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

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

PROVIDER: PRJNA996522 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25338469_1.fastq.gz	Fastqsanger.gz
	SRR25338469_2.fastq.gz	Fastqsanger.gz
	SRR25338470_1.fastq.gz	Fastqsanger.gz
	SRR25338470_2.fastq.gz	Fastqsanger.gz
	SRR25338471_1.fastq.gz	Fastqsanger.gz

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Project description:The presence of plastic and microplastic within the oceans as well as in marine flora and fauna have caused a multitude of problems which have been 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 1,000 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. The results showed that three candidate molecules (2,2'-methylene bis(6-tert-butyl-4-methylphenol, 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl)ethane, and 2,2'-methylene bis(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’. 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 problems in the liver, which could subsequently affect the entire organism.

Project description: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.

Project description:In recent years, plastic and especially microplastic in the oceans have caused huge problems to marine flora and fauna. Recently, such particles have also been detected in blood, breast milk, and placenta, underlining their ability to enter the human body presumably by the food chain and other yet unknown mechanisms. In addition, plastic contains plasticizers, antioxidants or lubricants, whose impact on human health is also under investigation. At the cellular level, the most important enzymes involved in the metabolism of xenobiotic compounds are the cytochrome P450 monooxygenases (CYPs). Despite their extensive characterization in the maintenance of cellular balance, their interaction with plastic and related products is elusive. In this study, the possible interactions between several plastic-related compounds and one of the most important cytochromes, CYP2C19, were analyzed. By applying virtual compound screening and molecular docking to more than 1000 commercially available plastic-related compounds, we identified candidates which are likely to interact with this protein. A growth inhibition assay confirmed their cytotoxic activity on a CYP2C19-transfected hepatic cell line. Subsequently, we studied the effect of selected compounds on the transcriptome-wide gene expression level by RNA-sequencing. Three candidate molecules, (i.e., 2,2'-methylene bis(6-tert-butyl-4-methylphenol; 1,1-bis(3,5-di-tert-butyl-2-hydroxyphenyl) ethane; 2,2'-methylene bis(6-cyclohexyl-4-methylphenol), which bound with high affinity to CYP2C19 in silico, exerted profound cytotoxicity in vitro, and interacted with several metabolic pathways of which the ‘cholesterol biosynthesis process’ was most affected. In addition, other affected pathways involving mitosis, DNA replication and inflammation have been identified, suggesting an increase of hepatotoxicity. These discoveries suggest that plastic-related compounds can damage the liver through their influence on several pathways.

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

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