In vitro model identifies chemicals that can cause neurodevelopmental disorders

Every day we are exposed to thousands of synthetically produced chemicals. They exist in our food, clothing, furniture and, not least, our drugs. Although many of these chemicals can cause neurodevelopmental disorders, few are tested enough to tell for sure. However, we do know that the human brain is most sensitive to external disturbance during its developmental phase – from the fetal stage to late adolescence – when damage can become permanent. Therefore, there is a great need for effective methods to determine the developmental neurotoxicity effects of chemicals on the central nervous system, and in a new PhD thesis at Uppsala University, Kimia Hosseini introduces an in vitro model that has already paved the way for several important findings.

“Currently, researchers and regulatory authorities are referred to animal-based approaches to assess how chemicals affect the human central nervous system. These are cost-ineffective, ethically challenging and of limited biological relevance considering species-specific differences. We have built this model on human embryonic stem cells that we matured into neuron cells, thereby enabling controlled studies of human brain development under the influence of chemicals,” says Kimia Hosseini.

In her thesis, Kimia reports on utilizing her in vitro model to study the effects of three antidepressant drugs in the SSRI class that are regularly prescribed to women of childbearing age. The results indicate that two of the three – Fluoxetine and Paroxetine – inhibit the development of neuronal cells, which points towards developmental neurotoxicity properties. Similar observations are described in a study of cholesterol-lowering drugs Atorvastatin and Rosuvastatin, that both tend to inhibit the development of neuronal cells.

“Since these drugs can be prescribed to pregnant women, the risk is obvious that they can cause neurodevelopmental disorders in the fetus. Our results suggest that the substances may be linked to, among other things, autism, which has already aroused great interest at scientific conferences in both Europe and the USA. Above all, my thesis confirm that this model system provides a more effective, ethical and biologically relevant alternative to animal studies, which is of value to both research and regulatory.”

The in vitro model is easy to reproduce and applicable to any form, dose and concentration of drugs and toxic chemicals. In the current version, the cells were grown in a two-dimensional culture, which offers ease of handling, compatibility with high-throughput and detailed and reproducible assessments of induced effects on neuronal development. Today the research team is discussing the possibilities to implement a three-dimensional culture, which would to an even greater extent reflect the actual conditions in a human brain.

“Incorporating a 3D culture into this model could enable the detection of a wider range of findings, so this is definitely on our radar. After my dissertation 17 October, we will overview the possibility to further elevate our results, and if conditions are right, it would definitely be interesting to engage in opening additional doors to a validated method to map the developmental neurotoxicity properties of chemicals without any need for animal studies,” says Kimia Hosseini

Text & photo: Magnus Alsne