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In Silico Modeling Method for Computational Aquatic Toxicology of Endocrine Disruptors: A Software-Based Approach Using QSAR Toolbox
Published on: August 28, 2019
Exploring the mechanism of plastic additives on reproductive disorders based on network toxicology and molecular
Aiqin Lian1, Wenwei Zheng2, Yi Ran Liu3,4
1Department of Reproductive Clinic, Quanzhou Hospital of Traditional Chinese Medicine, Quanzhou, Fujian Province, China.
Abstract:
Phthalate esters (PAEs) and organophosphate esters (OPEs) are pervasive 20 environmental pollutants with endocrine-disrupting properties. Despite growing 21 evidence linking PAE/OPE exposure to female reproductive disorders, the 22 diseasespecific molecular targets and cross-disease mechanistic convergence in 23 polycystic ovary syndrome (PCOS), recurrent pregnancy loss (RPL), and 24 endometriosis remain undefined. We employed an integrative network toxicology 25 framework combining molecular docking, network pharmacology, multi-omics 26 analysis to systematically elucidate PAE/OPE-target interactions across three 27 clinically interrelated reproductive disorders. Our analysis identified disease-specific28 hub genes, ESR1 and MMP9 for PCOS, CTNNB1 and BCL2 for RPL, and IL6 and 29 NFKB1 for endometriosis, along with shared pathogenic mechanisms including 30 NF-κB activation, PI3K-AKT dysregulation, and microRNA-mediated regulation. 31 Molecular docking confirmed direct binding of DEHP, MEHP, and TPHP to key hub32 targets. Diagnostic nomograms integrating hub genes achieved AUCs of 0.72-0.94, 33 suggesting their potential as biomarkers for risk stratification. This study provides a 34 cross-disease network framework linking PAE/OPE exposure to female reproductive35 toxicity, offering mechanistic insights and candidate biomarkers for risk assessment 36 and targeted prevention strategies.
Insights
Phthalate esters (PAEs) and organophosphate esters (OPEs) are linked to female reproductive disorders. This study identifies key molecular targets and biomarkers for conditions like PCOS, RPL, and endometriosis.
Area of Science:
- Toxicology
- Molecular Biology
- Genomics
Background:
- Phthalate esters (PAEs) and organophosphate esters (OPEs) are widespread environmental pollutants with endocrine-disrupting effects.
- Growing evidence suggests a link between PAE/OPE exposure and female reproductive disorders, but specific molecular targets and shared mechanisms remain unclear.
- Polycystic ovary syndrome (PCOS), recurrent pregnancy loss (RPL), and endometriosis are clinically related conditions potentially impacted by these exposures.
Purpose of the Study:
- To systematically investigate the molecular interactions between PAEs/OPEs and their targets across PCOS, RPL, and endometriosis.
- To identify disease-specific and shared molecular targets and pathogenic pathways.
- To explore the potential of identified targets as biomarkers for risk stratification.
Main Methods:
- Utilized an integrative network toxicology framework.
- Combined molecular docking, network pharmacology, and multi-omics analysis.
- Analyzed PAE/OPE-target interactions across the three reproductive disorders.
Main Results:
- Identified disease-specific hub genes: ESR1 and MMP9 for PCOS, CTNNB1 and BCL2 for RPL, IL6 and NFKB1 for endometriosis.
- Revealed shared pathogenic mechanisms including NF-κB activation, PI3K-AKT dysregulation, and microRNA-mediated regulation.
- Confirmed direct binding of specific PAEs/OPEs to key targets via molecular docking.
- Developed diagnostic nomograms with high AUCs (0.72-0.94) for risk stratification.
Conclusions:
- Established a cross-disease network framework connecting PAE/OPE exposure to female reproductive toxicity.
- Provided mechanistic insights into the molecular pathogenesis of PCOS, RPL, and endometriosis.
- Highlighted potential candidate biomarkers for risk assessment and targeted prevention strategies.
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