From plastics to prognosis: ANO4 susceptibility links phthalate exposure to prostate cancer progression.

From Plastics to Prognosis:Susceptibility Links Phthalate Exposure to Prostate Cancer Progression.

Ching-Yao Chang, Shih-Hao Huang, Ying-Nien Chen, L M Chen, Ching-Jang Huang, Chun-Shu Yu, V C Lin, Ting-Jang Lu, Bili Bao

Diagnostics (Basel)

Mar 7, 2026

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Abstract

Di-2-ethylhexyl phthalate and its bioactive metabolite mono-2-ethylhexyl phthalate (MEHP) are ubiquitous endocrine-disrupting chemicals implicated in carcinogenesis. However, the molecular mechanisms linking MEHP exposure, host genetic susceptibility, and prostate cancer progression remain incompletely defined.We integrated transcriptomic profiling of MEHP-exposed human prostate epithelial cells with a genetic association study of 630 patients with prostate cancer receiving androgen deprivation therapy. MEHP-responsive genes were identified from public microarray datasets and subjected to pathway enrichment analyses. Germline single-nucleotide polymorphisms (SNPs) in MEHP-regulated genes were evaluated for their association with progression-free survival, overall survival, and cancer-specific survival. The clinical and functional relevance of the key genes was further assessed using large-scale public prostate cancer expression datasets.MEHP exposure induced widespread transcriptional reprogramming, prominently suppressing focal adhesion and cell-matrix interaction pathways. Genetic analyses identified multiple prognostically relevant SNPs within MEHP-responsive genes, with anoctamin 4 () variants showing consistent associations across all clinical endpoints. The minor allele of rs17485225 inwas significantly associated with reduced all-cause and prostate cancer-specific mortality. Pooled analyses revealed reducedexpression levels in prostate cancer tissues and improved survival in patients with highexpression levels. Pathway analyses linked lowexpression levels with enhanced cell cycle activity and compromised cell adhesion.Our findings suggest thatmay act as a mediator of MEHP-associated prostate cancer progression and support a gene-environment interaction model in which environmental toxicant exposure and germline variation converge on focal adhesion dysregulation to potentially contribute to aggressive disease.