An in vitro pipeline for investigating species differences in developmental neurotoxicity

When evaluating performance of human in vitro models, they are regularly compared to rodent in vivo data, still considered the “gold standard” in most communities.

Discrepancies are often interpreted as failure of the in vitro model to mimic the in vivo situation, whereas they could instead be due to species differences, which would make the human in vitro model superior to the rodent in vivo situation.

One way to distinguish between species versus model differences is to parallel experiments in comparable rodent and human in vitro models. This is, however, hardly ever done.

The aim of this project is to establish an in vitro pipeline that allows for systematic comparison of chemical impacts on neural differentiation between human and rodent.

The pipeline will be validated by measuring endpoints which we have previously shown to be differentially affected by chemical exposure in rodent in vivo and human epidemiological data.

Further, we will employ the pipeline to predict human relevance of chemically-induced epigenetic changes in rat, and validate these predictions in human data.

By introducing the “missing link” for comparison between human in vitro and rodent in vivo data, this project will serve as proof-of-concept of how the strengths and limitations of human in vitro versus rodent in vivo models can be better demonstrated.

Ultimately, this will lead to increased confidence and thus broader use of in vitro models to replace in vivo studies, in toxicology and beyond.