百草枯的全身毒性及特异性耳毒性作用
发布时间：2018-07-26 12:50
【摘要】：百草枯是目前全球使用最广泛的除草剂之一,其对哺乳类生物体的毒性机制主要是在细胞内通过反复氧化还原反应而产生大量的过氧化物阴离子并引发脂质过氧化、线粒体损伤、DNA损害、蛋白质破坏,最终导致细胞凋亡等级联反应造成全身多器官的不可逆性损害。百草枯在急性中毒过程往往在肺泡细胞首先表现出特殊的高浓度聚集,这可能是因为百草枯与多胺的化学结构相似,而肺的Clara细胞和肺泡I型及II型上皮细胞具备较强的多胺转运系统,因此百草枯首先积聚在肺的Clara细胞和肺泡I型及II型细胞。百草枯还可穿越血脑屏障并通过多巴胺转运系统在多巴胺神经元中积累并首先造成多巴胺神经元的破坏,因此,百草枯慢性中毒可能与帕金森病的发病机制也具有一定的关系。各种耳毒性药物和强噪声以及重金属和老年性耳聋引起的内耳损伤都与氧自由基的损害作用密切相关,百草枯对细胞的氧化损伤作用使之成为研究内耳自由基损害和抗氧化剂保护效应的理想研究模型之一。百草枯引起的实验动物听觉障碍表现出高频听力首先受损的特点,百草枯引起的耳蜗毛细胞损害则首先发生在耳蜗底回对应高频听觉反应的区域。在百草枯引起的受损耳蜗细胞内,过氧化物阴离子首先在细胞质中的表达增强,随后凝聚到细胞核内,说明耳蜗细胞的损害确实是因为细胞内首先发生的氧化应激所引起,而这种自由基损害最终启动了细胞的自毁装置而导致了细胞的凋亡。我们在最近的实验研究中发现,百草枯对耳蜗细胞的损害首先是发生在耳蜗毛细胞底部和周围的支持细胞,由于这些支持细胞的破坏造成耳蜗Corti器的支持结构塌陷,从而使耳蜗毛细胞因失去周围细胞的连接和支持而发生排列散乱和位置漂移,这种因失去细胞之间的联系而发生的毛细胞"失巢凋亡"可能也是造成毛细胞破坏的重要机制之一。因此,百草枯引发的毛细胞凋亡不仅与细胞内发生的各种自由基损害有关,而且因丧失与周围支持细胞相联系的外基质而引发"失巢凋亡",显然这是一个值得思考的更重要的可能性损害机制。
[Abstract]:Paraquat is one of the most widely used herbicides in the world. The toxic mechanism of paraquat on mammalian organisms is to produce a large number of peroxide anions and induce lipid peroxidation through repeated redox reactions in cells. Mitochondria damage DNA damage, protein damage, and eventually lead to apoptosis grade reaction, resulting in irreversible damage to multiple organs. Paraquat tends to exhibit a special high concentration of aggregation in alveolar cells during acute poisoning, which may be due to the chemical structure of paraquat and polyamines. However, Clara cells and type I and type II epithelial cells of the lung have strong polyamine transport system, so paraquat first accumulates in the Clara cells and type I and type II cells of the lung. Paraquat can also cross the blood-brain barrier and accumulate in the dopamine neurons through the dopamine transporter system. Therefore, the chronic paraquat poisoning may be related to the pathogenesis of Parkinson's disease. All kinds of ototoxic drugs and strong noise, as well as heavy metals and deafness caused by the inner ear damage are closely related to the damage of oxygen free radicals, The oxidative damage of paraquat to cells makes it an ideal model to study the damage of inner ear free radicals and the protective effect of antioxidants. Paraquat induced hearing impairment in laboratory animals showed the characteristics of high frequency hearing loss first. Paraquat induced cochlear hair cell damage first occurred in the region of cochlear basal gyrus corresponding to high frequency auditory response. In the damaged cochlear cells induced by paraquat, the expression of peroxide anion was increased first in the cytoplasm and then condensed into the nucleus, indicating that the damage of the cochlear cells was indeed caused by the oxidative stress that occurred first in the cells. This free-radical damage eventually activates cell self-destruction and leads to cell apoptosis. In our recent experimental study, we found that paraquat damage to cochlear cells was primarily caused by supporting cells at and around the bottom of the cochlear hair cells, which caused the collapse of the supporting structure of the Corti organ in the cochlea. Thus, the hair cells of the cochlea lose the connection and support of the surrounding cells and cause the arrangement and position drift of the hair cells in the cochlea. The loss of the relationship between hair cells may also be one of the important mechanisms of hair cell destruction. Therefore, the apoptosis of hair cells induced by paraquat is not only related to the damage of free radicals occurring in the cells, Moreover, the loss of the extracellular matrix associated with peripheral Sertoli cells leads to "loss of nesting and apoptosis", which is obviously a more important possible damage mechanism to be considered.
