• HAMIDA HAMDI Zoology Department, Faculty of Science, Cairo University, Egypt


Objective: Despite the widespread of nickel oxide nanoparticles (NiO NPs) and their benefits in all fields, they have many negative effects on human life, especially expectant mothers and their fetus. The purpose of this study was to investigate the possible maternal and developmental toxicity-induced by NiO NPs administration during gestation.

Methods: Three groups of pregnant rats were administered orally during days 5–19 of gestation, the pregnant rats were haphazardly designed into three groups (six rat/group), as follows: Control group and NiO NPs administered groups, low (4 mg/kg), and high (8 mg/kg) doses.

Results: NiO NPs administration resulted in severe maternal and developmental toxicity which included reduction in uterine weight, mother weight gain, the average weight of placenta, the number corpora lutea, implantation sites, and the number of live fetuses. Furthermore, high pre/ postimplantation, fetal growth retardation, and morphological and skeletal anomalies, an elevation in liver and brain DNA damage in both mother and fetus, and histopathological alterations in different tissues (placenta, liver, kidney, and brain) of pregnant rats and fetuses. Lipid peroxidation showed a significant elevation in maternal, fetal liver, and brain tissues of NiO NPs ‐administered rats. Furthermore, glutathione content and catalase activity were decreased in both tissues of NiO NPs‐administered rats.

Conclusion: Finally, the detrimental impacts of NiO NPs in dams and fetuses probably through its potential generation of reactive oxygen species.

Keywords: Nickel oxide nanoparticles, Oxidative stress, DNA damage, Gestation, Teratogenicity

