ArticleCell biology and toxicology2023
Urinary extracellular vesicles prevent di-(2-ethylhexyl) phthalate-induced hypospadias by facilitating epithelial-mesenchymal transition via PFN2 delivery.
Article in Cell biology and toxicology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 4 papers, 1 of them a synthesis that pooled it.
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Who cites it
4 citing papers in PubMed, 1 synthesis or guideline pooled it, 4 citations in OpenAlex.
- The potential mechanisms underlying phthalate-induced hypospadias: a systematic review of rodent model studies.Frontiers in endocrinology · 2024Pooled it
- DEHP induces stress urinary incontinence by causing urethral sphincter dysfunction via inflammation and apoptosis: a mechanism study based on animal experiments, network toxicology, and molecular docking.Frontiers in cell and developmental biology · 2026Article
- DNMT1 targets SRD5A2 to induce mitochondrial homeostasis and EMT in urothelial cells of hypospadias.Molecular biology reports · 2025Article
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Corrections and comments
- Erratum issued
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7 authors at 1 institution in 1 country.
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Abstract
backgroundUrinary extracellular vesicles (EVs) have gained increasing interest in recent years as a potential source of noninvasive biomarkers of diseases related to urinary organs, but knowledge of the mechanism is still limited. The current study sought to clarify the mechanism of urinary EVs behind di-(2-ethylhexyl) phthalate (DEHP)-induced hypospadias via PFN2 delivery.
methodPFN2 expression in hypospadias was predicted by bioinformatics analysis. Following the induction of a hypospadias rat model using DEHP, rats were injected with EVs and/or underwent alteration of PFN2 and TGF-β1 to assess their effects in vivo. The extracted rat urothelial cells (UECs) were co-cultured with EVs extracted from urine for in vitro experiments.
resultMicroarray analysis predicted poor PFN2 expression in hypospadias. Upregulated PFN2 was found in urinary EVs, and restrained epithelial-mesenchymal transition (EMT) was observed in DEHP-exposed rats. Urinary EVs or PFN2 overexpression increased SMAD2, SMAD3, and TGF-β1 protein expression and SMAD2 and SMAD3 phosphorylation in UECs and DEHP-exposed rats. UEC migration, invasion, and EMT were augmented by EV co-culture or upregulation of PFN2. Of note, the silencing of TGF-β1 counterweighed the effect of PFN2. Besides, EV co-culture or overexpression of PFN2 or TGF-β1 elevated the body weight, anal-genital distance (AGD), anal-genital index (AGI), and EMT of DEHP-exposed rats.
conclusionIn summary, urinary EVs activated the SMAD/TGF-β1 pathway to induce EMT via PFN2 delivery, thus protecting against DEHP-induced hypospadias. (1) EMT in epithelial cells inhibits DEHP-induced hypospadias. (2) Urine-derived EVs deliver PFN2 to promote EMT in epithelial cells. (3) PFN2 can activate the SMAD/TGF-β1 signaling axis. (4) Urine-derived EVs can transmit PFN2 to activate the SMAD/TGF-β1 signaling axis, thus promoting EMT and inhibiting the occurrence of hypospadias.
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