Toxicogenomics Data for Chemical Safety Assessment : From Intrinsic Characteristics to Functional Potential

Research output: Book/ReportDoctoral thesisCollection of Articles

Abstract

The modern world surrounds us with a vast sea of chemicals of which a large majority remains uncharted in terms of their potential hazard for human health and the environment. At the same time, the rapid introduction of new chemicals necessitates a delicate balance between innovation and safety, presenting one of the key challenges of the 21st century.

Chemical safety assessment has been long focused on resource-intensive and ethically challenged animal experiments. Furthermore, the traditional approach focuses on phenotypic endpoints, providing limited insight into toxicity mechanisms which impedes the development of chemicals that are safe and sustainable by design (SSbD). Despite major efforts to advance in vitro and in silico alternatives for chemical safety assessment, the first generation of these non-animal approaches present similar challenges as their in vivo counterparts. This has resulted in major initiatives to shift the focus towards mechanistic toxicology, enabling a deeper understanding of chemical hazards. This mechanistic approach is fuelled by the introduction of adverse outcome pathways (AOPs) and toxicogenomics, offering unprecedented insights into the molecular underpinnings of chemical-induced toxicity. While the value of this mechanistic venture is broadly recognised, toxicogenomics-based evidence is not systematically integrated into chemical safety assessment.

Hence, the foundational premise of this dissertation lies in the recognition of the multifaceted challenges that surround the utilisation of toxicogenomics data in chemical safety assessment. These challenges were characterised through three critical aspects of toxicogenomics data: its intrinsic characteristics, functional properties, and translational potential. The intrinsic characteristics, defined as the FAIRness (Findability, Accessibility, Interoperability and Reusability) and quality of data, were investigated, and addressed through systematic data curation and annotation. This enabled a comprehensive review of the current state of toxicogenomics data, resulting in a resource with improved FAIRness and a robust foundation for subsequent analytical endeavours. Similarly, this effort established a systematic link between toxicogenomics-based evidence and the AOP framework, empowering the functional properties of both data types.

Innovative methodologies and approaches to data analysis form the cornerstone of the functional properties of data, aiming at the extraction of meaningful insights from complex, high-dimensional toxicogenomics datasets. By harnessing advanced computational techniques and the link established between AOPs and toxicogenomics, this dissertation further sought to distinguish subtle molecular signatures and discern the intricate interplay between chemicals and biological systems. This was exemplified by a model of a dynamic dose-dependent mechanism of action that revealed crucial mechanisms related known long-term adverse effects of multi-walled carbon nanotube exposure in a short-term in vitro exposure.

Finally, a pivotal facet of this research lies in the translation of toxicogenomics- derived evidence into biologically meaningful events that are comprehensible to a broader audience. Bridging the gap between raw data and actionable insights, this dissertation endeavored to provide a tangible link between molecular alterations and their potential implications for human health through the translation of toxicogenomics-based evidence into mechanistic new approach methodologies (NAMs). This dissertation highlighted how the intrinsic characteristics and functional properties of toxicogenomics data enable its translational potential, resulting in the AOP fingerprint and in vitro biomarkers for the evaluation of profibrotic potential of chemicals.

Ultimately, the results of this research have the potential to propel the field of chemical safety assessment forward by elucidating the intrinsic characteristics, functional properties, and translational potential of toxicogenomics data. By synergistically employing data curation, advanced analytical methodologies, and translational approaches, this dissertation endeavours to enhance the applicability of toxicogenomics in the broader context of chemical safety evaluation, thus contributing to the safeguarding of public health and the environment.
Original languageEnglish
Place of PublicationTampere
ISBN (Electronic)978-952-03-3387-4
Publication statusPublished - 2024
Publication typeG5 Doctoral dissertation (articles)

Publication series

NameTampere University Dissertations - Tampereen yliopiston väitöskirjat
Volume999
ISSN (Print)2489-9860
ISSN (Electronic)2490-0028

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