MOE Key Lab of Environment and Health, Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China; Key Lab of Birth Defects and Reproductive Health of National Health and Family Planning Commission, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing 400020, PR China.
Department of Pediatric Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Toxicol Appl Pharmacol. 2014 Jun 15;277(3):270-8. doi: 10.1016/j.taap.2014.03.027. Epub 2014 Apr 12.
Polychlorinated biphenyls (PCBs) are a group of persistent and widely distributed environmental pollutants that have various deleterious effects, e.g., neurotoxicity, endocrine disruption and reproductive abnormalities. In order to verify the hypothesis that the PI3K/Akt and MAPK pathways play important roles in hepatotoxicity induced by PCBs, Sprague-Dawley (SD) rats were dosed with PCB153 intraperitoneally at 0, 4, 16 and 32mg/kg for five consecutive days; BRL cells (rat liver cell line) were treated with PCB153 (0, 1, 5, and 10μM) for 24h. Results indicated that the PI3K/Akt and ERK pathways were activated in vivo and in vitro after exposure to PCB153, and protein levels of phospho-Akt and phospho-ERK were significantly increased. Nuclear factor-κB (NF-κB) activation and caspase-3, -8 and -9 inhibition caused by PCB153 were also observed. Inhibiting the ERK pathway significantly attenuated PCB153-induced NF-κB activation, whereas inhibiting the PI3K/Akt pathway hardly influenced phospho-NF-κB level. However, inhibiting the PI3K/Akt pathway significantly elevated caspase-3, -8 and -9 activities, while the ERK pathway only synergistically regulated caspase-9. Proliferating cell nuclear antigen (PCNA), a reliable indicator of cell proliferation, was also induced. Moreover, PCB153 led to hepatocellular hypertrophy and elevated liver weight. Taken together, PCB153 leads to aberrant proliferation and apoptosis of hepatocytes through NF-κB activation and caspase inhibition, and coactivated PI3K/Akt and ERK pathways play critical roles in PCB153-induced hepatotoxicity.
多氯联苯（PCBs）是一组持久性和广泛分布的环境污染物，具有多种有害作用，如神经毒性、内分泌干扰和生殖异常。为了验证 PI3K/Akt 和 MAPK 通路在 PCB 诱导的肝毒性中起重要作用的假说，将 SD 大鼠腹腔内注射 PCB153，剂量分别为 0、4、16 和 32mg/kg，连续 5 天；用 PCB153（0、1、5 和 10μM）处理 BRL 细胞（大鼠肝细胞系）24h。结果表明，暴露于 PCB153 后，体内和体外的 PI3K/Akt 和 ERK 通路均被激活，磷酸化 Akt 和磷酸化 ERK 的蛋白水平显著增加。还观察到 PCB153 引起的核因子-κB（NF-κB）激活和 caspase-3、-8 和 -9 抑制。抑制 ERK 通路可显著减弱 PCB153 诱导的 NF-κB 激活，而抑制 PI3K/Akt 通路几乎不影响磷酸化 NF-κB 水平。然而，抑制 PI3K/Akt 通路显著增加了 caspase-3、-8 和 -9 的活性，而 ERK 通路仅协同调节 caspase-9。增殖细胞核抗原（PCNA），细胞增殖的可靠指标，也被诱导。此外，PCB153 导致肝细胞肥大和肝重增加。综上所述，PCB153 通过 NF-κB 激活和 caspase 抑制导致肝细胞异常增殖和凋亡，共激活的 PI3K/Akt 和 ERK 通路在 PCB153 诱导的肝毒性中起关键作用。
