Department of Structural and Functional Biology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
Cancer Signaling and Epigenetics, Fox Chase Cancer Center, Philadelphia, USA.
Chemosphere. 2023 Nov;341:140020. doi: 10.1016/j.chemosphere.2023.140020. Epub 2023 Sep 8.
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.
作为全球男性癌症死亡的第二大主要原因，前列腺癌（PCa）的预防和检测仍然是一个重大挑战。PCa 研究的一个方面是确定可能增加 PCa 起始和进展风险的常见环境因素。内分泌干扰化学物质（EDCs）是危险因素的有力候选者，部分原因是它们改变了前列腺发育和癌变的重要途径。邻苯二甲酸酯是一组人类普遍接触的商业用塑化剂。在这里，我们表明，母体暴露于邻苯二甲酸酯混合物会干扰后代腹侧前列腺中 mRNA 和蛋白质的表达谱，并增加老年动物发生前列腺腺癌的易感性。这些数据突出了 Ubxn11、Aldoc、Kif5c、Tubb4a、Tubb3、Tubb2、Rab6b 和 Rab3b 作为年轻和成年后代（PND22 和 PND120）中差异表达的靶标。这些邻苯二甲酸酯诱导的靶标富集了多种途径，如：翻译后蛋白质修饰（PTPM）失调、细胞内稳态、HSP90 伴侣活性、间隙连接和激酶。此外，Kif5c、Tubb3、Tubb2b 和 Tubb4a 靶标富集了细胞周期和 GTPase 活性受损。此外，这些靶标与 12 个转录因子（TF）表现出强烈的关系，这些转录因子调节八种蛋白激酶的磷酸化。TF-激酶的相关性与免疫系统、RAS/ErbB/VEGF/雌激素/HIF-1 信号通路、细胞衰老、细胞周期、自噬和细胞凋亡的改变有关。下调 KIF5C、TUBB3 和 RAB6B 靶标与诊断为腺癌的患者的预后不良有关。总的来说，这项综合性研究建立了在妊娠和哺乳期母体暴露于邻苯二甲酸酯混合物时调节前列腺的转录后机制。
