Route of administration induced in vivo effects and toxicity responses of Zinc Oxide nanorods at molecular and genetic levels

Document Type: Reasearch Paper

Authors

1 Centre for Biotechnology and Bioinformatics, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Secunderabad, Telangana, India.

2 Department of Biotechnology, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, India.

3 Environmental Genomics Division, Council of Scientific and Industrial Research- National Environmental Engineering Research Institute (CSIR-NEERI), Nagpur, Maharashtra, India.

4 Department of Chemical Engineering, Jawaharlal Nehru Technological University Anantapur (JNTUA), Ananthapuramu, Andhra Pradesh, India.

5 Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi, India.

6 Department of Pathology, Nizam’s Institute of Medical Sciences (NIMS), Hyderabad, Telangana, India.

7 Centre for Biotechnology and Bioinformatics, Jawaharlal Nehru Institute of Advanced Studies, Buddha Bhawan, 6th Floor, M.G. Road, Secunderabad-500003, Telangana, India

Abstract

Zinc oxide (ZnO) nanoparticles have received growing attention for several biomedical applications. Nanoparticles proposed for these applications possess the potential to interact with biological components such as the blood, cells/ tissues following their administration into the body. Hence we carried out in vivo investigations in Swiss Albino Mice to understand the interaction of ZnO nanorods with the biological components following intravenous and oral routes of administration to assess nanoparticles safety. Intravenously injected ZnO nanorods were found to induce the significant reduction in the red blood cells and platelet counts. Elevated levels of serum enzymes such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase were observed following intravenous and oral administration. Also, increased levels (p < 0.05) of oxidative stress markers such as glutathione in the liver of intravenous treated mice and liver, spleen of oral treated mice; and lipid peroxidation in the spleen of intravenous treated mice compared to untreated mice. Significant DNA damage was observed in liver, spleen, and kidney of mice treated intravenously; liver and kidney of mice treated orally compared to untreated mice. Histology revealed focal venous congestion in the liver of intravenous and oral treated mice; more red pulp congestion in the spleen of oral treated mice compared to the intravenous treated group; pulmonary vascular congestion in intravenous (mild) and oral treated mice (moderate). In conclusion differences in the histology of the organs tested could be due to the differences in the distributed concentrations of nanoparticles. These findings can be considered helpful for the development of biocompatible nanoparticles for biomedical applications.

Keywords

Main Subjects


[1] Barenholz Y., (2012), Doxil®--the first FDA-approved nano-drug: lessons learned. J. Cont. Release. 160: 117-134.

[2] Reddy L. H., Bazile D., (2014), Drug delivery design for intravenous route with integrated physicochemistry, pharmacokinetics and pharmacodynamics: Illustration with the case of taxane therapeutics. Adv. Drug Deliv. Rev. 71: 34-57.

[3] Majedi A., Davar F., Abbasi A. R., (2016), Metal-organic framework materials as nano photocatalyst. Int. J. Nano Dimens. 7: 1-14. 

[4] Abdeen S., Geo S., Sukanya S., Praseetha P. K., Dhanya R. P., (2014), Biosynthesis of Silver nanoparticles from Actinomycetes for therapeutic applications. Int. J. Nano Dimens. 5: 155-162. 

[5] Aula S., Lakkireddy S., Jamil K., Kapley A., Swamy A. V. N., Reddy L. H., (2015), Biophysical, biopharmaceutical and toxicological significance of biomedical nanoparticles. RSC Adv. 5: 47830-47836.

[6] Guo D., Wu C., Jiang H., Li Q., Wang X., Chen B., (2008), Synergistic cytotoxic effect of different sized ZnO nanoparticles and daunorubicin against leukemia cancer cells under UV irradiation. J. Photochem. Photobiol. B. 93: 119-126.

[7] Deng Y., Zhang H., (2013), The synergistic effect and mechanism of doxorubicin-ZnO nanocomplexes as a multimodal agent integrating diverse anticancer therapeutics. Int. J. Nanomedic. 8: 1835-1841.

[8] Yamaki K., Yoshino S., (2009), Comparison of inhibitory activities of zinc oxide ultrafine and fine particulates on IgE-induced mast cell activation. Biometals. 22: 1031–1040.

