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Contents

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

Metal nanoparticles play an increasing role in consumer products, biomedical applications and in the work environment. Therefore, the effects of nanomaterials need to be properly understood. This applies especially to their potential reproductive toxicology (nanoreprotoxicity), because any shortcomings in this regard would be reflected into the next generation. This review is an attempt to summarize the current knowledge regarding the effects of nanoparticles on reproductive outcomes. A comprehensive collection of significant experimental nanoreprotoxicity data is presented, which highlight how the toxic effect of nanoparticles can be influenced, not only by the particles’ chemical composition, but also by particle size, surface modification, charge and to a considerable extent on the experimental set-up. The period around conception is characterized by considerable cytological and molecular restructuring and is therefore particularly sensitive to disturbances. Nanoparticles are able to penetrate through biological barriers into reproductive tissue and at least can have an impact on sperm vitality and function as well as embryo development. Particularly, further investigations are urgently needed on the repetitively shown effect of the ubiquitously used titanium dioxide nanoparticles on the development of the nervous system. It is recommended that future research focuses more on the exact mechanism behind the observed effects, because such information would facilitate the production of nanoparticles with increased biocompatibility.


Introduction

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

The rapidly growing field of nanotechnology has created the potential for increasing nanoparticle exposure to humans. A multitude of new products containing such particles reaches the market every year, often without thorough toxicology tests (Oberdorster et al. 2005) or on product information. Many of them reach the consumer in the form of commercial products (Fig. 1a, Woodrow Wilson Database). A predominant category in this context is nanoparticles made from silver (Fig. 1b, Woodrow Wilson Database), which have been often reported to be cytotoxic (Johnston et al. 2010). These are followed by carbon, zinc, silica, titanium and gold nanoparticles. Another area, where nanoparticles are increasingly used, is in medical and biomedical research. In this regard, the main emphasis is on selective sensing (Wang and Ma 2009) and imaging of target molecules (Qian et al. 2008), localized cancer therapy by plasmonic heating of malignant tissue (Gannon et al. 2008) and delivery of effector molecules to specific receptors or target areas (Han et al. 2006).

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Figure 1.  (a) Number of total products listed by date of inventory update, with regression analysis. (b) Numbers of products associated with specific materials [Woodrow Wilson Database, 2012 (http://www.nanotechproject.org)]

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Contact with nanoparticles does not necessarily result from the use of nanoparticle products. The working environment can lead also to exposure to a considerable dose of nanoparticles, for example, airborne fumes released during welding of chromium–nickel-based steels (Antonini 2003). In general, thermal processing of metals releases airborne particles into the workplace that may cause adverse health effects. The processing of materials by laser, for example, releases a high fraction of nanoparticles (Barcikowski et al. 2007). Even conventional welding sets free particles with comparable high-specific surface area (Pohlmann et al. 2008). Apart from external sources, internal exposure to nanoparticles derived from mechanical wear of surgical implants (usually consisting of nickel/titanium or cobalt/chrome alloys) also exists (Brown et al. 2006; Case et al. 1994).

The main sources and routes of exposure are summarized in Fig. 2.

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Figure 2.  Main sources and routes of nanoparticle exposure

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Compared with the corresponding bulk material, nanoscale particles are considerably more biologically active, which seems to derive mainly from their higher mass-specific surface area and is mirrored by a surface-specific dose–response (Faux et al. 2003; Oberdorster et al. 2005). The reasons suggested for cellular damage caused by nanoparticle exposure include production of reactive oxygen species (ROS; Oberdorster et al. 2005) and interaction with DNA (Singh et al. 2009). In somatic cells such insults cause inflammation or even malignant transformation. However, in case of germ line cells, either defect might lead to impaired fertility and/or congenital defects in the offspring. This hypothesis is supported by studies showing that male welders, especially those who work with stainless steel, have poorer sperm quality than those in other work. Moreover, an increase in either miscarriages or delayed conception was observed among welders and their spouses, compared with men in other professions (Antonini 2003). Consequently, it is surprising that there has been little more effort on studying the effects of nanoparticles on reproduction and on reproductively relevant cells and tissues.

This review will mainly focus on the potential reproductive toxicology of metal nanoparticles (nanoreprotoxicity), because of their high abundance in consumer as well as biomedical products.

