Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Matteo Rosellini
- Ejlal A Omer
- Alicia Schulze
- Nadeen T Ali
- Joelle C Boulos
- Federico Marini
- Jan-Heiner Kuepper
- Thomas Efferth
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:001132390700001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1007/s00204-023-03648-4
- eISSN
- 1432-0738
- Externe Identifier
- Clarivate Analytics Document Solution ID: HC2P6
- PubMed Identifier: 38160208
- ISSN
- 0340-5761
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- ARCHIVES OF TOXICOLOGY
- Schlüsselwörter
- Cytotoxicity
- Ecotoxicity
- Environmental pollution
- Hepatotoxicity
- Marine pollution
- Microplastic
- RNA-sequencing
- Paginierung
- 525 - 536
- Datum der Veröffentlichung
- 2024
- Status
- Published
- Titel
- Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4
- Sub types
- Article
- Ausgabe der Zeitschrift
- 98
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Abstract
- <jats:title>Abstract</jats:title><jats:p>The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems that have been the topic of numerous investigations for many years. However, their impact on human health remains largely unknown. Such plastic and microplastic particles have been detected in blood and placenta, underlining their ability to enter the human body. Plastics also contain other compounds, such as plasticizers, antioxidants, or dyes, whose impact on human health is currently being studied. Critical enzymes within the metabolism of endogenous molecules, especially of xenobiotics, are the cytochrome P450 monooxygenases (CYPs). Although their importance in maintaining cellular balance has been confirmed, their interactions with plastics and related products are poorly understood. In this study, the possible relationship between different plastic-related compounds and CYP3A4 as one of the most important CYPs was analyzed using hepatic cells overexpressing this enzyme. Beginning with virtual compound screening and molecular docking of more than 1000 plastic-related compounds, several candidates were identified to interact with CYP3A4. In a second step, RNA-sequencing was used to study in detail the transcriptome-wide gene expression levels affected by the selected compounds. Three candidate molecules ((2,2′-methylenebis(6-<jats:italic>tert</jats:italic>-butyl-4-methylphenol), 1,1-bis(3,5-di-<jats:italic>tert</jats:italic>-butyl-2-hydroxyphenyl)ethane, and 2,2′-methylenebis(6-cyclohexyl-4-methylphenol)) had an excellent binding affinity to CYP3A4 in-silico as well as cytotoxic effects and interactions with several metabolic pathways in-vitro. We identified common pathways influenced by all three selected plastic-related compounds. In particular, the suppression of pathways related to mitosis and ‘DNA-templated DNA replication’ which were confirmed by cell cycle analysis and single-cell gel electrophoresis. Furthermore, several mis-regulated metabolic and inflammation-related pathways were identified, suggesting the induction of hepatotoxicity at different levels. These findings imply that these compounds may cause liver problems subsequently affecting the entire organism.</jats:p>
- Autoren
- Matteo Rosellini
- Ejlal A Omer
- Alicia Schulze
- Nadeen T Ali
- Joelle C Boulos
- Federico Marini
- Jan-Heiner Küpper
- Thomas Efferth
- DOI
- 10.1007/s00204-023-03648-4
- eISSN
- 1432-0738
- ISSN
- 0340-5761
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Archives of Toxicology
- Sprache
- en
- Online publication date
- 2023
- Paginierung
- 525 - 536
- Datum der Veröffentlichung
- 2024
- Status
- Published
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1007/s00204-023-03648-4
- Datum der Datenerfassung
- 2024
- Titel
- Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4
- Ausgabe der Zeitschrift
- 98
Data source: Crossref
- Abstract
- The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems that have been the topic of numerous investigations for many years. However, their impact on human health remains largely unknown. Such plastic and microplastic particles have been detected in blood and placenta, underlining their ability to enter the human body. Plastics also contain other compounds, such as plasticizers, antioxidants, or dyes, whose impact on human health is currently being studied. Critical enzymes within the metabolism of endogenous molecules, especially of xenobiotics, are the cytochrome P450 monooxygenases (CYPs). Although their importance in maintaining cellular balance has been confirmed, their interactions with plastics and related products are poorly understood. In this study, the possible relationship between different plastic-related compounds and CYP3A4 as one of the most important CYPs was analyzed using hepatic cells overexpressing this enzyme. Beginning with virtual compound screening and molecular docking of more than 1000 plastic-related compounds, several candidates were identified to interact with CYP3A4. In a second step, RNA-sequencing was used to study in detail the transcriptome-wide gene expression levels affected by the selected compounds. Three candidate molecules ((2,2'-methylenebis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl)ethane, and 2,2'-methylenebis(6-cyclohexyl-4-methylphenol)) had an excellent binding affinity to CYP3A4 in-silico as well as cytotoxic effects and interactions with several metabolic pathways in-vitro. We identified common pathways influenced by all three selected plastic-related compounds. In particular, the suppression of pathways related to mitosis and 'DNA-templated DNA replication' which were confirmed by cell cycle analysis and single-cell gel electrophoresis. Furthermore, several mis-regulated metabolic and inflammation-related pathways were identified, suggesting the induction of hepatotoxicity at different levels. These findings imply that these compounds may cause liver problems subsequently affecting the entire organism.
