Environmental Dose MEOHP Promotes Bladder Cancer Progress through Hybrid EMT Mechanism: Based on the Adverse Outcome...

Area of Science:

• Environmental Health
• Toxicology
• Cancer Research

Background:

• Di(2-ethylhexyl) phthalate (DEHP) is a prevalent plasticizer pollutant with known adverse health effects.
• The impact of urinary DEHP metabolites on bladder cancer progression is not well understood.

Purpose of the Study:

• To identify key urinary plasticizer metabolites associated with bladder cancer risk.
• To investigate the mechanism by which these metabolites influence bladder cancer progression using an adverse outcome pathway (AOP) framework.

Main Methods:

• Utilized quantile-based g-computation (QGC) model with NHANES data (2005-2018) to analyze associations between urinary metabolites and bladder cancer risk.
• Employed in vitro experiments exposing human bladder cancer cells to environmentally relevant concentrations of mono(2-ethyl-5-oxohexyl) phthalate (MEOHP).
• Investigated molecular events including YAP and beta-catenin nuclear translocation and epithelial-mesenchymal transition (EMT) activation.

Main Results:

• A positive association was found between urinary plasticizer metabolites and bladder cancer risk in older men.
• Mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), a DEHP secondary metabolite, was identified as a primary driver.
• Exposure to 100 nM MEOHP induced a hybrid EMT phenotype in bladder cancer cells.
• MEOHP exposure increased nuclear translocation of YAP and beta-catenin, sustaining the hybrid EMT phenotype.

Conclusions:

• This study provides the first evidence linking a plasticizer secondary metabolite (MEOHP) to bladder cancer progression.
• Environmental exposure to MEOHP may pose a risk to urinary system health.
• Highlights the need for considering metabolite toxicity in environmental chemical assessments.