Production of Metal Nanoparticles

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

Nanoparticles are generally defined as separate particles between 1 and 100 nm in size (ASTM International). Their common generation states are solid powders, gaseous aerosols and colloidal dispersions in water or organic solvents, depending on preparation conditions and capping agents on the particle surface. Colloids are often preferred for use in research because of their safe and stable handling form, without the risk of particle inhalation.

In the last two decades, a multiplicity of fabrication methods has been established for nanoparticle synthesis covering chemical and physical processes. The principle of the chemical approach involves the stepwise formation of nanoclusters based on nucleation, growth and agglomeration of atoms or molecular entities in solution (Watzky and Finke 1997). To control subsequent agglomeration of nuclei and nanoparticle size, stabilizing agents like sodium citrate or tetraoctylammonium bromide are added to the reaction solution.

The physical synthesis approach has become a reliable alternative to these traditional chemical reduction methods for obtaining gold nanoparticles. For this method, nanoparticle generation is achieved by pulsed laser ablation in liquids by conversion of a solid metal target (Barcikowski et al. 2008). The basic experimental set-up was pioneered by Henglein (1993) and consists of a pulsed laser system, a set of beam guidance and focussing optical components, and a vessel, containing a solid gold plate at the bottom, covered with a liquid layer of ablation medium. The particles are directly ejected from the target material surface owing to photomechanical effects and as a consequence of the irradiation with intense laser light. Thereby, stable nanoparticles are obtained in water and organic liquids without precursor, stabilizing additives and further purification steps.

Influences on Nanoparticle Toxicity

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

A multitude of parameters influence what happens at the nano–bio interface and thus determine the toxic potential of any given nanoparticle (Nel et al. 2009). Besides the chemical composition of the nanoparticle, size, surface modification, shape and polarity have to be considered to be biologically active. A further effect is added by the suspending medium, which has a major role in determining the surface potential of the nanoparticles. Therefore, the results of nanoparticle toxicity studies can be of considerable heterogeneity, because the particles used, even if they are of the same material, can differ in other aspects.

This diversity can be sensed by looking exemplarily at the results of different cell culture studies concerning the toxicity of gold nanoparticles. In some trials, no toxicity was observed (Connor et al. 2005; Fu et al. 2005; Shenoy et al. 2006), whereas others detected low to medium (Massich et al. 2010; Thomas and Klibanov 2003, Tkachenko et al. 2004) and even high toxicity (Pan et al. 2007; Patra et al. 2007) (Table 1). The relevance of nanoparticle size can be seen in the study performed by Pan et al. (2007), showing that even a small difference in size can make particles up to six times more damaging. Experiments by Massich et al. (2010) highlighted the influence of surface modifications. These authors detected a cytotoxic effect of gold nanoparticles in conjunction with citrate, a common stabilizing agent in chemically derived nanoparticles, but none when bovine serum albumin or DNA was used. In two other studies, nanoparticles were produced by laser ablation in liquids. This method requires no stabilizing agent so that the particles remain entirely without any surface modification. Whereas Salmaso et al. (2009) did not notice any toxicity with such particles, Taylor et al. (2010a) showed a cytotoxic effect, but only if very few cells were exposed to large numbers of AuNP (6 × 106 particles/cell).

Table 1.   Cytotoxicity of gold nanoparticles with different modifications in various cell lines
ReferenceCell lineSurface modificationNP concentration and sizeExposure durationTestsResults
  1. N/A, no data.

Connor et al. (2005)Leukaemia cell line, K562Citrate, biotin, l-cysteine, glucose, CTAB0–250 μm Au d = 4, 12, 18 nm3 daysMTTToxic, only if modified with glucose and cystein and NP concentration >25 μm
Fu et al. (2005)Human breast carcinoma xenograft cells, MDA-MB-231Coumarin-PEG-thiol50–200 μg/ml d = 10 nm24 hCell Titre 96No Toxicity detected
Shenoy et al. (2006)Human breast carcinoma xenograft cells, MDA-MB-231Coumarin-PEG-thiol50–200 μg/ml d = 10 nm24 hCell Titre 96No Toxicity detected
Thomas and Klibanov (2003)COS-7 cellsPEI2N/A6 h, 42 hMTT20–30% loss of viablility
Tkachenko et al. (2004)Human liver carcinoma, HepG2BSA, four targeting peptidesN/A d = 20–25 nm12 hLDH5% loss of viability
Massich et al. (2010)Cervix carcinoma, HeLaCitrate, BSA, ssDNA, dsDNA, dsRNA10 nm d = 15 nm24 hGene expression analysis, Cell-cycle analysis, Annexin assayCitrate stabilized NP caused change in gene expression, disturbance of mitosis and ca. 20% increase in apotosis
Pan et al. (2007)Cervix carcinoma, HeLa; Melanoma, SK-Mel-28; mouse fibroblasts, L929; mouse macrophages (J774A1)Triphenylphosphine derivates0–6300 μm d = 8.0–15 nm48 hMicroscopy, MTT, Annexin assayHighest toxicity (threefold higher than any other size) at 1.4 nm diameter
Patra et al. (2007)Human lung carcinoma, A549; Human liver carcinoma, HepG2; Syrian hamster kidney fibroblasts, BHK21Citrate0–120 nm d (hydodynamic) = 33 nm48 hMicroscopy, PI, MTT, Cleavage of poly(ADP-ribose) polymeraseToxicity detected in A549 cells only, after exposure to 10 nm

