Impact of plastic-related compounds on the gene expression signature of HepG2 cells transfected with CYP3A4

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 particl...

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Bibliographic Details
Published in:Archives of toxicology 2024-02, Vol.98 (2), p.525-536
Main Authors: Rosellini, Matteo, Omer, Ejlal A., Schulze, Alicia, Ali, Nadeen T., Boulos, Joelle C., Marini, Federico, Küpper, Jan-Heiner, Efferth, Thomas
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Cell cycle
Cresols
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Cytochrome P450
Cytochromes P450
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA biosynthesis
Electrophoresis
Environmental Health
Ethane
Female
Flora
Gene expression
Gene sequencing
Hep G2 Cells
Hepatotoxicity
Humans
In Vitro Systems
Marine animals
Marine flora
Marine plants
Metabolic pathways
Metabolism
Microplastics
Mitosis
Molecular docking
Molecular Docking Simulation
Occupational Medicine/Industrial Medicine
Oceans
Pharmacology/Toxicology
Placenta
Plastic debris
Plastic foam
Plastic pollution
Plastics
Plastics - toxicity
Pregnancy
Transcriptome
Transcriptomes
Xenobiotics
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Summary: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.
ISSN:0340-5761
1432-0738
1432-0738
DOI:10.1007/s00204-023-03648-4