A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis
Ruoxing Yu1, Norio Miyamura1, Yoshimi Okamoto-Uchida1
1Department of Developmental and Regenerative Biology, Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan.
Abstract:
Mammalian fetal development is easily disrupted by exogenous agents, making it essential to test new drug candidates for embryotoxicity and teratogenicity. To standardize the testing of drugs that might be used to treat pregnant women, the U.S. Food and Drug Administration (FDA) formulated special grade categories, labeled A, B, C, D and X, that define the level of risk associated with the use of a specific drug during pregnancy. Drugs in categories (Cat.) D and X are those with embryotoxic and/or teratogenic effects on humans and animals. However, which stages of pregnancy are affected by these agents and their molecular mechanisms are unknown. We describe here an embryonic stem cell test (EST) that classifies FDA pregnancy Cat.D and Cat.X drugs into 4 classes based on their differing effects on primitive streak formation. We show that ~84% of Cat.D and Cat.X drugs target this period of embryogenesis. Our results demonstrate that our modified EST can identify how a drug affects early embryogenesis, when it acts, and its molecular mechanism. Our test may thus be a useful addition to the drug safety testing armamentarium.
Insights
A new embryonic stem cell test (EST) effectively classifies high-risk pregnancy drugs (Categories D and X) based on their effects on primitive streak formation, a key stage in early embryogenesis.
Area of Science:
- Developmental biology
- Toxicology
- Pharmacology
Background:
- Mammalian fetal development is vulnerable to exogenous agents, necessitating rigorous testing for drug-induced embryotoxicity and teratogenicity.
- The U.S. Food and Drug Administration (FDA) categorizes drug risks during pregnancy (A, B, C, D, X), with Categories D and X indicating known embryotoxic/teratogenic effects.
- The specific developmental stages and molecular mechanisms affected by Category D and X drugs remain largely uncharacterized.
Purpose of the Study:
- To develop and validate an embryonic stem cell test (EST) for classifying FDA pregnancy Category D and X drugs.
- To determine the impact of these drugs on primitive streak formation, a critical early embryonic event.
- To elucidate the timing and molecular mechanisms underlying drug-induced embryotoxicity.
Main Methods:
- Utilized a modified embryonic stem cell test (EST) to assess the effects of FDA Category D and X drugs.
- Classified drugs into four distinct groups based on their observed impact on primitive streak formation.
- Analyzed the stage-specific effects and potential molecular mechanisms of drug action during early embryogenesis.
Main Results:
- The modified EST successfully classified FDA pregnancy Category D and X drugs into four distinct effect classes.
- ~84% of tested Category D and X drugs were found to target the primitive streak formation stage of embryogenesis.
- The EST provided insights into the timing and molecular mechanisms by which these drugs affect early development.
Conclusions:
- The developed EST is a valuable tool for assessing drug effects on early mammalian embryogenesis.
- This assay can identify critical developmental windows targeted by embryotoxic and teratogenic drugs.
- The modified EST offers a standardized method to enhance drug safety evaluations for pregnant women.