- Addresses
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128, Mainz, Germany.
- Autoren
- Matteo Rosellini
- Ejlal A Omer
- Alicia Schulze
- Nadeen T Ali
- Joelle C Boulos
- Federico Marini
- Jan-Heiner Küpper
- Thomas Efferth
- DOI
- 10.1007/s00204-023-03648-4
- eISSN
- 1432-0738
- Externe Identifier
- PubMed Identifier: 38160208
- PubMed Central ID: PMC10794370
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: GRK 2015/2
- Johannes Gutenberg-Universität Mainz:
- Open access
- true
- ISSN
- 0340-5761
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Archives of toxicology
- Schlüsselwörter
- Humans
- Cresols
- Plastics
- Cytochrome P-450 Enzyme System
- Pregnancy
- Female
- Cytochrome P-450 CYP3A
- Hep G2 Cells
- Transcriptome
- Molecular Docking Simulation
- Microplastics
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2023
- Open access status
- Open Access
- Paginierung
- 525 - 536
- Datum der Veröffentlichung
- 2024
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2023
- Titel
- Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4.
- Sub types
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 98
Files
https://europepmc.org/articles/PMC10794370?pdf=render
Data source: Europe PubMed Central
- Abstract
- The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems that have been the topic of numerous investigations for many years. However, their impact on human health remains largely unknown. Such plastic and microplastic particles have been detected in blood and placenta, underlining their ability to enter the human body. Plastics also contain other compounds, such as plasticizers, antioxidants, or dyes, whose impact on human health is currently being studied. Critical enzymes within the metabolism of endogenous molecules, especially of xenobiotics, are the cytochrome P450 monooxygenases (CYPs). Although their importance in maintaining cellular balance has been confirmed, their interactions with plastics and related products are poorly understood. In this study, the possible relationship between different plastic-related compounds and CYP3A4 as one of the most important CYPs was analyzed using hepatic cells overexpressing this enzyme. Beginning with virtual compound screening and molecular docking of more than 1000 plastic-related compounds, several candidates were identified to interact with CYP3A4. In a second step, RNA-sequencing was used to study in detail the transcriptome-wide gene expression levels affected by the selected compounds. Three candidate molecules ((2,2'-methylenebis(6-tert-butyl-4-methylphenol), 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl)ethane, and 2,2'-methylenebis(6-cyclohexyl-4-methylphenol)) had an excellent binding affinity to CYP3A4 in-silico as well as cytotoxic effects and interactions with several metabolic pathways in-vitro. We identified common pathways influenced by all three selected plastic-related compounds. In particular, the suppression of pathways related to mitosis and 'DNA-templated DNA replication' which were confirmed by cell cycle analysis and single-cell gel electrophoresis. Furthermore, several mis-regulated metabolic and inflammation-related pathways were identified, suggesting the induction of hepatotoxicity at different levels. These findings imply that these compounds may cause liver problems subsequently affecting the entire organism.
- Date of acceptance
- 2023
- Autoren
- Matteo Rosellini
- Ejlal A Omer
- Alicia Schulze
- Nadeen T Ali
- Joelle C Boulos
- Federico Marini
- Jan-Heiner Küpper
- Thomas Efferth
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/38160208
- DOI
- 10.1007/s00204-023-03648-4
- eISSN
- 1432-0738
- Externe Identifier
- PubMed Central ID: PMC10794370
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: GRK 2015/2
- Ausgabe der Veröffentlichung
- 2
- Zeitschrift
- Arch Toxicol
- Schlüsselwörter
- Cytotoxicity
- Ecotoxicity
- Environmental pollution
- Hepatotoxicity
- Marine pollution
- Microplastic
- RNA-sequencing
- Pregnancy
- Female
- Humans
- Cytochrome P-450 CYP3A
- Hep G2 Cells
- Transcriptome
- Plastics
- Microplastics
- Molecular Docking Simulation
- Cytochrome P-450 Enzyme System
- Cresols
- Sprache
- eng
- Country
- Germany
- Paginierung
- 525 - 536
- PII
- 10.1007/s00204-023-03648-4
- Datum der Veröffentlichung
- 2024
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2024
- Titel
- Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 98
Data source: PubMed
- Author's licence
- CC-BY
- Autoren
- Matteo Rosellini
- Ejlal A Omer
- Alicia Schulze
- Nadeen T Ali
- Joelle C Boulos
- Federico Marini
- Jan-Heiner Küpper
- Thomas Efferth
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- DFG-491381577-H
- Resource version
- Published version
- DOI
- 10.1007/s00204-023-03648-4
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 1432-0738
- Zeitschrift
- Archives of toxicology
- Schlüsselwörter
- 570 Biowissenschaften
- 570 Life sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 525 - 536
- Datum der Veröffentlichung
- 2024
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/9969
- Herausgeber
- Springer
- Datum der Datenerfassung
- 2024
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2024
- Zugang
- Public
- Titel
- Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4
- Ausgabe der Zeitschrift
- 98
Files
impact_of_plasticrelated_comp-20240119102825747.pdf
Data source: OPENSCIENCE.UB
- Beziehungen:
-