[9] Kim M. H., Seo J. H., Kim H. M., Jeong H. J., (2014), Zinc oxide nanoparticles, a novel candidate for the treatment of allergic inflammatory diseases. Eur. J. Pharmacol. 738: 31-39.

[10] Xiong H. M., Xu Y., Ren Q. G., Xia Y. Y., (2008), Stable aqueous ZnO@polymer core−shell nanoparticles with tunable photoluminescence and their application in cell imaging. J. Am. Chem. Soc. 130: 7522–7523.

[11] Ng S. M., Wong D. S. N., Phung J. H. C., Chua H. S., (2013), Integrated miniature fluorescent probe to leverage the sensing potential of ZnO quantum dots for the detection of copper (II) ions. Talanta. 116: 514–519.

[12] Sharma H., Singh A., Kaur N., Singh N., (2013), ZnO-based imine-linked coupled biocompatible chemosensor for nanomolar detection of Co2+. ACS Sustain. Chem. Eng. 1: 1600–1608.

[13] Zhao D., Song H. J., Hao L. Y., Liu X., Zhang L. C., Lv Y., (2013), Luminescent ZnO quantum dots for sensitive and selective detection of dopamine. Talanta. 107: 133–139.

[14] Singh K., Chaudhary G. R., Singh S., Mehta S. K., (2014), Synthesis of highly luminescent water stable ZnO quantum dots as photoluminescent sensor for picric acid. J. Lumin. 154: 148–154.

[15] Zhang J., Zhao S. Q., Zhang K., Zhou J. Q., (2014), Cd-doped ZnO quantum dots-based immunoassay for the quantitative determination of bisphenol A. Chemosphere. 95: 105–110.

[16] Gu B. X., Xu C. X., Yang C., Liu S. Q., Wang M. L., (2011), ZnO quantum dot labeled immunosensor for carbohydrate antigen 19-9. Biosens. Bioelectron. 26: 2720–2723.

[17] Augustine R., Dominic E. A.,  Reju I.,  Kaimal B.,  Kalarikkal N.,  Thomas S., (2014), Investigation of angiogenesis and its mechanism using zinc oxide nanoparticle-loaded electrospun tissue engineering scaffolds. RSC Adv. 4: 51528-51536.

[18] Gojova A., Guo B., Kota R. S., Rutledge J. C., Kennedy I. M., Barakat A. I., (2007), Induction of inflammation in vascular endothelial cells by metal oxide nanoparticles: Effect of particle composition. Environ. Health Perspect. 115: 403–409.

[19] Jeng H. A., Swanson J., (2006), Toxicity of metal oxide nanoparticles in mammalian cells. J. Environ. Sci. Health A Tox. Hazard. Subst. Environ. Eng. 41: 2699–2711.

[20] Yang H., Liu C., Yang D., Zhang H., Xi Z., (2009), Comparative study of cytotoxicity, oxidative stress and genotoxicity induced by four typical nanomaterials: the role of particle size, shape and composition. J. Appl. Toxicol. 29: 69–78.

[21] Osman I. F., Baumgartner A., Cemeli E., Fletcher J. N., Anderson D., (2010), Genotoxicity and cytotoxicity of zinc oxide and titanium dioxide in HEp-2 cells. Nanomedicine (Lond.). 5: 1193–1203.

[22] Sharma V., Singh P., Pandey A. K., Dhawan A., (2012), Induction of oxidative stress, DNA damage and apoptosis in mouse liver after sub-acute oral exposure to zinc oxide nanoparticles. Mutat Res. 745: 84-91.

[23] Cho W. S., Kang B. C., Lee J. K., Jeong J., Che J. H., Seok S. H., (2013), Comparative absorption, distribution, and excretion of titanium dioxide and zinc oxide nanoparticles after repeated oral administration. Part. Fibre Toxicol. 10:  9-16.

[24] Lee C. M., Jeong H. J., Yun K. N., Kim D. W., Sohn M. H., Lee J. K., Jeong J., Lim S. T., (2012), Optical imaging to trace near infrared fluorescent zinc oxide nanoparticles following oral exposure. Int. J. Nanomedic. 7: 3203-3209.

