Integrated transcriptome and proteome analysis indicates potential biomarkers of prostate cancer in offspring of pregnant rats exposed to a phthalate mixture during gestation and lactation

Abstract

As the second leading cause of death for cancer among men worldwide, prostate cancer (PCa) prevention and detection remain a critical challenge. One aspect of PCa research is the identification of common environmental agents that may increase the risk of initiation and progression of PCa. Endocrine disrupting chemicals (EDCs) are strong candidates for risk factors, partially because they alter essential pathways for prostate gland development and oncogenesis. Phthalates correspond to a set of commercially used plasticizers that humans are exposed to ubiquitously. Here, we show that maternal exposure to a phthalate mixture interferes with the expression profile of mRNA and proteins in the ventral prostate of offspring and increases the susceptibility to prostate adenocarcinomas in aged animals. The data highlight Ubxn11, Aldoc, Kif5c, Tubb4a, Tubb3, Tubb2, Rab6b and Rab3b as differentially expressed targets in young and adult offspring descendants (PND22 and PND120). These phthalate-induced targets were enriched for pathways such as: dysregulation in post-translational protein modification (PTPM), cell homeostasis, HSP90 chaperone activity, gap junctions, and kinases. In addition, the Kif5c, Tubb3, Tubb2b and Tubb4a targets were enriched for impairment in cell cycle and GTPase activity. Furthermore, these targets showed strong relationships with 12 transcriptional factors (TF), which regulate the phosphorylation of eight protein kinases. The correlation of TF-kinases is associated with alterations in immune system, RAS/ErbB/VEGF/estrogen/HIF-1 signaling pathways, cellular senescence, cell cycle, autophagy, and apoptosis. Downregulation of KIF5C, TUBB3 and RAB6B targets is associated with poor prognosis in patients diagnosed with adenocarcinoma. Collectively, this integrative investigation establishes the post-transcriptional mechanisms in the prostate that are modulated by maternal exposure to phthalate mixture during gestation and lactation.

Keywords: DOHaD; Maternal exposure; Offspring; Phthalate mixture; Prostate; Proteome; mRNA.