Author Biography

HAMIDA HAMDI, Zoology Department, Faculty of Science, Cairo University, Egypt

Zoology Department


1. Long NV, Yang Y, Teranishi T, Thi CM, Cao Y, Nogami M. Biomedical applications of advanced multifunctional magnetic nanoparticles. J Nanosci Nanotechnol 2015;15:10091-107.
2. Räthel T, Mannell H, Pircher J, Gleich B, Pohl U, Krötz F. Magnetic stents retain nanoparticle-bound antirestenotic drugs transported by lipid microbubbles. Pharm Res 2012;29:1295-307.
3. Yuan YQ, Yuan FL, Li FL, Hao ZM, Guo J, Young DJ, et al. A cuboidal [Ni4O4] cluster as a precursor for recyclable, carbon-supported nickel nanoparticle reduction catalysts. Dalton Trans 2017;46:7154-58.
4. Melkhanova S, Haluska M, Hubner R, Kunze T, Keller A, Abrasonis G, et al. Carbon: Nickel nanocomposite templates-predefined stable catalysts for diameter-controlled growth of single-walled carbon nanotubes. Nanoscale 2016;8:14888-97.
5. Hyeon T. Chemical synthesis of magnetic nanoparticles. Chem Commun (Camb) 2003;8:927-34.
6. Ates M, Demir V, Arslan Z, Camas M, Celik F. Toxicity of engineered nickel oxide and cobalt oxide nanoparticles to Artemia salina in seawater. Water Air Soil Pollut 2016;227:70.
7. Mishra S, Yogi P, Sagdeo PR, Kumar R. Mesoporous nickel oxide (NiO) nanopetals for ultrasensitive glucose sensing. Nanoscale Res Lett 2018;13:16.
8. Parsaee Z. Synthesis of novel amperometric urea-sensor using hybrid synthesized NiO-NPs/GO modified GCE in aqueous solution of cetrimonium bromide. Ultrason Sonochem 2018;44:120-8.
9. Shen Y, Lua AC, Xi J, Qiu X. Ternary platinum-copper-nickel nanoparticles anchored to hierarchical carbon supports as free-standing hydrogen evolution electrodes. ACS Appl Mater Interfaces 2016;8:3464-72.
10. Talapin DV, Lee JS, Kovalenko MV, Shevchenko EV. Prospects of colloidal nanocrystals for electronic and optoelectronic applications. Chem Rev 2010;110:389-458.
11. Fratila RM, Rivera-Fernández S, de la Fuente JM. Shape matters: Synthesis and biomedical applications of high aspect ratio magnetic nanomaterials. Nanoscale 2015;7:8233-60.
12. Sousa CA, Soares HM, Soares EV. Nickel oxide (NiO) nanoparticles disturb physiology and induce cell death in the yeast Saccharomyces cerevisiae. Appl Microbiol Biotechnol 2018;102:2827-38.
13. Kang GS, Gillespie PA, Gunnison A, Moreira AL, Tchou-Wong KM, Chen LC. Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model. Environ Health Perspect 2011;119:176-81.
14. Glista-Baker EE, Taylor AJ, Sayers BC, Thompson EA, Bonner JC. Nickel nanoparticles cause exaggerated lung and airway remodeling in mice lacking the T-box transcription factor, TBX21 (T-bet). Part Fibre Toxicol 2014;11:7.
15. Liberda EN, Cuevas AK, Gillespie PA, Grunig G, Qu Q, Chen LC. Exposure to inhaled nickel nanoparticles causes a reduction in number and function of bone marrow endothelial progenitor cells. Inhal Toxicol 2010;22 Suppl 2:95-9.
16. Phillips JI, Green FY, Davies JC, Murray J. Pulmonary and systemic toxicity following exposure to nickel nanoparticles. Am J Ind Med 2010;53:763-7.
17. Magaye R, Zhou Q, Bowman L, Zou B, Mao G, Xu J, et al. Metallic nickel nanoparticles may exhibit higher carcinogenic potential than fine particles in JB6 cells. PLoS One 2014;9:e92418.
18. Kong L, Tang M, Zhang T, Wang D, Hu K, Lu W, et al. Nickel nanoparticles exposure and reproductive toxicity in healthy adult rats. Int J Mol Sci 2014;15:21253-69.
19. Ispas C, Andreescu D, Patel A, Goia DV, Andreescu S, Wallace KN. Toxicity and developmental defects of different sizes and shape nickel nanoparticles in zebrafish. Environ Sci Technol 2009;43:6349-56.
20. Dumala N, Mangalampalli B, Chinde S, Kumari SI, Mahoob M, Rahman MF, et al. Genotoxicity study of nickel oxide nanoparticles in female Wistar rats after acute oral exposure. Mutagenesis 2017;32:417-27.
21. Dumala N, Mangalampalli B, Kamal SS, Grover P. Biochemical alterations induced by nickel oxide nanoparticles in female Wistar albino rats after acute oral exposure. Biomarkers 2018;23:33-43.
