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ToxSci Advance Access originally published online on August 23, 2006
Toxicological Sciences 2006 94(1):163-174; doi:10.1093/toxsci/kfl090
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

In Utero Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Amphiregulin Gene Expression in the Developing Mouse Ureter

Sharon SH. Choi*,{dagger}, Margaret A. Miller{dagger} and Patricia A. Harper*,{dagger},1

* Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and {dagger} Program in Developmental Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Received July 21, 2006; accepted August 17, 2006

Exposure to the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), produces hydronephrosis in developing mice, the etiology of which involves hyperplasia within the ureteric luminal epithelium. Dysregulation of epidermal growth factor receptor (EGFR), EGF, and transforming growth factor-{alpha} expression has been implicated as playing a role in TCDD-induced hydronephrosis. In this study, changes in the expression of genes encoding the EGFR and its cognate ligands in response to TCDD were evaluated within the developing ureter. C57BL/6 dams were injected ip with 30 µg/kg TCDD on gestational day (GD) 13 or 16 and fetal tissues removed on GD 17. Aryl hydrocarbon receptor (AHR) and AHR nuclear translocator messenger RNA (mRNA) were expressed in control and treated fetal tissues at GD 14 and 17. Prototypical AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1 were upregulated in TCDD-exposed fetal tissues, demonstrating AHR transcriptional activity at these developmental stages. Amphiregulin (AREG) and epiregulin, ligands for the EGFR, were induced at the transcriptional level in ureters of fetuses exposed to TCDD for 24 h. AREG mRNA was also induced by TCDD dose- and time-dependently in the mouse hepatoma cell line Hepa-1c1c7 (Hepa-1), mimicking the induction patterns of CYP1A1 mRNA. Other AHR ligands also induced AREG mRNA in Hepa-1 cells. Furthermore, variant Hepa-1 cells (TAOBPrc1 cells) virtually deficient in the AHR failed to display an increase in AREG mRNA in response to TCDD. Taken together, these data suggest that the AHR cross talks with the EGFR signaling pathway by directly inducing the expression of growth factors that are important for EGFR signaling in the developing mouse ureter.

Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; aryl hydrocarbon receptor; hydronephrosis; epidermal growth factor receptor; amphiregulin.


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