Multi-omics analysis reveals ITGA2 mediates DEHP-induced decidual endothelial dysfunction in recurrent pregnancy loss
4 affiliations
- 1Department of NICU, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- 2Department of Pediatrics, Jiangshan People's Hospital, Quzhou, Zhejiang, China
- 3Department of NICU, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Corresponding authors.
- 4Department of Reproductive Endocrinology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Corresponding authors.
Abstract
Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental endocrine disruptor, has been detected in over 97% of pregnant women. Epidemiological studies have linked DEHP exposure to increased risk of recurrent pregnancy loss (RPL); however, the underlying mechanistic pathways remain poorly characterized. This study employed an integrated multi-omics approach combining network toxicology, machine learning, Mendelian randomization (MR), single-cell RNA sequencing (scRNA-seq), and molecular dynamics (MD) simulation to elucidate the molecular mechanism by which DEHP exposure induces RPL. Network toxicology analysis identified 143 shared targets between DEHP-associated genes and RPL-related genes, which were significantly enriched in focal adhesion and PI3K-Akt signaling pathways. Integration of machine learning analysis on RPL transcriptomic data with MR identified ITGA2 as a genetically supported protective factor causally associated with RPL. scRNA-seq precisely localized ITGA2 expression to decidual endothelial cells, where it was significantly downregulated in RPL patients. In silico gene knockout predicted that ITGA2 deficiency leads to dysregulation of angiogenesis- and immune regulation-associated genes, impairing decidual endothelial cell function and the immunological microenvironment. MD simulation predicted that DEHP forms a direct, stable complex with the extracellular domain of ITGA2. In HUVECs, DEHP dose-dependently reduced ITGA2 mRNA and protein levels and impaired migration. Silencing ITGA2 reproduced this migration defect, indicating that ITGA2 downregulation contributes to DEHP-induced endothelial dysfunction. Collectively, these findings identify ITGA2 as a biologically and genetically supported candidate linking DEHP exposure to impaired decidual endothelial function in RPL and provide a basis for future biomarker and mechanistic studies.
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BibTeX
@article{jiang2026multiomics,
title = {{Multi-omics analysis reveals ITGA2 mediates DEHP-induced decidual endothelial dysfunction in recurrent pregnancy loss}},
author = {Zhou Jiang and Xun Wu and Yujia Luo and Yuanyuan Zhou},
journal = {Ecotoxicology and Environmental Safety},
year = {2026},
month = oct,
doi = {10.1016/j.ecoenv.2026.120960},
url = {https://doi.org/10.1016/j.ecoenv.2026.120960},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multi-omics analysis reveals ITGA2 mediates DEHP-induced decidual endothelial dysfunction in recurrent pregnancy loss
AU - Zhou Jiang
AU - Xun Wu
AU - Yujia Luo
AU - Yuanyuan Zhou
PY - 2026
DA - 2026/10/23
JO - Ecotoxicology and Environmental Safety
DO - 10.1016/j.ecoenv.2026.120960
UR - https://doi.org/10.1016/j.ecoenv.2026.120960
AB - Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental endocrine disruptor, has been detected in over 97% of pregnant women. Epidemiological studies have linked DEHP exposure to increased risk of recurrent pregnancy loss (RPL); however, the underlying mechanistic pathways remain poorly characterized. This study employed an integrated multi-omics approach combining network toxicology, machine learning, Mendelian randomization (MR), single-cell RNA sequencing (scRNA-seq), and molecular dynamics (MD) simulation to elucidate the molecular mechanism by which DEHP exposure induces RPL. Network toxicology analysis identified 143 shared targets between DEHP-associated genes and RPL-related genes, which were significantly enriched in focal adhesion and PI3K-Akt signaling pathways. Integration of machine learning analysis on RPL transcriptomic data with MR identified ITGA2 as a genetically supported protective factor causally associated with RPL. scRNA-seq precisely localized ITGA2 expression to decidual endothelial cells, where it was significantly downregulated in RPL patients. In silico gene knockout predicted that ITGA2 deficiency leads to dysregulation of angiogenesis- and immune regulation-associated genes, impairing decidual endothelial cell function and the immunological microenvironment. MD simulation predicted that DEHP forms a direct, stable complex with the extracellular domain of ITGA2. In HUVECs, DEHP dose-dependently reduced ITGA2 mRNA and protein levels and impaired migration. Silencing ITGA2 reproduced this migration defect, indicating that ITGA2 downregulation contributes to DEHP-induced endothelial dysfunction. Collectively, these findings identify ITGA2 as a biologically and genetically supported candidate linking DEHP exposure to impaired decidual endothelial function in RPL and provide a basis for future biomarker and mechanistic studies.
SN - 0147-6513
SN - 1090-2414
ER -