Compound selection for in vitro modeling of developmental neurotoxicity

Area of Science:

• Toxicology
• Neuroscience
• Stem Cell Biology

Background:

• In vitro systems for developmental neurotoxicity (DNT) assessment require carefully selected test compounds.
• Existing methods need refinement for accurate prediction of DNT.
• Embryonic stem cell differentiation models are increasingly used but rely on appropriate controls.

Purpose of the Study:

• To provide a framework for selecting adequate test and training compounds for in vitro DNT models.
• To introduce the concept of toxicity endophenotypes (TEPs) for DNT assessment.
• To guide the scientific and technical aspects of compound selection for reliable DNT testing.

Main Methods:

• Recommending two classes of positive controls: "gold standard compounds" (proven DNT in humans) and "pathway compounds" (disrupting key neuronal differentiation pathways).
• Introducing toxicity endophenotypes (TEPs) to characterize changes in neuronal connectivity.
• Suggesting the inclusion of compounds with unspecific toxicity and negative controls.
• Advocating for tandem approaches to determine relative toxicities.

Main Results:

• TEPs offer a scientific rationale for modeling DNT using in vitro systems.
• Distinguishing between unspecific cytotoxicity and specific DNT is essential.
• A systematic approach to compound selection enhances the reliability of in vitro DNT models.

Conclusions:

• The proposed compound selection strategy, including TEPs and specific control types, improves the scientific validity of in vitro DNT models.
• Careful selection of test compounds is paramount for accurate developmental neurotoxicity assessment.
• This framework aids in avoiding pitfalls and ensuring the specificity of DNT evaluations.