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Diethyl Phthalate (DEP) as a potential osteosarcoma risk factor: a multi-omics study integrating network Toxicology,
Shangqi Yin1, Wuzheng Liu1, Chunxiao Gao1
1Department of Clinical Laboratory, Beijing Jishuitan Hospital, Capital Medical University, Beijing, PR China.
Abstract:
Diethyl phthalate (DEP), a common plasticiser and endocrine disruptor, has been linked to cancer, but its role in osteosarcoma (OS) remains unclear. This study integrated network toxicology, transcriptomics, protein-protein interaction (PPI) analysis, machine learning, molecular docking, molecular dynamics (MD), single-cell RNA sequencing (scRNA-seq), and external validation to investigate DEP-related mechanisms in OS. We identified 45 DEP-responsive genes enriched in extracellular matrix-related pathways. PPI network analysis revealed 11 hub genes, of which LASSO, SVM-RFE, and Boruta algorithms consistently prioritised P4HA2, COL18A1, and COL10A1. Docking and MD simulations supported stable binding of DEP to P4HA2 and COL18A1 via hydrogen bonds and hydrophobic interactions. scRNA-seq demonstrated celltype-specific expression of these genes. Validation cohorts confirmed their upregulation in OS, with AUC values up to 0.950. These findings suggest that DEP may promote OS progression by targeting extracellular matrix remodelling, offering new diagnostic biomarkers and hypothesis-generating evidence for environmental osteocarcinogenesis.
Insights
Diethyl phthalate (DEP) exposure may drive osteosarcoma (OS) progression by altering extracellular matrix remodeling. Key genes like P4HA2 and COL18A1 are identified as potential diagnostic biomarkers for this environmental carcinogenicity.
Area of Science:
- Toxicology
- Genomics
- Oncology
Background:
- Diethyl phthalate (DEP) is an endocrine disruptor linked to cancer.
- Its specific role in osteosarcoma (OS) pathogenesis is not well understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which DEP influences osteosarcoma.
- To identify potential diagnostic biomarkers for DEP-induced osteosarcoma.
Main Methods:
- Integrated network toxicology, transcriptomics, PPI analysis, machine learning, molecular docking, MD simulations, and scRNA-seq.
- Utilized LASSO, SVM-RFE, and Boruta algorithms for gene prioritization.
- Performed external validation on patient cohorts.
Main Results:
- Identified 45 DEP-responsive genes, primarily involved in extracellular matrix (ECM) pathways.
- Prioritized P4HA2, COL18A1, and COL10A1 as key hub genes.
- Confirmed stable binding of DEP to P4HA2 and COL18A1.
- Validated upregulation of these genes in OS tissues, showing high diagnostic accuracy (AUC up to 0.950).
Conclusions:
- DEP may promote OS progression by targeting ECM remodeling.
- P4HA2, COL18A1, and COL10A1 represent promising diagnostic biomarkers for OS.
- Findings provide evidence for environmental factors in osteocarcinogenesis.
