Qualitative and quantitative concentration-response modelling of gene co-expression networks to unlock hepatotoxic mechanisms for next generation chemical safety assessment

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Steven J. Kunnen, Emma Arnesdotter, Christian Tobias Willenbockel, Mathieu Vinken, Bob van de Water
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Next generation risk assessment of chemicals revolves around the use of mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool to elucidate the mechanisms underlying the adverse effects of xenobiotics. In the present study, two widely used human hepatocyte culture systems, namely primary human hepatocytes (PHH) and human hepatoma HepaRG cells, were exposed to liver toxicants known to induce liver cholestasis, steatosis, or necrosis. Benchmark concentration (BMC) response modelling was applied to transcriptomics gene co-expression networks (modules) to derive BMCs and to gain mechanistic insight into the hepatotoxic effects. BMCs derived by concentration-response modelling of gene co-expression modules recapitulated concentration-response modelling of individual genes. Although PHH and HepaRG cells showed overlap in the genes and modules deregulated by the liver toxicants, PHH demonstrated a higher responsiveness, based on the lower BMCs of co-regulated gene modules. Such BMCs can be used as transcriptomics points of departure (tPOD) for assessing module-associated cellular (stress) pathways/processes. This approach identified clear tPODs of around maximum systemic concentration (Cmax) levels for the tested drugs, while for cosmetics ingredients the BMCs were 10-100-fold higher than the estimated plasma concentrations. This approach could serve next generation risk assessment practice to identify early responsive modules at low BMCs that could be linked to key events in liver adverse outcome pathways. In turn, this can assist in delineating potential hazards of new test chemicals using in vitro systems and be used in a risk assessment where BMCs are paired with chemical exposure assessment.

Plain language summary
Risk assessment of chemicals has traditionally been focused on animal experiments. In contrast, next generation risk assessment uses biological information obtained from experiments in cell culture models without animals to identify potential hazards. Since the liver is the main target organ of toxicity, many liver cell models have been developed and applied for hazard assessment. In this study, two widely used human liver cell models were exposed to liver toxic chemicals. Biological changes in gene expression were measured in a concentration range to identify the concentration at which a biological response started to be perturbed using a mathematical modelling approach. Genes belonging to the same bio­logical process were linked based on co-expression to derive an average concentration for this process. This animal-free approach could be applied to risk assessment by relating the biological response concentrations to the expected human exposure to identify the potential hazard of test chemicals.

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Kunnen, S. J. (2024) “Qualitative and quantitative concentration-response modelling of gene co-expression networks to unlock hepatotoxic mechanisms for next generation chemical safety assessment”, ALTEX - Alternatives to animal experimentation, 41(2), pp. 213–232. doi: 10.14573/altex.2309201.

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