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The toxicity of niridazole in rat embryos in vitro
Abstract:
The antischistosomal drug niridazole (NDZ) was found to be teratogenic in a concentration-dependent manner from 10 to 50 micrograms/ml (47-233 microM) in rat embryos cultured from day 10 to day 11. A striking malformation consisting of axial asymmetry in which the right side of the embryo showed severe necrosis was the predominant malformation. The drug showed significantly greater dysmorphogenic activity at low (5%) compared to high (20%) oxygen tensions in cultures. Coincubation of embryos and NDZ with an exogenous source of metabolic enzymes and cofactors (NADPH) failed to modify teratogenicity. Inclusion of CO in the culture atmosphere significantly reduced the malformation incidence as did preincubation of the drug with S-9 and cofactors in medium with low O2 tension. Treatment of gravida with NDZ up to and including the maternal-lethal dose failed to result in observable malformations despite the use of several routes of exposure. These data lead us to hypothesize that rat embryos are capable of performing the reductive activation of NDZ in a fashion analogous to the schistosome but that reductive extraembryonic metabolism may result in teratogenic bioinactivation.
Insights
The antischistosomal drug niridazole (NDZ) is teratogenic in rat embryos, causing severe malformations. Embryonic metabolism appears responsible for this toxicity, as maternal exposure did not yield similar results.
Area of Science:
- Developmental toxicology
- Pharmacology
- Embryology
Background:
- Niridazole (NDZ) is an antischistosomal drug.
- Teratogenicity of NDZ in mammalian embryos is not fully understood.
Purpose of the Study:
- To investigate the teratogenic potential of niridazole in rat embryos.
- To explore the role of embryonic metabolism in NDZ-induced teratogenicity.
Main Methods:
- Rat embryos (day 10-11) were cultured in vitro with varying concentrations of NDZ.
- Embryo development and malformations were assessed.
- Effects of different oxygen tensions and metabolic cofactors were examined.
- In vivo studies involved maternal exposure to NDZ.
Main Results:
- NDZ induced teratogenicity in a concentration-dependent manner (10-50 µg/ml).
- Predominant malformation was axial asymmetry with severe necrosis.
- Teratogenic activity was higher under low oxygen (5%) compared to high oxygen (20%).
- Carbon monoxide and S-9 mix reduced malformations, suggesting a reductive activation mechanism.
- Maternal treatment with NDZ did not result in observable fetal malformations.
Conclusions:
- Rat embryos can metabolically activate NDZ, leading to teratogenicity.
- Extraembryonic reductive metabolism may be responsible for NDZ's teratogenic effects.
- Embryonic metabolism differs from maternal metabolism regarding NDZ activation and toxicity.