22. Saquib Q, Attia SM, Ansari SM, Al-Salim A, Faisal M, Alatar AA, et al. p53, MAPKAPK-2 and caspases regulate nickel oxide nanoparticles induce cell death and cytogenetic anomalies in rats. Int J Biol Macromol 2017;105:228-37.
23. Liu J, Feng X, Wei L, Chen L, Song B, Shao L. The toxicology of ion-shedding zinc oxide nanoparticles. Crit Rev Toxicol 2016;46:348-84.
24. Zhou L, Zhuang W, Wang X, Yu K, Yang S, Xia S. Potential acute effects of suspended aluminum nitride (AlN) nanoparticles on soluble microbial products (SMP) of activated sludge. J Environ Sci 2017;57:284-92.
25. National Toxicology Program. Nickel compounds and metallic nickel. Rep Carcinog 2011;12:280-3. Available from: https://www.ntp.niehs.
26. El Ghareeb AW, Hamdi H, El Bakry A, Abo Hmela H. Teratogenic effects of the titanium dioxide nanoparticles on the pregnant female rats and their off springs. Res J Pharm Biol Chem Sci 2015;6:510-23.
27. Young AD, Phipps DE, Astroff AB. Large-scale double-staining of rat fetal skeletons using Alizarin Red S and alcian blue. Teratology 2000;61:273-6.
28. Nandhakumar S, Parasuraman S, Shanmugam MM, Rao KR, Chand P, Bhat BV. Evaluation of DNA damage using single-cell gel electrophoresis (Comet Assay). J Pharmacol Pharmacother 2011;2:107-11.
29. El-shorbagy HM, Hamdi H. Genotoxic and mutagenic studies of the antiepileptic drug levetiracetamin pregnant rats and their fetuses. Int J Pharm Pharm Sci 2015;8:82-8.
30. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8.
31. Beutler E, Duron O, Kelly MB. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882-8.
32. Aebi H. Catalase in vitro. Methods Enzymol 1984;105:121-6.
33. Bancroft JD, Gamble M. Theory and Practice of Histological Techniques. 6th ed. Edinburgh, UK: Churchill Livingstone; 2008.
34. Griffitt RJ, Luo J, Gao J, Bonzongo JC, Barber DS. Effects of particle composition and species on toxicity of metallic nanomaterials in aquatic organisms. Environ Toxicol Chem 2008;27:1972-8.
35. Singh SP, Kumari M, Kumari SI, Rahman MF, Mahboob M, Grover P. Toxicity assessment of manganese oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral exposure. J Appl Toxicol 2013;33:1165-79.
36. Kumari M, Singh SP, Chinde S, Rahman MF, Mahboob M, Grover P. Toxicity study of cerium oxide nanoparticles in human neuroblastoma cells. Int J Toxicol 2014;33:86-97.
37. Schleh C, Semmler-Behnke M, Lipka J, Wenk A, Hirn S, Schäffler M, et al. Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology 2012;6:36-46.
38. Yamashita K, Yoshioka Y, Higashisaka K, Mimura K, Morishita Y, Nozaki M, et al. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol 2011;6:321-8.
39. Shah PS, Balkhair T. Knowledge Synthesis Group on Determinants of Preterm/LBW Births. Air pollution and birth outcomes: A systematic review. Environ Int 2011;37:498-516.
40. Takeda K, Shinkai Y, Suzuki K, Yanagita S, Umezawa M, Yokota S, et al. Health effects of nanomaterials on next generation. Yakugaku Zasshi 2011;131:229-36.
41. Qi W, Bi J, Zhang X, Wang J, Wang J, Liu P, et al. Damaging effects of multi-walled carbon nanotubes on pregnant mice with different pregnancy times. Sci Rep 2014;4:4352.
42. Andersen H, Larsen S, Spliid H, Christensen ND. Multivariate statistical analysis of organ weights in toxicity studies. Toxicology 1999;136:67-77.
43. Bailey SA, Zidell RH, Perry RW. Relationships between organ weight and body/brain weight in the rat: What is the best analytical endpoint? Toxicol Pathol 2004;32:448-66.
44. Chung MK, Kim CY, Kim JC. Reproductive toxicity evaluation of a new camptothecin anticancer agent, CKD-602, in pregnant/lactating female rats and their offspring. Cancer Chemother Pharmacol 2007;59:383-95.
45. Fujitani T, Ohyama K, Hirose A, Nishimura T, Nakae D, Ogata A. Teratogenicity of multi-wall carbon nanotube (MWCNT) in ICR mice. J Toxicol Sci 2012;37:81-9.
