Systematic comparison of temporal transcriptional responses to hepatotoxicants in primary human hepatocytes and HepaRG cells using concentration-response modelling of gene co-expression networks DOI Creative Commons
Steven J. Kunnen, Emma Arnesdotter,

Christian Tobias Willenbockel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 3, 2023

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

Language: Английский

Qualitative and quantitative concentration-response modelling of gene co-expression networks to unlock hepatotoxic mechanisms for next generation chemical safety assessment_Suppl7 DOI Creative Commons
Steven J. Kunnen, Emma Arnesdotter,

Christian Tobias Willenbockel

et al.

ALTEX, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Next generation risk assessment of chemicals revolves around the use mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool elucidate underlying mechanisms adverse effects xenobiotics. present study, two widely used human in vitro hepatocyte culture systems, namely primary hepatocytes (PHH) and hepatoma HepaRG cells, were exposed liver toxicants known induce cholestasis, steatosis or necrosis. Benchmark concentration-response modelling was applied transcriptomics gene co-expression networks (modules) derive benchmark concentrations (BMCs) gain insight into hepatotoxic effects. BMCs derived by modules recapitulated individual genes. Although PHH cells showed overlap deregulated genes toxicants, demonstrated higher responsiveness, based on lower co-regulated modules. Such can as point departure (tPOD) for assessing module-associated cellular (stress) pathways/processes. This approach identified clear tPODs maximum systemic concentration (Cmax) levels tested drugs, while cosmetics ingredients 10-100-fold than estimated plasma concentrations. could serve next practice identify early responsive at low BMCs, that linked key events outcome pathways. turn, assist delineating potential hazards new test using systems when are paired with chemical exposure assessment. Plain language summaryRisk traditionally been focused experiments. contrast, uses biological obtained from experiments cell models animals hazards. Since is main target organ toxicity, many (hepatocyte) have developed hazard models, HepaRG, toxic chemicals. Biological changes expression measured range which response perturbed modelling. Genes belonging same process joined an average process. animal-free related expected

Language: Английский

Citations

0
Qualitative and quantitative concentration-response modelling of gene co-expression networks to unlock hepatotoxic mechanisms for next generation chemical safety assessment_Suppl8 DOI Creative Commons
Steven J. Kunnen, Emma Arnesdotter,

Christian Tobias Willenbockel

et al.

ALTEX, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Next generation risk assessment of chemicals revolves around the use mechanistic information without animal experimentation. In this regard, toxicogenomics has proven to be a useful tool elucidate mechanisms underlying adverse effects xenobiotics. present study, two widely used human hepatocyte culture systems, namely primary hepatocytes (PHH) and hepatoma HepaRG cells, were exposed liver toxicants known induce cholestasis, steatosis, or necrosis. Benchmark concentration (BMC) response modelling was applied transcriptomics gene co-expression networks (modules) derive BMCs gain insight into hepatotoxic effects. derived by concentration-response modules recapitulated individual genes. Although PHH cells showed overlap in genes deregulated toxicants, demonstrated higher responsiveness, based on lower co-regulated modules. Such can as points departure (tPOD) for assessing module-associated cellular (stress) pathways/processes. This approach identified clear tPODs maximum systemic (Cmax) levels tested drugs, while cosmetics ingredients 10-100-fold than estimated plasma concentrations. could serve next practice identify early responsive at low that linked key events outcome pathways. turn, assist delineating potential hazards new test using vitro systems where are paired with chemical exposure assessment. Plain language summary Risk traditionally been focused experiments. contrast, uses biological obtained from experiments cell models animals hazards. Since is main target organ toxicity, many have developed hazard toxic chemicals. Biological changes expression measured range which started perturbed mathematical approach. Genes belonging same bio­logical process an average process. animal-free relating concentrations expected

Language: Английский

Citations

0
Multi-omics Profiles are Applicable to Human Diseases and Drug Development DOI
Adriana Montserrat Espinosa‐González, José del Carmen Benítez-Flores, Juan Carlos Gómez-Verján

et al.

Recent advances in biotechnology, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 19

Published: March 12, 2024

Traditional medicine has been a reliable source for the discovery of molecules with therapeutic activity against human diseases clinical interest. In past, knowledge traditional was mainly transmitted orally and in writing. Recently, advent “multiomics” tools (transcriptomics, metabolomics, epigenomics, proteomics, lipidomics, among others) increased merged our knowledge, both that gained these new multiomics technologies. this way, development medicines 'multiomics technologies' allowed pharmaceutical advances drugs. addition, 'multiomics' technologies have made it possible to uncover biological activities drugs are currently used therapy. same 'personalized medicine', is, particular specific treatment and/or diagnosis patient respect disease. Therefore, facilitated therapeutics disease, as well allowing an individual personalized way.

Language: Английский

Citations

0
Characterizing the effects of triclosan and triclocarban on the intestinal epithelial homeostasis using small intestinal organoids DOI
Xiao‐Wen Cheng,

Hongzhi Shen,

Wen Zhang

et al.

Journal of Hazardous Materials, Journal Year: 2024, Volume and Issue: 479, P. 135734 - 135734

Published: Sept. 3, 2024

Language: Английский

Citations

0
Systematic comparison of temporal transcriptional responses to hepatotoxicants in primary human hepatocytes and HepaRG cells using concentration-response modelling of gene co-expression networks DOI Creative Commons
Steven J. Kunnen, Emma Arnesdotter,

Christian Tobias Willenbockel

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Feb. 3, 2023

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

Language: Английский

Citations

0