Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer

Yuh-Shyan Tsai; Yeong-Chin Jou; Ian Seng Cheong; Hsiu-Ting Tung; Lin-Nei Hsu; Hsin-Tzu Tsai; Tzong-Shin Tzai

doi:10.1016/j.ecoenv.2025.117759

Phthalate exposure induces microRNA-5010/Nrf2-EGR1/GDF15 signaling expression in prostate cancer

Ecotoxicol Environ Saf. 2025 Jan 20:290:117759. doi: 10.1016/j.ecoenv.2025.117759. Online ahead of print.

Authors

Yuh-Shyan Tsai¹, Yeong-Chin Jou², Ian Seng Cheong³, Hsiu-Ting Tung⁴, Lin-Nei Hsu⁵, Hsin-Tzu Tsai⁴, Tzong-Shin Tzai⁶

Affiliations

¹ Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: [email protected].
² Division of Urology, Department of Surgery, St Martin De Porres Hospital, Chia-Yi City, Taiwan.
³ Department of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan.
⁴ Department of Urology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ Department of Urology, An-Nan Hospital, China Medical University, Tainan, Taiwan.
⁶ Department of Urology, An-Nan Hospital, China Medical University, Tainan, Taiwan. Electronic address: [email protected].

PMID: 39837010
DOI: 10.1016/j.ecoenv.2025.117759

Abstract

Phthalate exposure is linked to prostate enlargement through sex hormonal changes and oxidative stress. However, its role and action mechanism in prostate cancer remain unclear. This study examined two patient cohorts: 204 patients undergoing prostate biopsy (24 benign and 180 malignancies) and 85 with confirmed prostate cancer receiving robotic-assisted radical prostatectomy. Urine samples, collected with informed consent, were analyzed for urinary DEHP metabolites using HPLC-MS and ELISA. Patients with prostate cancer exhibited significantly higher urinary MEOHP and ΣDEHP metabolite levels than those who underwent benign biopsy (unpaired t-test, p = 0.027 and 0.039, respectively). MIR-5010 upregulation and MIR-205 downregulation were observed in two paired small RNA sequencing analyses (urine pellets of benign vs. malignant patients and PC3 cells without or with DEHP treatment), correlating with tumor staging in the TCGA prostate cancer cohort. Unlike MIR-205, a known tumor suppressor gene in prostate cancer, gene set enrichment analysis revealed that higher MIR-5010 expression was linked to increased Nrf-2 downstream signaling (enriched score: 0.35; p = 0.17). In vitro assays in prostate cancer cells showed that DEHP enhanced Nrf-2 protein expression and its downstream signaling molecules (i.e., SOD2, Heme oxygenase-1, and EGR-1) while increasing GDF15 mRNA expression via EGR-1 regulation in a dose- and time-dependent manner. Furthermore, urinary GDF15 levels were positively associated with urinary MEOHP and MEHP metabolites in the biopsy cohort (p = 0.0007 and 0.011, respectively) and with urinary oxidative stress marker 8-OHdG, aggressive marker VEGF, and CCL2/MCP-1 levels in the prostatectomy cohort (p = 0.0004, 0.006, and 0.0034, respectively). These findings suggest that phthalate exposure induces Nrf-2 and its downstream signaling (i.e., EGR-1/GDF-15) through microRNA regulation, contributing to prostate cancer aggressiveness.

Keywords: GDF-15; Nrf-2; microRNA; phthalate ester; prostate cancer.