Abstract：
Parabens are esters of p-hydroxybenzoic acid, which have been used as preservatives and considered safe for nearly a century, until the last two decades when concerns began to be raised about their association with cancers. Knowledge of the mode of action of parabens on the metastatic properties of different cancer cells is still very limited. In the present study, we investigated the effects of methylparaben (MP) and propylparaben (PP) on cell invasion and/or migration in multiple human cancerous and noncancerous cells, including hepatocellular carcinoma cells (HepG2), cervical carcinoma cells (HeLa), breast carcinoma cells (MCF-7), and human placental trophoblasts (HTR-8/SVneo). MP and PP at concentrations in a range of 5-500 μg/L significantly promoted the invasion of four cell lines, with a minimum effective concentration of 5 μg/L. MP and PP up-regulated the expression levels and enzymatic activities of matrix metalloproteinase 2 and 9 (MMP2 and MMP9), as well as altered the expression of the tissue inhibitors of metalloproteinase 1 and 2 (TIMP1 and TIMP2) in four cell lines, suggesting MMPs/TIMPs as potential key events (KEs) for paraben-induced cell invasion. Activation of the p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal protein kinases 1/2 (JNK1/2) signaling pathways was required for MP- and PP-promoted invasion of four cell lines, suggesting MAPK signaling pathways as candidates for KEs in cancer or noncancerous cells response to paraben exposure. This study showed for the first time that the two widely used parabens, MP and PP, promoted invasive capacity of multiple human cells through a common mode of action. This study provides evidence for the establishment of a potential cancer-associated AOP for parabens based on pathway-specific mechanism(s), which contributes towards assessing the health risks of these environmental chemicals.
摘要：
对羟基苯甲酸酯是对羟基苯甲酸的酯，它们被用作防腐剂，被认为是安全的近一个世纪，直到最近的二十年，人们开始担心它们与癌症的关系。对羟基苯甲酸酯对不同癌细胞的转移特性的作用方式的了解仍然非常有限。在本研究中,我们研究了对羟基苯甲酸甲酯（MP）和对羟基苯甲酸丙酯（PP）对多种人类癌细胞和非癌细胞中细胞侵袭和/或迁移的影响，包括肝细胞癌细胞（HepG2），宫颈癌细胞（HeLa），乳腺癌细胞（MCF-7），和人胎盘滋养层（HTR-8/SVneo）。浓度在5-500μg/L范围内的MP和PP显着促进了四种细胞系的侵袭，最低有效浓度为5μg/LMP和PP上调基质金属蛋白酶2和9（MMP2和MMP9）的表达水平和酶活性，以及改变了四种细胞系中金属蛋白酶1和2（TIMP1和TIMP2）的组织抑制剂的表达，提示MMPs/TIMPs是对羟基苯甲酸酯诱导的细胞侵袭的潜在关键事件（KE）。p38丝裂原活化蛋白激酶（p38MAPK）和c-JunN末端蛋白激酶1/2（JNK1/2）信号通路的激活对于MP和PP促进四种细胞系的侵袭是必需的，提示MAPK信号通路在对羟基苯甲酸酯暴露的癌症或非癌细胞中作为KEs的候选信号。这项研究首次表明，这两种广泛使用的对羟基苯甲酸酯，MP和PP,通过共同的作用方式促进多种人类细胞的侵袭能力。本研究为基于通路特异性机制建立对羟基苯甲酸酯的潜在癌症相关AOP提供了证据。这有助于评估这些环境化学品的健康风险。
