Effects of epidermal growth factor receptor deficiency and 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal development in mice.
Dioxins are persistent environmental contaminants that cause multiple disorders in laboratory animals, including teratogenesis. In mice, the most important teratogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are hydronephrosis and cleft palate. Aryl hydrocarbon receptor (AHR) mediates most of the TCDD-induced effects, but modulation of these effects by other factors such as epidermal growth factor receptor (EGFR) has been propounded. TCDD changes the expression of both EGF and its receptor EGFR, which may be one step in the pathway leading to cleft palate and hydronephrosis. In the present study, the importance of EGFR in TCDD-induced teratogenicity was evaluated. Heterozygous EGFR(+/-)-mice were mated and pregnant females exposed to 1.5-106.0 microg/kg TCDD on gestation day (GD) 10 and killed on GD 18. The fetuses were studied for cleft palate, hydronephrosis, and open eyes. There was no marked difference among the three genotypes in sensitivity to cleft palate or hydronephrosis, but in EGFR(-/-)-mice frequency of the open eye malformation decreased dose-dependently. In conclusion, EGFR signaling is not required for TCDD-induced cleft palate or hydronephrosis but TCDD appears to counteract the effect of EGFR deficiency on eye opening.
Miettinen
Hanna M
HM
Laboratory of Toxicology, Department of Environmental Health, National Public Health Institute, P.O. Box 95, FIN-70701 Kuopio, Finland. hanna.miettinen@ktl.fi
Huuskonen
Hannele
H
Partanen
Anna-Maija
AM
Miettinen
Päivi
P
Tuomisto
Jouni T
JT
Pohjanvirta
Raimo
R
Tuomisto
Jouko
J
D000818:Animals; D002972:Cleft Palate / Q000196:embryology / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000172:deficiency* / Q000235:genetics; D005124:Eye Abnormalities / Q000196:embryology / Q000209:etiology; D005260:Female; D047109:Fetal Development / Q000187:drug effects* / Q000235:genetics; D005838:Genotype; D006869:Hydronephrosis / Q000196:embryology / Q000209:etiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008963:Molar / Q000187:drug effects / Q000196:embryology; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013723:Teratogens / Q000633:toxicity*
D000072317:Polychlorinated Dibenzodioxins; D013723:Teratogens; D066246:ErbB Receptors