【作者单位】： 中南大学附属湘雅医院耳鼻咽喉头颈外科;Center
【基金】：“973”国家重大科学研究计划项目(2014CB943003) 国家自然科学基金面上项目(81170912)~~
【分类号】：R595.4;R764
本文编号：2146068
[Abstract]:Paraquat is one of the most widely used herbicides in the world. The toxic mechanism of paraquat on mammalian organisms is to produce a large number of peroxide anions and induce lipid peroxidation through repeated redox reactions in cells. Mitochondria damage DNA damage, protein damage, and eventually lead to apoptosis grade reaction, resulting in irreversible damage to multiple organs. Paraquat tends to exhibit a special high concentration of aggregation in alveolar cells during acute poisoning, which may be due to the chemical structure of paraquat and polyamines. However, Clara cells and type I and type II epithelial cells of the lung have strong polyamine transport system, so paraquat first accumulates in the Clara cells and type I and type II cells of the lung. Paraquat can also cross the blood-brain barrier and accumulate in the dopamine neurons through the dopamine transporter system. Therefore, the chronic paraquat poisoning may be related to the pathogenesis of Parkinson's disease. All kinds of ototoxic drugs and strong noise, as well as heavy metals and deafness caused by the inner ear damage are closely related to the damage of oxygen free radicals, The oxidative damage of paraquat to cells makes it an ideal model to study the damage of inner ear free radicals and the protective effect of antioxidants. Paraquat induced hearing impairment in laboratory animals showed the characteristics of high frequency hearing loss first. Paraquat induced cochlear hair cell damage first occurred in the region of cochlear basal gyrus corresponding to high frequency auditory response. In the damaged cochlear cells induced by paraquat, the expression of peroxide anion was increased first in the cytoplasm and then condensed into the nucleus, indicating that the damage of the cochlear cells was indeed caused by the oxidative stress that occurred first in the cells. This free-radical damage eventually activates cell self-destruction and leads to cell apoptosis. In our recent experimental study, we found that paraquat damage to cochlear cells was primarily caused by supporting cells at and around the bottom of the cochlear hair cells, which caused the collapse of the supporting structure of the Corti organ in the cochlea. Thus, the hair cells of the cochlea lose the connection and support of the surrounding cells and cause the arrangement and position drift of the hair cells in the cochlea. The loss of the relationship between hair cells may also be one of the important mechanisms of hair cell destruction. Therefore, the apoptosis of hair cells induced by paraquat is not only related to the damage of free radicals occurring in the cells, Moreover, the loss of the extracellular matrix associated with peripheral Sertoli cells leads to "loss of nesting and apoptosis", which is obviously a more important possible damage mechanism to be considered.
【作者单位】： 中南大学附属湘雅医院耳鼻咽喉头颈外科;Center
【基金】：“973”国家重大科学研究计划项目(2014CB943003) 国家自然科学基金面上项目(81170912)~~
【分类号】：R595.4;R764
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