46. Pietruska JR, Liu X, Smith A, McNeil K, Weston P, Zhitkovich A, et al. Bioavailability, intracellular mobilization of nickel, and HIF-1? activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles. Toxicol Sci 2011;124:138-48.
47. Yamaguchi M, Ehara Y. Effect of essential trace metal on bone metabolism in the femoral-metaphyseal tissues of rats with skeletal unloading: Comparison with zinc-chelating dipeptide. Calcif Tissue Int 1996;59:27-32.
48. Gough JE, Downes S. Osteoblast cell death on methacrylate polymers involves apoptosis. J Biomed Mater Res 2001;57:497-505.
49. Kapanen A, Ilvesaro J, Danilov A, Ryhänen J, Lehenkari P, Tuukkanen J. Behaviour of nitinol in osteoblast-like ROS-17 cell cultures. Biomaterials 2002;23:645-50.
50. Chovancová H, Martiniaková M, Omelka R, Grosskopf B, Toman R. Structural changes in femoral bone tissue of rats after intraperitoneal administration of nickel. Pol J Environ Stud 2011;20:1147-52.
51. Semmler-Behnke M, Fertsch S, Schmid O, Wenk A, Kreyling WG: Uptake of 1.4 mm Versus 18 mm Gold Particles by Secondary Target Organs is Size Dependent in Control and Pregnants Rats after Intertracheal or Intravenouz Application, Euro Nanoforum- Nanotechnology in Industrial Applications; 2007. p. 102-4. Available from: euronanoforum2007-proceedings_en.pdf.
52. Takeda K, Suzuki KI, Ishihara A, Kubo-Irie M, Fujimoto R, Tabata M, et al. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 2009;55:95-102.
53. Chu M, Wu Q, Yang H, Yuan R, Hou S, Yang Y, et al. Transfer of quantum dots from pregnant mice to pups across the placental barrier. Small 2010;6:670-8.
54. Sumner SC, Fennell TR, Snyder RW, Taylor GF, Lewin AH. Distribution of carbon-14 labeled C60 ([14C]C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine. J Appl Toxicol 2010;30:354-60.
55. Refuerzo JS, Godin B, Bishop K, Srinivasan S, Shah SK, Amra S, et al. Size of the nanovectors determines the transplacental passage in pregnancy: Study in rats. Am J Obstet Gynecol 2011;204:546.
56. Brohi RD, Wang L, Talpur HS, Wu D, Khan FA, Bhattarai D, et al. Toxicity of nanoparticles on the reproductive system in animal models: A review. Front Pharmacol 2017;8:606.
57. Kannan S, Misra DP, Dvonch JT, Krishnakumar A. Exposures to airborne particulate matter and adverse perinatal outcomes: A biologically plausible mechanistic framework for exploring potential effect modification by nutrition. Environ Health Perspect 2006;114:1636-42.
58. Wells PG, Bhuller Y, Chen CS, Jeng W, Kasapinovic S, Kennedy JC, et al. Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicol Appl Pharmacol 2005;207:354-66.
59. Perez-Garcia V, Fineberg E, Wilson R, Murray A, Mazzeo CI, Tudor C, et al. Placentation defects are highly prevalent in embryonic lethal mouse mutants. Nature 2018;555:463-8.
60. Yu S, Liu F, Wang C, Zhang J, Zhu A, Zou L, et al. Role of oxidative stress in liver toxicity induced by nickel oxide nanoparticles in rats. Mol Med Rep 2018;17:3133-9.
61. Dobrzy?ska MM, Gajowik A, Radzikowska J, Lankoff A, Dušinská M, Kruszewski M. Genotoxicity of silver and titanium dioxide nanoparticles in bone marrow cells of rats in vivo. Toxicology 2014;315:86-91.
62. Reliene R, Hlavacova A, Mahadevan B, Baird WM, Schiestl RH. Diesel exhaust particles cause increased levels of DNA deletions after transplacental exposure in mice. Mutat Res 2005;570:245-52.
63. Balansky R, Longobardi M, Ganchev G, Iltcheva M, Nedyalkov N, Atanasov P, et al. Transplacental clastogenic and epigenetic effects of gold nanoparticles in mice. Mutat Res 2013;751-752:42-8.
64. Jackson P, Halappanavar S, Hougaard KS, Williams A, Madsen AM, Lamson JS, et al. Maternal inhalation of surface-coated nanosized titanium dioxide (UV-Titan) in C57BL/6 mice: Effects in prenatally exposed offspring on hepatic DNA damage and gene expression. Nanotoxicology 2013;7:85-96.
65. Dumala N, Mangalampalli B, Kamal SS, Grover P. Repeated oral dose toxicity study of nickel oxide nanoparticles in Wistar rats: A histological and biochemical perspective. J Appl Toxicol 2019;39:1012-29.
