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Updated: Jan 7, 2026
A High-throughput Assay for the Prediction of Chemical Toxicity by Automated Phenotypic Profiling of Caenorhabditis elegans
Published on: March 14, 2019
Unraveling diethyl phthalate-induced prostate carcinogenesis: core targets revealed by integrated network toxicology,
Hao Liu1, Junyi Jiang2, Ying Tan3
1Department of Urology, Zhongshan City People's Hospital, Zhongshan, Guangdong Province, China.
Purpose:
Diethyl phthalate (DEP), a widely distributed environmental contaminant, is epidemiologically linked to prostate cancer (PCa). However, its molecular mechanisms beyond endocrine disruption remain poorly defined. We aimed to investigate the core mechanisms potentially underlying DEP-associated prostate carcinogenesis within a genome-exposome interaction framework.
Methods:
We employed an integrated, multi-level framework combining: (1) Integrated chemical structure-based target prediction; (2) Cross-dataset meta-analysis of PCa transcriptomics (7 GEO datasets) for Differentially Expressed Gene (DEG) identification and Weighted Gene Co-expression Network Analysis (WGCNA); (3) Ensemble machine learning (113 models incorporating RF, XGBoost) for core target screening, augmented by SHAP interpretable to predict potential DEP targets.e AI; and (4) Molecular docking validation (AutoDock Vina, binding free energy assessment).
Results:
Integration pinpointed 9 key DEP-PCa targets. Functional enrichment implicated calcium signaling dysregulation, neuroendocrine pathway disruption, and smooth muscle dysfunction as central mechanisms. Machine learning distilled five core regulators: TRPM8, CTSB, CA14, GSTM2, and MYLK. SHAP analysis quantified TRPM8 and CA14 as dominant predictors and revealed critical non-linear interactions: synergistic TRPM8-MYLK co-expression and a CTSB expression threshold effect. Computational validation predicted high-affinity binding of DEP to all five core targets, suggesting potential direct interactions.
Conclusion:
Our integrated analysis suggests that DEP may promote prostate carcinogenesis via a multidimensional network centered on calcium signaling perturbation, neuroendocrine dysregulation, and tumor microenvironment acidification, potentially illustrating a genome-exposome interaction mechanism beyond endocrine disruption. We propose that our analytical framework could serve as a reproducible approach for translational exposomics.
Insights
Diethyl phthalate (DEP) exposure is linked to prostate cancer (PCa). Our study reveals DEP may disrupt calcium signaling and neuroendocrine pathways, offering a new understanding of PCa mechanisms beyond endocrine disruption.
Area of Science:
- Environmental Health
- Molecular Biology
- Computational Biology
Background:
- Diethyl phthalate (DEP) is a widespread environmental contaminant with epidemiological links to prostate cancer (PCa).
- The precise molecular mechanisms of DEP's role in prostate carcinogenesis, beyond endocrine disruption, require further elucidation.
- Understanding genome-exposome interactions is crucial for deciphering environmental impacts on cancer development.
Purpose of the Study:
- To investigate the core molecular mechanisms underlying DEP-associated prostate carcinogenesis.
- To explore potential genome-exposome interactions in DEP-induced PCa.
- To identify key molecular targets and pathways affected by DEP exposure.
Main Methods:
- Integrated multi-level framework combining chemical structure-based target prediction, meta-analysis of PCa transcriptomics, and ensemble machine learning.
- Utilized Differentially Expressed Gene (DEG) identification and Weighted Gene Co-expression Network Analysis (WGCNA).
- Employed SHAP analysis for interpretable AI predictions and molecular docking for computational validation.
Main Results:
- Identified 9 key DEP-PCa targets, implicating calcium signaling, neuroendocrine pathways, and smooth muscle dysfunction.
- Distilled five core regulators: TRPM8, CTSB, CA14, GSTM2, and MYLK, with TRPM8 and CA14 as dominant predictors.
- Predicted high-affinity binding of DEP to these targets, suggesting direct molecular interactions.
Conclusions:
- DEP may promote prostate carcinogenesis through a network involving calcium signaling, neuroendocrine dysregulation, and tumor microenvironment acidification.
- This study suggests a genome-exposome interaction mechanism for DEP-induced PCa beyond endocrine disruption.
- The proposed analytical framework offers a reproducible approach for translational exposomics research.
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