hydrocarbon (agonists, metabolism)
• Severity of Illness Index
• Species Specificity
• Time Factors