Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Department of Medical Genetics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Environ Toxicol. 2019 Nov;34(11):1191-1198. doi: 10.1002/tox.22820. Epub 2019 Jul 16.
The phthalate plasticizer, di(2-ethyl-hexyl) phthalate (DEHP), and its derived metabolites are common anthropogenic environmental toxins, which are known to act as endocrine disruptors. Numerous studies have associated DEHP with disruption of sex hormones, abnormal development of reproductive organs, allergies, and inflammation. Its role in promoting inflammation has been reported by both human epidemiological and animal studies. In stomach tissue, chronic inflammation is known to accompany mucosal damage, and pave the way to gastritis, stomach ulcers, and ultimately gastric cancer. Eastern Asian populations possess the highest gastric cancer incidences in the world. Coincidentally, East Asia is one of the world's major sites for plastics manufacture and export. Thus, possible correlations between DEHP, a common plasticizer, and gastric cancer are of great interest. Our study revealed several critical findings. First, even at very low dosage, mimicking the residual plasticizer exposure, detrimental effects of DEHP on gastric cells can be detected. Second, gastric cells treated with DEHP increased cyclooxygenase-2 (COX-2) in a time-dependent manner. Third, promoter deletion studies revealed a critical role of nuclear factor-kappa B (NF-κB) for COX-2 gene responses. Finally, our results indicated that a low concentration of DEHP is able to trigger COX-2 activation via the extracellular signal-regulated kinase (ERK1/2) and NF-κB signaling pathway. Taken together, we demonstrate that very low doses of DEHP enhance the expression of the prototypical inflammatory gene, COX-2, in gastric cancer cells via ERK1/2 and NF-κB activation. This study provides important insights into the inflammatory process and damages associated with phthalate plasticizers exposure.
邻苯二甲酸酯类增塑剂，邻苯二甲酸二（2-乙基己基）酯（DEHP）及其衍生代谢物是常见的人为环境毒素，已知其具有内分泌干扰作用。大量研究表明，DEHP 会干扰性激素，导致生殖器官发育异常、过敏和炎症。人类流行病学和动物研究都报告了 DEHP 促进炎症的作用。在胃组织中，慢性炎症通常伴随着黏膜损伤，为胃炎、胃溃疡，最终为胃癌铺平道路。东亚人群的胃癌发病率居世界之首。巧合的是，东亚是世界上主要的塑料制造和出口地之一。因此，DEHP（一种常见的增塑剂）与胃癌之间可能存在关联，这引起了人们的极大关注。我们的研究揭示了一些关键发现。首先，即使在非常低的剂量下，模仿残留增塑剂暴露，也可以检测到 DEHP 对胃细胞的有害影响。其次，用 DEHP 处理的胃细胞以时间依赖性方式增加环氧化酶-2（COX-2）。第三，启动子缺失研究表明核因子-κB（NF-κB）在 COX-2 基因反应中起关键作用。最后，我们的结果表明，低浓度的 DEHP 能够通过细胞外信号调节激酶（ERK1/2）和 NF-κB 信号通路触发 COX-2 的激活。总之，我们证明了非常低剂量的 DEHP 通过 ERK1/2 和 NF-κB 激活增强胃癌细胞中原型炎症基因 COX-2 的表达。这项研究为与邻苯二甲酸酯类增塑剂暴露相关的炎症过程和损伤提供了重要的见解。