The impact of the nanoparticles surface potential can nicely be seen in experiments conducted by Ding et al. (2010). The surface potential is usually described as zeta potential, the potential difference between the dispersion medium and the stationary layer of fluid attached to the dispersed particle. An increased loss of cell viability was observed after exposure to gold nanoparticles with a zeta potential of 40 mV, compared with 20 and 30 mV.

The listed results derived from cell culture studies show that the biocompatibility of nanoparticles is by no means simply a matter of the particle material in conjunction with the dosage, but is the outcome of complex interactions at the nano–bio interface influenced by many factors. This has to be considered when studying the reprotoxical effects of nanoparticles.

Translocation to Reproduction-Relevant Sites

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

Mammalian gametes and the developing embryo are highly vulnerable and therefore situated in rather protected environments. However, of several studies reported, most have shown the ability of nanoparticles to effectively crossbiological barriers including the ones protecting the reproductive tissue (Table 2). Kim et al. (2006) showed in a mouse study that magnetic nanoparticles with a SiO2 surface modification effectively crossed the blood-testis barrier after intraperitoneal injection. Aujuro et al. (1999) noted polymethyl (2-14C) methacrylate nanoparticles in rat testis after oral administration, whereas Balasubramanian et al. (2010) observed the same for gold nanoparticles after intravenous injection. Neither of the latter two authors analysed the toxic effects of the particles. However, because several types of nanoparticles administered via different routes using two animal models lead to the same result, it seems prudent to conclude that the blood-testis barrier does not stop nanoparticles from entering the testis.

Table 2.   Translocation of metal nanoparticles through reproduction-relevant physiological barriers
AuthorBarrierAnimal/ModelNanoparticleExposureResults
  1. MNPs@SiO2, Magnetic nanoparticles coated with silicium dioxide; PMMA, Polymethyl (2-14C) methacrylate nanoparticles; AuNP, Gold nanoparticle; TiO2NP, Titanium dioxide nanoparticles; SiO2NP, Silicium dioxide nanoparticles; AuNP@PEG, Gold nanoparticles coated with polyethylene glycol.

Yamashita et al. (2011)Placental barrierMiceTiO2NP SiO2NPivCrossed, embryo toxic effects
Balasubramanian et al. (2010)Blood-testis-barrierMale Wistar ratsAuNP0.2 ml iv of a suspension containing 15.1 μg/ml AuNPCrossed
Wick et al. (2010)Placental barrierHuman placentaPolystyrenePerfusion modelCrossed
Chu et al. (2010)Placental barrierMiceCdTe/CdS quantum dotsivCrossed, embryo toxic effects
Takeda et al. (2009)Placental barrierPregnant Slc:ICR miceTiO2NP100 μg/mouse/day on GD 3,7, 10,14 scCrossed, toxic effects in testis and brain of offspring
Myllynen et al. (2008)Placental barrierHuman placentaAuNP@PEGPerfusion modelNo crossing
Sadauskas et al. (2007)Placental barrierPregnant C57BL/6 miceAuNPiv on GD 16–18No crossing
Semmler-Behnke et al. (2007)Placental barrierWKY rats198AuNPiv 3rd trimesterCrossed
Kim et al. (2006)Blood-testis-barrierMale IRC mice (6 weeks)MNPs@SiO2Up to 100 mg/kg ipCrossed, to toxicity
Araujo et al. (1999)Blood-testis-barrierMale Wistar ratsPMMAoralCrossed
Takahashi and Matsuoka (1981)Placental barrierWistar rats198AuNPiv on GD 19Crossed
Challier et al. (1973)Placental barrierPregnant SD rats198AuNPSingle injection into iliac arteryNo crossing

