Iron Oxide Nanoparticles Induces Cell Cycle-Dependent Neuronal Apoptosis in Mice
- 123 Downloads
Iron oxide (Fe2O3) nanoparticles (NPs) with its unique magnetic and paramagnetic properties are popular in biomedical applications. Some of their neurotoxic mechanisms due to repeated administration are proven. However, we speculate that the neuronal damage might be due to apoptosis resulting from unusual cell cycle entry. Moreover, iron accumulation has been shown to be closely associated with most of the neurodegenerative disorders. Thus, in the current study, mice were orally (po) treated with the Fe2O3-NPs to investigate cell cycle-associated events/components and occurrence of apoptosis. A subsequent increase in oxidant levels was observed with the iron accumulation due to Fe2O3-NPs exposure. The accumulated β-amyloid and reduced level of cdk5 seem to aid in the cell cycle entry and forcing progression towards apoptosis. Expression of Cyclin D1 and pRb (Ser 795) indicate the cell cycle re-entry of neurons. Overexpression of RNA Pol II and PARP cleavage suggests DNA damage due to Fe2O3-NPs exposure. Further, hyperphosphorylation of p38 (Thr 180/Tyr 182) confirms the activation of DNA damage-dependent checkpoint. Expression patterns of pro- and anti-apoptotic markers, TUNEL and TEM indicate the occurrences of apoptosis.
KeywordsIron oxide NPs Cell cycle Apoptosis β-amyloid Oxidative stress
The authors would like to acknowledge Sophisticated Analytical Instrument Facility, All India Institute of Medical science (AIIMS), New Delhi, for the technical assistance in transmission electron microscopy. Vijayprakash Manickam acknowledges the UGC-BSR fellowship (UGC-BSR-No.F.7-25/2007) funded by UGC-BSR, New Delhi, India. We also thank the UGC-SAP DRS II (F-3-30/2013) and DST FIST (SR/FST/LSI-618/2014), New Delhi, India, for their partial financial assistance.
Compliance with Ethical Standards
All the experiments were conducted in accordance with the ethical norms approved by Institutional Animal Ethical Committee (722/02/A/CPCSEA).
Conflict of Interest
The authors declare that they have no conflict of interest.
All procedures performed in this study involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
- Busca G (2006) The surface acidity and basicity of solid oxides and zeolites. In: Fierro JLG (ed) Metal oxides, chemistry and applications. CRC Press, pp 247–318Google Scholar
- Chen MJ, Ng JM, Peng ZF, Manikandan J, Yap YW, Llanos RM, Beart PM, Cheung NS (2013) Gene profiling identifies commonalities in neuronal pathways in excitotoxicity: evidence favouring cell cycle re-activation in concert with oxidative stress. Neurochem Int 62(5):719–730. https://doi.org/10.1016/j.neuint.2012.12.015 CrossRefPubMedGoogle Scholar
- Czapski GA, Gąssowska M, Songin M, Radecka UD, Strosznajder JB (2011) Alterations of cyclin dependent kinase 5 expression and phosphorylation in amyloid precursor protein (APP) transfected PC12 cells. FEBS Lett 585(8):1243–1248. https://doi.org/10.1016/j.febslet.2011.03.058 CrossRefPubMedGoogle Scholar
- Fu PP, Xia Q, Hwang H, Ray PC, Yu H (2014) Mechanisms of nanotoxicity: generation of reactive oxygen species. J Food Drug Anal 22(64–7):5Google Scholar
- Katsuda K, Kataoka M, Uno F, Murakami T, Kondo T, Roth JA, Tanaka N, Fujiwara T (2002) Activation of caspase-3 and cleavage of Rb are associated with p16-mediated apoptosis in human non-small cell lung cancer cells. Oncogene 21(13):2108–2123. https://doi.org/10.1038/sj.onc.1205272 CrossRefPubMedGoogle Scholar
- Kulkarni PV, Roney CA, Antich PP, Bonte FJ, Raghu AV, Aminabhavi TM (2010) Quinolinenbutylcyanoacrylate based nanoparticles for brain targeting for the diagnosis of Alzheimer’s disease. Wiley Interdisciplinary Rev Nanomed Nanobiotechnol 2(1):35–47. https://doi.org/10.1002/wnan.59 CrossRefGoogle Scholar
- Lee EY, Hu N, Yuan SS, Cox LA, Bradley A, Lee WH, Herrup K (1994) Dual roles of the retinoblastoma protein in cell cycle regulation and neuron differentiation. Genes Dev 8:21–36Google Scholar
- Naser R, Vandenbosch R, Omais S, Hayek D, Jaafar C, Lafi SA, Saliba A, Baghdadi M, Skaf L, Ghanem N (2016) Role of the retinoblastoma protein, Rb, during adult neurogenesis in the olfactory bulb. Sci Rep 6(1). https://doi.org/10.1038/srep20230
- Pelegrí C, Duran-Vilaregut J, del Valle J, Crespo-Biel N, Ferrer I, Pallàs M, Camins A, Vilaplana J (2008) Cell cycle activation in striatal neurons from Huntington’s disease patients and rats treated with 3-nitropropionic acid. Int J Dev Neurosci 26(7):665–671. https://doi.org/10.1016/j.ijdevneu.2008.07.016 CrossRefPubMedGoogle Scholar
- Schwartz EI, Smilenov LB, Price MA, Osredkar T, Baker RA, Ghosh S, Shi F, Vollmer TL, Lencinas A, Stearns DM, Gorospe M, Kruman II (2007) Cell cycle activation in postmitotic neurons is essential for DNA repair. Cell Cycle 6(3):318–329. https://doi.org/10.4161/cc.6.3.3752 CrossRefPubMedGoogle Scholar
- Stone JG, Siedlak SL, Tabaton M, Hirano A, Castellani RJ, Santocanale C, Perry G, Smith MA, Zhu X, Lee H (2011) The cell cycle regulator phosphorylated retinoblastoma protein is associated with tau pathology in several tauopathies. J Neuropathol Exp Neur 70(7):578–587. https://doi.org/10.1097/NEN.0b013e3182204414 CrossRefGoogle Scholar
- Vogel CF, Charrier JG, Wu D, McFall AS, Li W, Abid A, Kennedy IM, Anastasio C (2016) Physicochemical properties of iron oxide nanoparticles that contribute to cellular ROS-dependent signaling and acellular production of hydroxyl radical. Free Radic Res 50(11):1153–1164. https://doi.org/10.3109/10715762.2016.1152360 CrossRefPubMedPubMedCentralGoogle Scholar
- Wang B, Feng WY, Wang M, Shi JW, Zhang F, Ouyang H, Zhao YL, Chai ZF, Huang YY, Xie YN, Wang HF, Wang J (2007a) Transport of intranasally instilled fine Fe2O3 particles into the brain: micro-distribution, chemical states, and histopathological observation. Biol Trace Elem Res 118(3):233–243. https://doi.org/10.1007/s12011-007-0028-6 CrossRefPubMedGoogle Scholar
- Wang J, Zhoua G, Chena C, Yu H, Wang T, Mad Y, Jia G, Gao Y, Li B, Suna J, Li Y, Jiao F, Zhao Y, Chai Z (2007b) Acute toxicity and bio distribution of different sized titanium dioxide particles in mice after oral administration. J. Toxicol Lett 168(2):176–185. https://doi.org/10.1016/j.toxlet.2006.12.001 CrossRefPubMedGoogle Scholar