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Updated: Aug 24, 2026
Long-term Behavioral and Reproductive Consequences of Embryonic Exposure to Low-dose Toxicants
Published on: March 6, 2018
Effects of epidermal growth factor receptor deficiency and 2,3,7,8-tetrachlorodibenzo-p-dioxin on fetal development
Hanna M Miettinen1, Hannele Huuskonen, Anna-Maija Partanen
1Laboratory of Toxicology, Department of Environmental Health, National Public Health Institute, P.O. Box 95, FIN-70701 Kuopio, Finland. hanna.miettinen@ktl.fi
Abstract:
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.
Insights
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes birth defects in mice. Epidermal growth factor receptor (EGFR) is not essential for TCDD-induced cleft palate or hydronephrosis, but influences eye opening.
Area of Science:
- Environmental toxicology
- Developmental biology
- Teratology
Background:
- Dioxins, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are persistent environmental contaminants known to induce teratogenesis in laboratory animals.
- The aryl hydrocarbon receptor (AHR) is the primary mediator of TCDD's toxic effects.
- Epidermal growth factor receptor (EGFR) signaling has been implicated as a potential modulator of TCDD-induced developmental disorders.
Purpose of the Study:
- To investigate the role of epidermal growth factor receptor (EGFR) in mediating the teratogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
- To determine if EGFR signaling is essential for TCDD-induced cleft palate and hydronephrosis in mice.
Main Methods:
- Exposure of pregnant heterozygous EGFR(+/-)-mice to varying doses of TCDD on gestation day 10.
- Evaluation of fetuses on gestation day 18 for malformations, including cleft palate, hydronephrosis, and open eyes.
- Comparison of malformation frequencies across different EGFR genotypes (wild-type, heterozygous, and homozygous null).
Main Results:
- No significant differences in susceptibility to TCDD-induced cleft palate or hydronephrosis were observed among the three EGFR genotypes.
- A dose-dependent decrease in the frequency of the open eye malformation was noted in EGFR(-/-)-mice exposed to TCDD.
- TCDD exposure appeared to counteract the effects of EGFR deficiency on eye opening.
Conclusions:
- Epidermal growth factor receptor (EGFR) signaling is not a critical pathway for the development of TCDD-induced cleft palate or hydronephrosis.
- EGFR plays a role in TCDD's effects on eye development, as TCDD can mitigate the consequences of EGFR deficiency on eye opening.
