文献类型：期刊文献

英文题名：Benzo[a]pyrene exposure promotes RIP1-mediated necroptotic death of osteocytes and the JNK/IL-18 pathway activation via generation of reactive oxygen species

作者：Zhang, Tao[1];Shen, Yuchen[1];Zhu, Ruirong[1];Shan, Weiyan[1];Li, Yurong[1];Yan, Ming[2];Zhang, Yun[1]

机构：[1]Shaoxing Univ, Coll Med, Huancheng West Rd 508, Shaoxing 312000, Peoples R China;[2]Hangzhou Dianzi Univ, Sch Automat, Xiasha Higher Educ Zone, 1158 2nd Ave, Hangzhou 310018, Peoples R China

年份：2022

卷号：476

外文期刊名：TOXICOLOGY

收录：SCI-EXPANDED(收录号：WOS:000881615200001)、、Scopus(收录号：2-s2.0-85133462787)、WOS

基金：This work was supported by Natural Science Foundation of Zhejiang Province (LY21H060001) and National Natural Science Foundation of China (30900301, 81700936).

语种：英文

外文关键词：Benzo(a)pyrene; Osteocytes; Necroptosis; JNK/IL-18 pathway; Reactive oxygen species

外文摘要：Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) of environmental pollutants, readily produced during the processing of petroleum and fatty foods. BaP exposure can cause skeletal deformities. However, whether BaP affects osteocytes, making up over 95% of all the bone cells, remains unknown. This study aimed to investigate the effect of BaP on osteocytes in vivo and in vitro, as well as explore the underlying mechanisms. The in vivo data showed that BaP (50 mg/kg) exposure for 12 weeks could cause bone destruction, and increase osteocytes death in mouse cortical femur. Our in vitro results revealed that BaP (25-100 mu mol/L) exposure inhibited cell viability of MLO-Y4 cells, and resulted in cell death in a dose-dependent manner. Furthermore, BaP exposure significantly triggered necroptosis of MLO-Y4 cells, as indicated by increased propidium iodide (PI)positive cells and up-regulation of necroptosis-related protein expressions of receptor-interacting protein kinase 1 (RIP1), RIP3, and mixed lineage kinase domain-like protein (MLKL). This necrotic effect was reversed by the RIP1 inhibitor necrostatin-1 (Nec-1). Simultaneously, BaP activated the downstream c-Jun N-terminal kinase (JNK)/ interleukin (IL)-18 signaling pathway, which was suppressed after the JNK inhibitor SP600125 or Nec-1 treatment. In addition, BaP exposure promoted the production of intracellular reactive oxygen species (ROS), mitochondrial ROS (mtROS), and elevated malondialdehyde (MDA) levels; while BaP decreased superoxide dismutase (SOD) activity and antioxidant enzymes including nuclear factor E-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels, leading to oxidative damage. The ROS scavenger N-acetylcysteine (NAC) inhibited this necroptotic death and the JNK/IL-18 pathway activation. Collectively, BaP exposure may cause RIP1-mediated necroptotic death of osteocytes and activate the JNK/IL-18 pathway via ROS generation.