Epidermal growth factor receptor as a mediator of developmental toxicity of dioxin in mouse embryonic teeth.
We have previously shown that dioxins at prevailing levels in mothers' milk may cause mineralization defects in the developing teeth of their children. Developmental dental defects have also been reported in rhesus macaques and rats experimentally exposed to dioxin. The most toxic dioxin congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is a potent modulator of epithelial cell growth and differentiation. To clarify whether epidermal growth factor receptor (EGFR), implicated in the mediation of the developmental toxicity of TCDD, is involved in dental toxicity, we cultured embryonic molar teeth from EGFR-deficient mice with TCDD, epidermal growth factor (EGF), and both agents in combination. In teeth of the normal embryos, TCDD caused depolarization of odontoblasts and ameloblasts. Consequently, the dentin matrix failed to undergo mineralization, the enamel matrix was not deposited, and cuspal morphology was disrupted. In teeth of the null mutant embryos, only the cuspal contour was mildly modified. EGF alone retarded the molar tooth development of normal embryos, but not that of EGFR-deficient embryos. When coadministered with TCDD, EGF for the most part prevented the adverse effects of TCDD on teeth of the normal embryos. These results show that the interference of TCDD with mouse molar tooth development in vitro involves EGFR signaling. Thus, EGFR may also play a role in the developmental defects that dioxins cause in human teeth. Because EGFR is widely expressed in developing organs, EGFR signaling may even be of general relevance in the mediation of the developmental toxicity of TCDD.
Partanen
A M
AM
Department of Pedodontics and Orthodontics, Institute of Dentistry, University of Helsinki, Finland.
Alaluusua
S
S
Miettinen
P J
PJ
Thesleff
I
I
Tuomisto
J
J
Pohjanvirta
R
R
Lukinmaa
P L
PL
D000818:Animals; D002648:Child; D005314:Embryonic and Fetal Development; D066246:ErbB Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006720:Homozygote; D006801:Humans; D008334:Mandible; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects; D009805:Odontogenesis / Q000187:drug effects*; D009924:Organ Culture Techniques; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D012016:Reference Values; D012867:Skin / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D013363:Submandibular Gland / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D014083:Tooth Germ / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D014738:Vibrissae / Q000187:drug effects / Q000196:embryology / Q000473:pathology
D000072317:Polychlorinated Dibenzodioxins; D066246:ErbB Receptors