Concerning the placental barrier, the results listed in the literature are less conclusive. While Wick et al. (2010) showed placental crossing for polystyrene nanoparticles in a human placenta explant, Myllynen et al. (2008) noted no crossing for gold nanoparticles in the same model. Several studies on rodent models investigated placental crossing of gold nanoparticles after administration directly into the blood stream. Despite the similarity in the experimental set-up, particles were observed to have passed through the placenta in two studies (Semmler-Behnke et al. 2007; Takahashi and Matsuoka 1981), whereas two other groups reported the opposite effect (Challier et al. 1973; Sadauskas et al. 2007). The crossing of the placenta by titanium dioxide nanoparticles after intravenous injection of pregnant mice was proven by two authors along with embryo toxic effects (Takeda et al. 2009; Yamashita et al. 2011). Chu et al. (2010) showed the same for CdTe/CdS quantum dots. In summary, transplacental crossing of nanoparticles is likely, but seems to depend on currently unknown mechanisms that prevent certain particle preparations from passing through.

Whether nanoparticles can penetrate into ovaries or follicles has not been studied as yet, but given the above-mentioned data, it seems a likely scenario, at least for some types of nanoparticles.

Effect of Nanoparticles on Male Gametes

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

Few studies have focussed on the effect of nanoparticles on germ cells. A summary is listed in Table 3. The evaluations of sperm toxic effects made so far were conducted with nanoparticles made from TiO2 (Guo et al. 2008), gold (Taylor et al. 2010c; Wiwanitkit et al. 2009; Zakhidov et al. 2010), polyvinyl alcohol (PVA)-coated iron oxide (Makhluf et al. 2006), europium dioxide, europium hydroxide in conjunction with polyvinylpyrollidone (PVP) and PVA (Makhluf et al. 2008) and zinc oxide and titanium dioxide (Gopalan et al. 2009). While Fe3O4-PVA particles showed no detrimental effects on spermatozoa, AuNP caused a drop in sperm motility and, according to Wiwanitkit et al. (2009), also sperm fragmentation, an effect which was not noted by Taylor et al. (2010c). Differences between the two studies might be explained by the fact that the former authors used chemically derived nanoparticles, whereas the latter worked with precursor-free made, laser-generated particles. Therefore, the observed effect might be due to remnants of the chemical fabrication process or the stabilizing agent rather than the nanoparticle itself. Zakhidov et al. (2010) tested very small gold nanoparticles with a diameter of 2.5 nm. Interestingly, the authors noted a disruption of nuclear chromatin decondensation. ZnONP and TiO2NP were also found to lead to sperm DNA damage. Interestingly, whereas Eu2O3NP with a diameter of 30 nm and positive zeta potential caused a complete cessation of sperm motility, particles made from Eu(OH)3 conjugates with a diameter of 15 and 9 nm, respectively, and a slightly negative zeta potential had no effect, even though in the latter case more nanoparticles were actually found inside the spermatozoa. This example shows how nanoparticles, seemingly of similar material, can have widely different effects.

Table 3.   Effects of metal nanoparticles on male reproduction
AuthorAnimal/ModelNanoparticleConcentrationSizeExposureResults
  1. AuNP, Gold nanoparticle; TiO2NP, Titanium dioxide nanoparticles; ZnONP, Zinc oxide nanoparticles; PVA, Polyvinyl alcohol; Eu2O3NP, Europium oxide nanoparticles; PVP-Eu(OH)3 NP, Polyvinylpyrrolidon–europiumhydroxide nanoparticles; PVA-Eu(OH)3 NP, Polyvinyl alcohol–europiumhydroxide nanoparticles; Fe3O4NP, iron oxide nanoparticles; MoO3NP, Molybdenum oxide nanoparticles; AlNP, Aluminium oxide nanoparticles; N/A, no data.

