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Use of cultured cells in the identification of potential teratogens
Abstract:
An agent can be teratogenic either if it preferentially affects specific differentiating cell types or if it acts on all cells, differentiating cells being particularly vulnerable. The general effect is more easily revealed because it also causes cell death or growth inhibition, phenomena that can be measured in cell cultures. The concentration that an administered teratogen reaches in the embryo can be measured in rodents. Such biologic results as well as measurements of physicochemical constants (partition coefficients, pK values), uptake rates, cell surface binding constants, and the inhibition of specific biochemical reactions can be correlated with each other, thereby enabling one to predict the potential teratogenicity of a new compound. The probability with which such a prediction is valid for humans (and the price of the investigation) increases with the use of physical, chemical, biochemical, and cellular test systems, and is highest if the gestating mammal is used. For the evaluation of large numbers of compounds, such a tier approach seems necessary. Measurements on the effects of lipophilic acids are mentioned in more detail.
Insights
Predicting teratogenicity involves understanding how agents affect differentiating cells. A tiered testing approach, from biochemical assays to whole animal studies, improves prediction accuracy for new compounds.
Area of Science:
- Toxicology
- Developmental Biology
- Pharmacology
Background:
- Teratogenic agents can act specifically on differentiating cells or broadly, with differentiating cells being particularly vulnerable.
- General teratogenic effects, such as cell death or growth inhibition, are more readily detectable and measurable in cell cultures.
Purpose of the Study:
- To outline a tiered approach for predicting the teratogenicity of new chemical compounds.
- To correlate various biological and physicochemical measurements for improved teratogenicity prediction.
Main Methods:
- Measuring teratogen concentration in rodent embryos.
- Assessing physicochemical properties (partition coefficients, pK values) and biochemical reactions.
- Utilizing cell cultures and whole gestating mammal models in a tiered testing strategy.
Main Results:
- Correlations between biologic results and physicochemical/biochemical measurements can predict teratogenicity.
- The accuracy of human teratogenicity prediction increases with the complexity of the test system, culminating in gestating mammal studies.
Conclusions:
- A tiered approach integrating physical, chemical, biochemical, and cellular tests is necessary for evaluating large numbers of compounds.
- The use of gestating mammals provides the highest probability of accurate prediction for human teratogenicity.