Mostovenko Ekaterina, Saunders Samantha, Muldoon Pretal P, Bishop Lindsey, Campen Matthew J, Erdely Aaron, Ottens Andrew K
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
Toxicol Sci. 2021 Jul 16;182(1):107-119. doi: 10.1093/toxsci/kfab042.
The unique physicochemical properties of carbon nanomaterials and their ever-growing utilization generate a serious concern for occupational risk. Pulmonary exposure to these nanoparticles induces local and systemic inflammation, cardiovascular dysfunction, and even cognitive deficits. Although multiple routes of extrapulmonary toxicity have been proposed, the mechanism for and manner of neurologic effects remain minimally understood. Here, we examine the cerebral spinal fluid (CSF)-derived peptidomic fraction as a reflection of neuropathological alterations induced by pulmonary carbon nanomaterial exposure. Male C57BL/6 mice were exposed to 10 or 40 µg of multiwalled carbon nanotubes (MWCNT) by oropharyngeal aspiration. Serum and CSFs were collected 4 h post exposure. An enriched peptide fraction of both biofluids was analyzed using ion mobility-enabled data-independent mass spectrometry for label-free quantification. MWCNT exposure induced a prominent peptidomic response in the blood and CSF; however, correlation between fluids was limited. Instead, we determined that a MWCNT-induced peptidomic shift occurred specific to the CSF with 292 significant responses found that were not in serum. Identified MWCNT-responsive peptides depicted a mechanism involving aberrant fibrinolysis (fibrinopeptide A), blood-brain barrier permeation (homeobox protein A4), neuroinflammation (transmembrane protein 131L) with reactivity by astrocytes and microglia, and a pro-degradative (signal transducing adapter molecule, phosphoglycerate kinase), antiplastic (AF4/FMR2 family member 1, vacuolar protein sorting-associated protein 18) state with the excitation-inhibition balance shifted to a hyperexcited (microtubule-associated protein 1B) phenotype. Overall, the significant pathologic changes observed were consistent with early neurodegenerative disease and were diagnostically reflected in the CSF peptidome.
碳纳米材料独特的物理化学性质及其不断增长的应用引发了对职业风险的严重担忧。肺部暴露于这些纳米颗粒会引发局部和全身炎症、心血管功能障碍，甚至认知缺陷。尽管已经提出了多种肺外毒性途径，但神经效应的机制和方式仍知之甚少。在此，我们研究了源自脑脊液（CSF）的肽组部分，以反映肺部碳纳米材料暴露引起的神经病理改变。通过口咽吸入法，将雄性C57BL/6小鼠暴露于10或40μg的多壁碳纳米管（MWCNT）中。暴露后4小时收集血清和脑脊液。使用离子淌度辅助的非数据依赖型质谱对两种生物流体的富集肽部分进行分析，以进行无标记定量。MWCNT暴露在血液和脑脊液中引发了显著的肽组反应；然而，两种流体之间的相关性有限。相反，我们确定MWCNT诱导的肽组变化特定于脑脊液，发现了292种血清中未出现的显著反应。鉴定出的MWCNT反应性肽描绘了一种机制，涉及异常纤维蛋白溶解（纤维蛋白肽A）、血脑屏障渗透（同源框蛋白A4）、神经炎症（跨膜蛋白131L），星形胶质细胞和小胶质细胞具有反应性，以及一种促降解（信号转导衔接分子、磷酸甘油酸激酶）、抗可塑性（AF4/FMR2家族成员1、液泡蛋白分选相关蛋白18）状态，兴奋-抑制平衡转变为过度兴奋（微管相关蛋白1B）表型。总体而言，观察到的显著病理变化与早期神经退行性疾病一致，并在脑脊液肽组中得到诊断性反映。
