MOE Key Lab of Environmental Remediation and Ecosystem Health, Research Center for Air Pollution and Health, Institute of Environmental Health, College of Environmental and Resource Sciences, Zhejiang University, Hangzhou 310058, China.
Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Developmental and Regenerative Biology, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
Sci Total Environ. 2024 May 20;926:172015. doi: 10.1016/j.scitotenv.2024.172015. Epub 2024 Mar 26.
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.
对羟基苯甲酸酯是对羟基苯甲酸的酯类，作为防腐剂使用已有近一个世纪，直到过去二十年，人们开始担忧其与癌症的关联性。对羟基苯甲酸酯对不同癌细胞转移特性的作用模式的了解仍然非常有限。在本研究中，我们研究了甲基对羟基苯甲酸酯（MP）和丙基对羟基苯甲酸酯（PP）对多种人类癌细胞和非癌细胞（包括肝癌细胞（HepG2）、宫颈癌细胞（HeLa）、乳腺癌细胞（MCF-7）和人胎盘滋养层细胞（HTR-8/SVneo））的细胞侵袭和/或迁移的影响。浓度在 5-500μg/L 范围内的 MP 和 PP 显著促进了四种细胞系的侵袭，最小有效浓度为 5μg/L。MP 和 PP 上调了四种细胞系中基质金属蛋白酶 2 和 9（MMP2 和 MMP9）的表达水平和酶活性，并改变了组织金属蛋白酶抑制剂 1 和 2（TIMP1 和 TIMP2）的表达，表明 MMPs/TIMPs 是对羟基苯甲酸酯诱导的细胞侵袭的潜在关键事件（KEs）。MP 和 PP 促进四种细胞系侵袭需要激活丝裂原活化蛋白激酶 p38（p38 MAPK）和 c-Jun N-末端蛋白激酶 1/2（JNK1/2）信号通路，表明 MAPK 信号通路是癌症或非癌细胞对环境中化学物质暴露产生反应的 KEs 的候选。本研究首次表明，两种广泛使用的对羟基苯甲酸酯，MP 和 PP，通过一种共同的作用模式促进了多种人类细胞的侵袭能力。该研究为建立基于特定途径的机制的对羟基苯甲酸酯潜在癌症相关 AOP 提供了证据，有助于评估这些环境化学物质的健康风险。
