Developmental toxicity of intravenously injected zinc oxide nanoparticles in rats

Abstract

Recent toxicity studies of zinc oxide nanoparticles by oral administration showed relatively low toxicity, which may be resulted from low bioavailability. So, the intrinsic toxicity of zinc oxide nanoparticles needs to be evaluated in the target organs by intravenous injection for full systemic concentration of the administered dosage. Although the exposure chance of injection route is low compared to oral and/or inhalation route, it is important to see the toxicity with different exposure routes to get better risk management tool. In this study, the effects of zinc oxide nanoparticles on dams and fetuses were investigated in rats after intravenous injection (5, 10, and 20 mg/kg) from gestation day 6 to 20. Two of 20 dams in the 20 mg/kg treatment group died during the treatment period. Hematological examination and serum biochemistry showed dose-dependent toxicity in treated dams. Histopathological analysis of treated dams revealed multifocal mixed cell infiltration and thrombosis in lung, tubular dilation in kidneys, and extramedullary hemopoiesis in liver. Total dead fetuses (post-implantation loss) were increased and the body weight of fetus was decreased in the 20 mg/kg treatment group. Statistical differences in corpora lutea, resorption, placental weight, morphological alterations including external, visceral and skeletal malformations were not observed in treated groups. Based on the data, lowest observed adverse effect level of injection route was suggested to be 5 mg/kg in dams and no observed adverse effect level was suggested to be 10 mg/kg in fetal developmental toxicity.

Exposure to Alumina Nanoparticles in Female Mice During Pregnancy Induces Neurodevelopmental Toxicity in the Offspring

“…Previous research on metal oxidative NPs found developmental toxicity induced by nano-silver ( Xin et al, 2015 ; Charehsaz et al, 2016 ; Ema et al, 2017 ; Pecoraro et al, 2017b ), nano-silica ( Yi et al, 2016 ), graphene oxide ( Buccheri et al, 2016 ; Pecoraro et al, 2017a ), zinc oxide ( Bonfanti et al, 2015 ; Zhou et al, 2015 ; Lee et al, 2016 ; Spence et al, 2016 ), iron oxide ( Di Bona et al, 2015 ), copper oxide ( Maisano et al, 2015 ; Ganesan et al, 2016 ; Torres-Duarte et al, 2016 ), magnesium oxide ( Ghobadian et al, 2015 ), titanium dioxide ( Scuderi et al, 2014 ; Parivar et al, 2015 ; Rollerova et al, 2015 ; Brundo et al, 2016 ), and cerium oxide ( Andersen et al, 2016 ). Moreover, studies have shown that bulk-Al, once entering the brain, persists for a very long time with a half-life ranging from 20% of the lifespan to greater than the entire lifespan ( Yokel, 2000 , 2002 ; Priest, 2004 ; Exley and House, 2011 ).…”

Translocation of (ultra)fine particles and nanoparticles across the placenta; a systematic review on the evidence of in vitro, ex vivo, and in vivo studies

“…, poly(glycidyl methacrylate) (PGMA), and PS) (Table 3 ). Fetal/embryonic NP accumulation was observed in 32 of the included animal studies, more specifically NPs were detected in the fetal brain [ 27 , 44 , 48 , 52 , 60 , 73 , 78 , 80 , 81 , 91 ], fetal liver [ 27 , 48 , 50 , 52 , 60 , 69 , 73 , 83 , 84 , 86 ], fetal lung [ 27 , 48 , 52 , 75 ], fetal kidney [ 48 , 52 , 84 ], fetal gastrointestinal tract (GIT) [ 88 ], and fetal blood [ 92 ]. The preferred method for NP administration was intravenous (i.v.)…”

“… [ 82 ] Sprague Dawley rats 4 ZnO NPs/ citrate 20 a oral/ 0 or 400 mg/kg/ GD5–19 d ICP-OES / No significant difference in fetal Zn content between control and ZnO NP exposed group. [ 83 ] Sprague Dawley rats 10 ZnO NPs/ APTES > 35 a i.v./ 0 or 20 mg/kg/ GD6–20 d ICP-MS / Significantly elevated Zn levels in fetal liver after IV injection of pregnant rats with ZnO NPs. [ 84 ] Sprague Dawley rats 24 ZnO NPs < 100 a oral/ 0 or 500 mg/kg/ 14 days before mating-day 4 of lactation g ICP-MS / Significantly higher levels of Zn in liver and kidneys, but not in blood and brain of rat offspring exposed to ZnO NPs before, during, and after gestation.…”

“…This supports the finding that the placenta is not an impenetrable barrier, as already confirmed for other xenobiotics such as drugs and alcohol [ 131 ]. In animal models, transplacental passage has been reported for Ag NPs [ 47 – 54 ], Al 2 O 3 NPs [ 44 ], Au NPs [ 57 , 59 – 61 ], CeO 2 NPs [ 67 ], DEP [ 91 ], QDs [ 62 ], SiO 2 NPs [ 70 , 71 , 73 , 74 ], TiO 2 NPs [ 73 , 75 , 76 , 78 , 80 , 81 ], ZnO NPs [ 83 – 85 ], ZrO 2 NPs [ 86 ], Fe 2 O 3 NPs [ 69 ], C60 fullerenes [ 87 ], PGMA NPs [ 89 ], and PS NPs [ 27 ]. Among these particles, only Ag NPs [ 37 ], Au NPs [ 31 , 38 ], and PS NPs [ 40 – 43 ] showed transplacental transfer in an ex vivo perfusion model, whereas SiO 2 NPs [ 25 ] and TiO 2 NPs [ 34 ] were retained in the placental tissue.…”

Nano Zinc Oxide Induced Fetal Mice Growth Restriction, Based on Oxide Stress and Endoplasmic Reticulum Stress

“…During the pregnancy stage, harmful effects of new products such as those containing ZnO NPs, affect the reproductive route inducing fetal malformation or even fetal death. Recently, some researches showed that ZnO NPs could cause reproductive and development toxicity, but insufficient studies had been devoted to determination of the internal mechanism involved in the reproductive toxicity of ZNOs [7,18,19].…”