Exploring the toxicological network in diabetic microvascular disease

Area of Science:

• Endocrinology and Toxicology
• Molecular Biology and Bioinformatics
• Diabetology

Background:

• Diabetic microvascular complications, including kidney disease, retinopathy, and neuropathy, pose significant health challenges.
• Endocrine-disrupting chemicals (EDCs) are environmental agents that interfere with hormonal systems and are increasingly implicated in metabolic diseases.

Purpose of the Study:

• To investigate the molecular mechanisms by which EDCs contribute to the development of diabetic microvascular diseases.
• To identify specific toxic targets and pathways affected by EDCs in diabetic kidney disease, retinopathy, and sensory polyneuropathy.

Main Methods:

• Utilized databases (PubChem, ChEMBL) to assess EDC toxicity and identified potential targets using SwissTargetPrediction and Similarity Ensemble Approach.
• Integrated gene targets for diabetic microvascular diseases from CTD, GeneCards, and OMIM to find overlapping EDC and disease-related targets.
• Constructed protein-protein interaction networks (STRING) to identify hub genes, performed functional enrichment analysis (Metascape), and conducted molecular docking (Discovery Studio, CDOCKER).
• Validated key targets through immunohistochemistry, single-cell analysis, subcellular localization, and gene expression analysis of public datasets.

Main Results:

• Identified 843, 474, and 623 potential toxic targets for diabetic kidney disease, retinopathy, and sensory polyneuropathy, respectively.
• KEGG pathway analysis revealed EDC-associated pathways in diabetic kidney disease (cancer, apoptosis, calcium signaling), retinopathy (MAPK, ERBB), and neuropathy (chemokine, apoptosis, ERBB).
• Key hub targets identified across diseases include EGFR, ALB, MYC, ESR1, and BCL2, with confirmed strong binding between EDCs and these targets via molecular docking.

Conclusions:

• This study provides a comprehensive theoretical framework for understanding the toxic targets and mechanisms through which EDCs contribute to diabetic microvascular diseases.
• The identified hub genes and pathways offer potential targets for future therapeutic interventions aimed at mitigating EDC-induced diabetic complications.