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Integrated Omic Analyses Identify Pathways and Transcriptomic Regulators Associated With Chemical Alterations of In
Carmen A Marable1,2, Christopher L Frank1, Roland F Seim3,4
1Rapid Assay Development Branch, Biomolecular and Computational Toxicology Division, Center for Computational Toxicology and Exposure, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Summary
New methods reveal molecular changes underlying chemical-induced developmental neurotoxicity (DNT). This study integrates gene and metabolite data to identify pathways and regulators, enhancing DNT hazard assessment.
Area of Science:
- Toxicology
- Neuroscience
- Computational Biology
Background:
- In vitro new approach methodologies (NAMs) are crucial for developmental neurotoxicity (DNT) hazard assessment of numerous chemicals.
- Existing DNT assays, like network formation, lack mechanistic insights into observed toxicity.
- Understanding molecular pathways is essential for robust DNT risk assessment and the development of adverse outcome pathways (AOPs).
Purpose of the Study:
- To investigate the nervous system signaling pathways and upstream regulators involved in chemically induced neural network dysfunction.
- To integrate transcriptomic and metabolomic data for a mechanistic understanding of DNT.
- To explore how different chemical classes impact neural network function at a molecular level.
Main Methods:
- Primary rat cortical neural networks were cultured on microelectrode arrays and exposed to six known DNT chemicals for 12 days in vitro.
- Gene expression profiling (RNA-seq) and metabolomic analysis (GC/MS) were performed on exposed neural networks and media.
- Ingenuity Pathway Analysis (IPA) was used to integrate transcriptomic and metabolomic data and identify affected pathways and upstream regulators.
Main Results:
- All six tested chemicals altered gene expression linked to developmental disorders and neurological diseases.
- Specific chemical classes showed overlapping pathway enrichments, such as cytosine arabinoside and 5-fluorouracil impacting axonal guidance pathways.
- Integrated analysis revealed heterogeneous upstream regulators, including CREB1, SOX2, NOTCH1, and PRODH, across different compounds.
Conclusions:
- Chemical-induced changes in neural network formation are associated with significant transcriptomic and metabolomic alterations.
- Different classes of neurotoxicants elicit distinct molecular responses, providing class-specific mechanistic information.
- This integrated multi-omics approach enhances NAMs, aiding in the identification and development of DNT-related adverse outcome pathways.
