School of Food Science and Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
School of Food Science and Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China.
Toxicol In Vitro. 2019 Mar;55:43-50. doi: 10.1016/j.tiv.2018.11.010. Epub 2018 Nov 26.
Lead (Pb) has long been known as a metallic toxin to exert detrimental effects on human health, particularly on the central nervous system (CNS). Misregulated autophagy was regularly associated with multiple cellular dysfunctions and human diseases. However, the role of autophagy underlying Pb-induced neurotoxicity remains to be elucidated. In this study, we demonstrated that Pb promoted the accumulation of autophagosomes in PC12 cells, and subsequent findings revealed that this autophagosome accumulation was primarily caused by the inhibition of autophagic flux. Moreover, the results showed that Pb affected autophagy course through increasing Beclin 1 and ATG5 expression levels. Specifically, by double labeling with LC3-II (a marker of autophagosome) and LAMP-1 (a marker of lysosome), Pb impaired fusion between autophagosomes and lysosomes. Additionally, Pb exposure significantly reduced the number or size of lysosomes via decreasing the level of LAMP1, which is confirmed by the LysoTracker Red staining. Furthermore, the impairment of lysosomal activity was also signaled by the altered pH value of this acidic organelle. Overall, Pb exposure led to injuries of autophagy of neural cells through inhibiting the genesis and activity of lysosomes. The data provides insight with the neurotoxicity of Pb in a novel perspective, autophagy.
铅（Pb）作为一种金属毒素，长期以来一直被认为对人类健康，尤其是中枢神经系统（CNS）有有害影响。失调的自噬通常与多种细胞功能障碍和人类疾病有关。然而，自噬在 Pb 诱导的神经毒性中的作用仍有待阐明。在这项研究中，我们证明 Pb 促进了 PC12 细胞中自噬体的积累，随后的研究结果表明，这种自噬体的积累主要是由于自噬流的抑制。此外，结果表明，Pb 通过增加 Beclin 1 和 ATG5 的表达水平来影响自噬过程。具体来说，通过用 LC3-II（自噬体的标志物）和 LAMP-1（溶酶体的标志物）双重标记，Pb 损害了自噬体与溶酶体之间的融合。此外，Pb 暴露通过降低 LAMP1 水平显著减少了溶酶体的数量或大小，这一点通过 LysoTracker Red 染色得到了证实。此外，溶酶体活性的损害也通过该酸性细胞器 pH 值的改变来发出信号。总之，Pb 暴露通过抑制溶酶体的发生和活性导致神经细胞自噬损伤。这些数据从自噬这一新的角度提供了对 Pb 神经毒性的深入了解。
