benzofurans and benz(a)anthracene

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 mug/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 (TAOBP(r)c1 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.

Topics: Amphiregulin; Animals; Benz(a)Anthracenes; Benzo(a)pyrene; Benzofurans; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 CYP1A1; Dose-Response Relationship, Drug; EGF Family of Proteins; Female; Gene Expression Regulation, Developmental; Gestational Age; Glycoproteins; Injections, Intraperitoneal; Intercellular Signaling Peptides and Proteins; Male; Maternal Exposure; Mice; Mice, Inbred C57BL; Polychlorinated Dibenzodioxins; Pregnancy; Receptors, Aryl Hydrocarbon; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Teratogens; Ureter

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), and benz[a]anthracene (BA) highly induce cytochrome P4501A1, determined by aryl hydrocarbon hydroxylase (AHH) activity, in human hepatoma HepG2 cells within 24 h. AHH activity induced by TCDD and TCDF persists for at least 48 h. In contrast, AHH activity induced by BA rapidly declines, although the amounts applied are 4-5 orders of magnitude higher than those of TCDD or TCDF. AHH induction in HepG2 cells differs from that in rat hepatoma cells H4IIEC3/T in two aspects: (1) HepG2 cells are 20 times less sensitive to the test compounds than H4IIEC3/T cells. (2) TCDF-induced AHH activity does not persist in the rat cells. The results suggest that human HepG2 cells, because of their low sensitivity, are inferior to rat H4IIEC3/T cells for determining TCDD equivalents in environmental samples. They may be useful for investigating species dependent differences in the toxicokinetics of individual polyhalogenated aromatic hydrocarbon congeners.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Benz(a)Anthracenes; Benzofurans; Biological Assay; Carcinoma, Hepatocellular; Cytochrome P-450 CYP1A1; Environmental Pollutants; Humans; Liver Neoplasms; Polychlorinated Dibenzodioxins; Rats; Tumor Cells, Cultured