66. Horie M, Fukui H, Nishio K, Endoh S, Kato H, Fujita K, et al. Evaluation of acute oxidative stress induced by NiO nanoparticles in vivo and in vitro. J Occup Health 2011;53:64-74.
67. Morimoto Y, Oyabu T, Ogami A, Myojo T, Kuroda E, Hirohashi M, et al. IInvestigation of gene expression of MMP-2 and TIMP-2 mRNA in rat lung in inhaled nickel oxide and titanium dioxide nanoparticles. Ind Health 2011;49:344-52.
68. Ahamed M, Akhtar MJ, Siddiqui MA, Ahmad J, Musarrat J, Al- Khedhairy AA, et al. Oxidative stress mediated apoptosis induced by nickel ferrite nanoparticles in cultured A549 cells. Toxicology 2011;283:101-8.
69. Sutunkova MP, Solovyeva SN, Minigalieva IA, Gurvich VB, Valamina IE, Makeyev OH, et al. Toxic effects of low-level long-term inhalation exposures of rats to nickel oxide nanoparticles. Int J Mol Sci 2019;20:1778.
70. Yokota S, Mizuo K, Moriya N, Oshio S, Sugawara I, Takeda K. Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Neurosci Lett 2009;449:38-41.
71. Sugamata M, Ihara T, Takano H, Oshio S, Takeda K. Maternal diesel exhaust exposure damages newborn murine brains. J Health Sci 2006;52:82-4.
72. Jackson P, Vogel U, Wallin H, Hougaard KS. Prenatal exposure to carbon black (printex 90): Effects on sexual development and neurofunction. Basic Clin Pharmacol Toxicol 2011;109:434-7.
73. Watson RE, Desesso JM, Hurtt ME, Cappon GD. Postnatal growth and morphological development of the brain: A species comparison. Birth Defects Res B Dev Reprod Toxicol 2006;77:471-84.
74. Lee Y, Choi J, Kim P, Choi K, Kim S, Shon W, et al. A transfer of silver nanoparticles from pregnant rat to offspring. Toxicol Res 2012;28:139-41.
75. Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, et al. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 2007;168:176-85.
76. Hu R, Zheng L, Zhang T, Gao G, Cui Y, Cheng Z, et al. Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 2011;191:32-40.
77. Engler-Chiurazzi EB, Stapleton PA, Stalnaker JJ, Ren X, Hu H, Nurkiewicz TR, et al. Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition. J Toxicol Environ Health A 2016;79:447-52.
78. Ghaderi S, Tabatabaei SR, Varzi HN, Rashno M. Induced adverse effects of prenatal exposure to silver nanoparticles on neurobehavioral development of offspring of mice. J Toxicol Sci 2015;40:263-75.
79. Lee S, Hwang SH, Jeong J, Han Y, Kim SH, Lee DK, et al. Nickel oxide nanoparticles can recruit eosinophils in the lungs of rats by the direct release of intracellular eotaxin. Part Fibre Toxicol 2016;13:30.
80. Kanold JM, Wang J, Brümmer F, Šiller L. Metallic nickel nanoparticles and their effect on the embryonic development of the sea urchin Paracentrotus lividus. Environ Pollut 2016;212:224-9.
81. Duan WX, He MD, Mao L, Qian FH, Li YM, Pi HF, et al. NiO nanoparticles induce apoptosis through repressing SIRT1 in human bronchial epithelial cells. Toxicol Appl Pharmacol 2015;286:80-91.
82. Faisal M, Saquib Q, Alatar AA, Al-Khedhairy AA, Hegazy AK, Musarrat J. Phytotoxic hazards of NiO-nanoparticles in tomato: A study on mechanism of cell death. J Hazard Mater 2013;250-251:318-32.
83. Kawanishi S, Oikawa S, Inoue S, Nishino K. Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides. Environ Health Perspect 2002;110 Suppl 5:789-91.
84. Cempel M, Janicka K. Distribution of nickel, zinc, and copper in rat organs after oral administration of nickel(II) chloride. Biol Trace Elem Res 2002;90:215.
85. Saini S, Nair N, Saini MR. Embryotoxic and teratogenic effects of nickel in Swiss albino mice during organogenetic period. Biomed Res Int 2013;2013:701439.
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How to Cite
HAMDI, H. “MATERNAL AND FETAL TOXICITY-INDUCED BY NICKEL OXIDE NANOPARTICLES ADMINISTRATION IN ALBINO RATS DURING GESTATION”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 13, no. 9, June 2020, pp. 98-109, doi:10.22159/ajpcr.2020.v13i9.38655.
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