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Teratogenicity and embryotoxicity of titanocene dichloride in mice
Abstract:
The teratogenic and embryotoxic effects of the antitumor agent titanocene dichloride (TDC) were investigated after application of single doses of TDC (30 or 60 mg/kg) to pregnant mice on days 8, 10, 12, 14 or 16 of gestation. The fetuses were removed on day 18 by caesarian section and examined for external, internal and skeletal malformations as well as for toxic phenomena. The most striking result was the occurrence of cleft palate in numerous fetuses (10% of the fetuses, 30 mg/kg; 40-50%, 60 mg/kg) after TDC application on days 10 and 12. Besides the additional appearance of costal malformations in some fetuses, no other malformations were recognizable. On the other hand, the embryotoxic influence of TDC was significant and caused diminution of the number of live fetuses per litter, marked and dose-dependent reduction of mean fetal body weight after TDC application on day 8 through day 16 and distinct retardation of skeletal ossification.
Insights
Titanocene dichloride (TDC) causes significant birth defects, including cleft palate, in mouse fetuses when administered during critical developmental periods. This antitumor agent also exhibits embryotoxic effects, reducing live fetuses and fetal weight.
Area of Science:
- Toxicology
- Developmental Biology
- Pharmacology
Background:
- Titanocene dichloride (TDC) is an antitumor agent with potential applications in cancer therapy.
- Understanding the developmental toxicity of therapeutic agents is crucial for risk assessment during pregnancy.
Purpose of the Study:
- To investigate the teratogenic and embryotoxic effects of titanocene dichloride (TDC) in a mouse model.
- To determine the impact of TDC administration on fetal development at different gestational stages.
Main Methods:
- Pregnant mice received single doses of TDC (30 or 60 mg/kg) on specific days of gestation (8, 10, 12, 14, or 16).
- Fetuses were examined on day 18 for external, internal, and skeletal malformations, as well as toxic effects.
- Evaluated parameters included malformation incidence, litter size, fetal body weight, and skeletal ossification.
Main Results:
- TDC administration on days 10 and 12 of gestation resulted in a high incidence of cleft palate (10-50% depending on dose).
- Costal malformations were observed in some fetuses, but no other major malformations were noted.
- Significant embryotoxic effects included reduced litter size, dose-dependent fetal weight reduction, and delayed skeletal ossification.
Conclusions:
- Titanocene dichloride (TDC) is a potent teratogen, particularly affecting palate development when given during mid-gestation.
- TDC exhibits significant embryotoxicity, impacting fetal growth and skeletal development.
- These findings highlight the risks associated with TDC exposure during pregnancy and necessitate careful consideration in therapeutic use.