Exploratory Toxicogenomic Profiling Identifies Candidate DINCH-Responsive Genes Relevant to Prostate Cancer.

چکیده اصلی

Diisononyl cyclohexane-1,2-dicarboxylate (DINCH), a non-phthalate plasticizer adopted as a safer alternative for food-contact and medical-grade materials, is ubiquitously detected in human biomonitoring studies. Despite widespread exposure, its transcriptional effects in prostate cells and the potential prostate cancer relevance of DINCH-responsive genes remain unclear. We integrated transcriptomic profiling of DINCH-exposed human prostate epithelial cells with exploratory genetic association analyses in 630 patients with prostate cancer receiving androgen deprivation therapy (ADT). Haplotype-tagged single-nucleotide polymorphisms (SNPs) in candidate DINCH-responsive genes were evaluated for their association with overall survival (OS) and cancer-specific survival (CSS). The prostate cancer relevance of the prioritized genes was further validated using pooled multi-cohort bioinformatic analyses. DINCH exposure produced an exploratory molecular signature comprising 83 genes across all tested doses, broadly suppressing cell-matrix adhesion pathways and activating chromatin remodeling. Exploratory genetic screening identified nominal associations of LPP rs1040033 with OS (p = 0.0002, q = 0.131) and FAM111B rs7110278 with CSS (p = 0.0010, q = 0.575); neither association remained significant after multiple-testing correction. DINCH exposure significantly downregulated LPP and upregulated FAM111B expression in prostate epithelial cells. Independently, pooled analyses demonstrated reduced LPP and elevated FAM111B expression in prostate cancer tissues compared with normal prostate tissues. Higher LPP expression predicted a favorable prognosis, whereas elevated FAM111B predicted worse survival. Pathway analyses linked low LPP expression to impaired adhesion signaling and metabolic reprogramming, whereas high FAM111B expression was associated with mitotic and cell-cycle activation. DINCH exposure induced exploratory transcriptional alterations involving LPP-related adhesion pathways and FAM111B-related proliferative signaling. The genetic findings are exploratory and require independent validation. Although public datasets support the prognostic relevance of LPP and FAM111B in prostate cancer, they do not link these genes to DINCH exposure.

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