Maadurshni Gobichettipalayam Balasubramaniam, Nagarajan Manikandan, Mahalakshmi Balamurali, Sivasubramanian Jeganathan, Hemamalini Vedagiri, Manivannan Jeganathan
Environmental Health and Toxicology Laboratory, Department of Environmental Sciences, School of Life Sciences, Bharathiar University, Coimbatore - 641046, Tamil Nadu, India.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65212, United States of America.
Toxicol Res (Camb). 2024 Oct 15;13(5):tfae173. doi: 10.1093/toxres/tfae173. eCollection 2024 Oct.
Bisphenol A (BPA) is a ubiquitous pollutant worldwide and 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) is considered a major active metabolite of BPA with a wide range of potent toxicological properties. However, its adverse outcome pathway (AOP) on the hepatic and renal system has not yet been explored.
Hence, the current study evaluated its effect on cell survival, oxidative stress, and apoptosis. In addition, the influence of signalling pathways on cytotoxicity and ROS generating enzymes (NOX2 and XO) on oxidative stress was explored by siRNA knockdown experiments. Further, its molecular interaction with SOD, CAT, and HSA (molecular docking and dynamics) was evaluated and validated with spectroscopy (fluorescence and FTIR) based methods.
The outcome indicates that MBP exposure dose dependently increased the cytotoxic response, oxidative stress, and apoptosis in both hepatocytes and kidney cells. Further, MAPK signalling pathways and oxidative stress influenced the overall cytotoxic response in both cells. In addition, the stimulatory (NOX2 and XO) and inhibitory (SOD and CAT) effects of MBP were observed, along with a robust interaction with HSA.
The overall observation illustrates that MBP exposure adversely impacts hepatic and renal cells through oxidative stress and relevant molecular pathways which may connect the missing links during risk assessment of BPA.
双酚A（BPA）是一种在全球范围内普遍存在的污染物，4-甲基-2,4-双（4-羟苯基）戊-1-烯（MBP）被认为是BPA的一种主要活性代谢物，具有广泛的强效毒理学特性。然而，其对肝脏和肾脏系统的不良结局途径（AOP）尚未得到探索。
因此，本研究评估了其对细胞存活、氧化应激和细胞凋亡的影响。此外，通过小干扰RNA（siRNA）敲低实验，探讨了信号通路对细胞毒性的影响以及活性氧生成酶（NOX2和XO）对氧化应激的影响。此外，还评估了其与超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和人血清白蛋白（HSA）的分子相互作用（分子对接和动力学），并通过基于光谱学（荧光和傅里叶变换红外光谱）的方法进行了验证。
结果表明，MBP暴露剂量依赖性地增加了肝细胞和肾细胞的细胞毒性反应、氧化应激和细胞凋亡。此外，丝裂原活化蛋白激酶（MAPK）信号通路和氧化应激影响了两种细胞的整体细胞毒性反应。此外，观察到MBP的刺激作用（NOX2和XO）和抑制作用（SOD和CAT），以及与HSA的强烈相互作用。
总体观察结果表明，MBP暴露通过氧化应激和相关分子途径对肝细胞和肾细胞产生不利影响，这可能在BPA风险评估过程中连接缺失的环节。
