USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111, USA.
Radiat Res. 2011 Dec;176(6):761-9. doi: 10.1667/rr2605.1. Epub 2011 Sep 30.
Exposing young rats to particles of high energy and charge (HZE particles), a ground-based model for exposure to cosmic rays, enhances indices of oxidative stress and inflammation, disrupts the functioning of neuronal communication, and alters cognitive behaviors. Even though exposure to HZE particles occurs at low fluence rates, the cumulative effects of long-term exposure result in molecular changes similar to those seen in aged animals. In the present study, we assessed markers of autophagy, a dynamic process for intracellular degradation and recycling of toxic proteins and organelles, as well as stress and inflammatory responses, in the brains of Sprague-Dawley rats irradiated at 2 months of age with 5 and 50 cGy and 1 Gy of ionizing oxygen particles ((16)O) (1000 MeV/n). Compared to nonirradiated controls, exposure to (16)O particles significantly inhibited autophagy function in the hippocampus as measured by accumulation of ubiquitin inclusion bodies such as P62/SQSTM1, autophagosome marker microtubule-associated protein 1 beta light chain 3 (MAP1B-LC3), beclin1 and proteins such as mammalian target of rapamycin (mTOR). The molecular changes measured at short (36 h) and long (75 days) intervals after (16)O-particle exposure indicate that the loss of autophagy function occurred shortly after exposure but was recovered via inhibition of mTOR. However, HZE-particle radiation caused significant sustained loss of protein kinase C alpha (PKC-α), a key G protein modulator involved in neuronal survival and functions of neuronal trophic factors. Exposure to (16)O particles also caused substantial increases in the levels of nuclear factor kappa B (NF-κB) and glial fibrillary acidic protein (GFAP), indicating glial cell activation 75 days after exposure. This is the first report to show the molecular effects of (16)O-particle radiation on oxidative stress, inflammation and loss of autophagy in the brain of young rats.
将幼鼠暴露于高能荷电粒子（HZE 粒子）中，这是一种模拟宇宙射线暴露的地面模型，会增强氧化应激和炎症指标，破坏神经元通讯功能，并改变认知行为。尽管 HZE 粒子的暴露率很低，但长期暴露的累积效应会导致类似于老年动物的分子变化。在本研究中，我们评估了自噬的标志物，自噬是一种用于降解和回收有毒蛋白质和细胞器的细胞内动态过程，以及应激和炎症反应，在 2 个月大的 Sprague-Dawley 大鼠的大脑中，这些大鼠接受了 5、50 和 1 Gy 的电离氧粒子（(16)O）（1000 MeV/n）的照射。与未照射对照相比，暴露于（16）O 粒子显著抑制了海马体中的自噬功能，这可通过泛素包含体（如 P62/SQSTM1）、自噬体标志物微管相关蛋白 1 轻链 3（MAP1B-LC3）、beclin1 和哺乳动物雷帕霉素靶蛋白（mTOR）等蛋白的积累来衡量。在（16）O 粒子暴露后的短（36 h）和长（75 天）间隔测量的分子变化表明，自噬功能的丧失发生在暴露后不久，但通过抑制 mTOR 得到了恢复。然而，HZE 粒子辐射导致蛋白激酶 Cα（PKC-α）的显著持续丧失，PKC-α 是一种参与神经元存活和神经元营养因子功能的关键 G 蛋白调节剂。暴露于（16）O 粒子还导致核因子 kappa B（NF-κB）和胶质纤维酸性蛋白（GFAP）的水平显著增加，表明暴露后 75 天胶质细胞被激活。这是第一项表明（16）O 粒子辐射对幼鼠大脑中氧化应激、炎症和自噬丧失的分子影响的报告。