[25] Baek M., Chung H. E., Yu J., Lee J. A., Kim T. H, Oh J. M., Lee W. J., Paek S M., Lee J. K., Jeong J., Choy J. H., Choi S. J., (2012), Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles. Int. J. Nanomedicine. 7: 3081-3097.

[26] Esmaeillou M., Moharamnejad M., Hsankhani R., Tehrani A. A., Maadi H., (2013), Toxicity of ZnO nanoparticles in healthy adult mice. Environ. Toxicol. Pharmacol. 35: 67-71.

[27] Choi J., Kim H., Kim P., Jo E., Kim H. M., Lee M. Y., Jin S. M., Park K., (2015), Toxicity of zinc oxide nanoparticles in rats treated by two different routes: single intravenous injection and single oral administration. J. Toxicol Environ. Health A. 78: 226-243.

[28] Cho W. S., Duffin R., Howie S. E., Scotton C. J., Wallace W. A., Macnee W., Bradley M., Megson I. L., Donaldson K., (2011), Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part. Fibre. Toxicol. 8: 27-34.

[29] http://ilocis.org/documents/chpt82e.htm.

[30] Aula S., Lakkireddy S., Swamy A. V. N., Kapley A., Jamil K., Tata N. R., Hembram K., (2014), Biological interactions in vitro of zinc oxide nanoparticles of different characteristics. Mater. Res. Express. 1: 035041-035046.

[31] Beutler E., Duron O., Kelly B. M., (1963), Improved method for the determination of blood glutathione. J. Lab. Clin. Med. 61: 882-888.

[32] Laughton M. J., Halliwell B., Evans P. J., Hoult J. R., (1989), Antioxidant and pro-oxidant actions of the plant phenolicsquercetin, gossypol and myricetin. Effects on lipid peroxidation, hydroxyl radical generation and bleomycin-dependent damage to DNA. Biochem. Pharmacol. 38: 2859-2865.

[33] Tice R. R., Agurell E., Anderson D., Burlinson B., Hartmann A., Kobayashi H., Miyamae Y., Rojas E., Ryu J. C., Sasaki Y. F., (2000), Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing. Environ. Mol. Mutagen. 35: 206–221.

[34] Khaitan D., Chandna S., Arya M. B., Dwarakanath B. S., (2006), Differential mechanisms of radiosensitization by 2-deoxy-D-glucose in the monolayers and multicellular spheroids of a human glioma cell line. Cancer Biol. Ther. 5: 1142-1151.

[35] Countryman P. I., Heddle J. A., (1976), Production of micronuclei from chromosome aberrations in irradiated cultures of human lymphocytes. Mutat. Res. 41: 321–332.

[36] Alvarez A. M., Mukherjee D., (2011), Liver abnormalities in cardiac diseases and heart failure. Int. J. Angiol. 20: 135-142.

[37] Khan M. F., Boor P. J., Gu Y., Alcock N. W., Ansari G. A., (1997), Oxidative stress in the splenotoxicity of aniline. Fundam. Appl. Toxicol. 35: 22-30.

[38] Souris J. S., Lee C. H., Cheng S. H., Chen C. T., Yang C. S., Ho J. A., Mou C. Y., Lo L. W., (2010), Surface charge-mediated rapid hepatobiliary excretion of mesoporous silica nanoparticles. Biomaterials. 31: 5564–5574.

[39] Burns A. A., Vider J., Ow H., Herz E., Penate-Medina O., Baumgart M., Larson S. M., Wiesner U., Bradbury M., (2009), Fluorescent silica nanoparticles with efficient urinary excretion for nanomedicine. Nano Lett. 9: 442-448.

[40] Minigalieva I. A., Katsnelson B. A., Panov V. G., Privalova L. I., Varaksin A. N., Gurvich V. B., Sutunkova M. P., Shur V. Y., Shishkina E. V., Valamina I. E., Zubarev I. V., Makeyev O. H., Meshtcheryakova E. Y., Klinova S. V., (2017), In vivo toxicity of copper oxide, lead oxide and zinc oxide nanoparticles acting in different combinations and its attenuation with a complex of innocuous bio-protectors. Toxicology. 380: 72-93.