title: Interference by 2,3,7,8-tetrachlorodibenzo-p-dioxin with cultured mouse submandibular gland branching morphogenesis involves reduced epidermal growth factor receptor signaling.
abstract: Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to mouse embryonic teeth, sharing features of early development with salivary glands in common, involves enhanced apoptosis and depends on the expression of epidermal growth factor (EGF) receptor. EGF receptor signaling, on the other hand, is essential for salivary gland branching morphogenesis. To see if TCDD impairs salivary gland morphogenesis and if the impairment is associated with EGF receptor signaling, we cultured mouse (NMRI) E13 submandibular glands with TCDD or TCDD in combination with EGF or fibronectin (FN), both previously found to enhance branching morphogenesis. Explants were examined stereo-microscopically and processed to paraffin sections. TCDD exposure impaired epithelial branching and cleft formation, resulting in enlarged buds. The glands were smaller than normal. EGF and FN alone concentration-dependently stimulated or inhibited branching morphogenesis but when co-administered with TCDD, failed to compensate for its effect. TCDD induced cytochrome P4501A1 expression in the glandular epithelium, indicating activation of the aryl hydrocarbon receptor. TCDD somewhat increased epithelial apoptosis as observed by terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling method but the increase could not be correlated with morphological changes. The frequency of proliferating cells was not altered. Corresponding to the reduced cleft sites in TCDD-exposed explants, FN immunoreactivity in the epithelium was reduced. The results show that TCDD, comparably with EGF and FN at morphogenesis-inhibiting concentrations, impaired salivary gland branching morphogenesis in vitro. Together with the failure of EGF and FN at morphogenesis-stimulating concentrations to compensate for the effect of TCDD this implies that TCDD toxicity to developing salivary gland involves reduced EGF receptor signaling.
authors.affiliation: Department of Pedodontics and Orthodontics, Institute of Dentistry, University of Helsinki, Helsinki, Finland. anummela@mappi.helsinki.fi
authors.forename: Anu
authors.initials: A
authors.lastname: Kiukkonen
authors.forename: Carin
authors.initials: C
authors.lastname: Sahlberg
authors.forename: Anna-Maija
authors.initials: AM
authors.lastname: Partanen
authors.forename: Satu
authors.initials: S
authors.lastname: Alaluusua
authors.forename: Raimo
authors.initials: R
authors.lastname: Pohjanvirta
authors.forename: Jouko
authors.initials: J
authors.lastname: Tuomisto
authors.forename: Pirjo-Liisa
authors.initials: PL
authors.lastname: Lukinmaa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004785:Environmental Pollutants / Q000633:toxicity*; D004790:Enzyme Induction; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005353:Fibronectins / Q000494:pharmacology; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects*; D009924:Organ Culture Techniques; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects*; D013363:Submandibular Gland / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D004338:Drug Combinations; D004785:Environmental Pollutants; D005353:Fibronectins; D000072317:Polychlorinated Dibenzodioxins; D004815:Epidermal Growth Factor; D019363:Cytochrome P-450 CYP1A1; D066246:ErbB Receptors