Braydich-Stolle et al. (2010)Mouse spermatogonial stem cells C18-4Hydrocarbon- and polysaccharide-coated AgNP5–100 μg/ml10, 15, 25 and 80 nmSuspended in cell culture medium, 24–48 hAt 10 μg/ml disruption of Fyn kinase signalling, at 25 μg/ml decline in proliferation
Taylor et al. (2010c)Bovine spermatozoaAuNP0.5–50 μm Au5–65 nmSuspended in medium, 2 h22% loss in sperm motility after exposure to 50 μm Au
Zakhidov et al. (2010)Mouse epididymal spermatozoaAuNP0.5 and 1 × 1015 particles/ml2,5 nmSuspended in mediumDisruption of nuclear chromatin decondensation
Guo et al. (2008)ICR miceTiO2NP200 and 500 μg/kgN/AIntraperitoneal injection every other day for five timesReduced sperm density and motility, increased sperm abnormality, germ cell apoptosis
Gopalan et al. (2009)Human spermatozoaZnONP, TiO2NPZnONP: 11.5–93.2 μg/ml TiO2NP: 3.73–59.7 μg/ml40–70 nmSuspended in mediumConcentration-dependant induction of DNA damage
Wiwanitkit et al. (2009)Human spermatozoa, single donorAuNPN/A9 nmSuspended in medium, 15 min20% loss in sperm motility, fragmentation of spermatozoa
Makhluf (2008)Bovine spermatozoaEu2O3NP PVP-Eu(OH)3 NP PVA-Eu(OH)3 NP2.5 mg/ml Eu2O330 nm 9 nm 15 nmSuspended in medium, 24 hEu2O3NP: complete loss of motility PVP-Eu(OH)3 NP and PVA-Eu(OH)3 NP: no effect
Makhluf et al. (2006)Bovine spermatozoaPVA-coated Fe3O4NP7.35 mm Fe5 nmSuspended in modified Tyrode medium, up to 150 minNo toxicity observed
Braydich-Stolle et al. (2005)Mouse spermatogonial stem cells C18-4AgNP, MoO3NP, AlNP5, 10, 25, 50 and 100 μg/mlAgNP: 15 nm MoO3NP, AlNP: 30 nmSuspended in PBS, 48 hConcentration-dependent toxicity for all particle types, Ag > Al > MoO3, no effect of soluble salts

In none of the studies where sperm toxicity was observed was the mode of action investigated. Tests on spermatogonial stem cells (Braydich-Stolle et al. 2005, 2010) using silver, molybdenum trioxide and alumina nanoparticles showed a concentration-dependent cytotoxicity for all types of particles, with AgNP being the most and MoO3NP the least toxic. In case of AgNP, the toxicity seems to be due to interactions of nanoparticles with a cell proliferation associated, intracellular kinase. Therefore, despite the scarcity of experimental data, there is a clear tendency for nanoparticles to have toxic effects on cells relevant to male reproduction.

Effect of Nanoparticles on Female Gametes

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

Nano-toxicity in female reproduction has only been investigated in two studies. Huo et al. (2009) cocultured pre-antral follicles obtained from rats with titanium dioxide particles, which caused morphological changes in the follicles and lead to a reduced number of matured oocytes. The second study by Hsieh et al. (2009) investigated the effect of CdSe-core QDs on oocyte maturation, fertilization, and subsequent pre- and post-implantation development of mouse oocytes/embryos in vitro. The authors reported a reduction in the rates of oocyte maturation, fertilization and in vitro embryo development along with increased resorption of post-implantation embryos and decreased placental and foetal weights. The effects were obliterated when the quantum dots were ZnS-coated.

Embryo Development

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

Embryo development after exposure to nanoparticles is comparatively well investigated. The majority of studies on embryo toxicology have concentrated on piscine embryos, mostly derived from zebra fish. A summary is given in Table 4. The types of nanoparticles tested in these systems include metals and metal oxides such as gold (Bar-Ilan et al. 2009; Browning et al. 2009), silver (Bar-Ilan et al. 2009; Laban et al. 2010; Lee et al. 2007; Ringwood et al. 2010; Wu et al. 2010; Yeo and Yoon 2009), nickel (Ispas et al. 2009), zinc oxide (Bai et al. 2010b; Yeo and Kang 2009; Zhu et al. 2008) titanium dioxide (Musee et al. 2010; Zhu et al. 2008), aluminium trioxide (Zhu et al. 2008) and copper (Bai et al. 2010a). Severe toxic effects in the form of decreased survival rates and deformations were observed after exposure to AgNP, CuNP and ZnONP, even in low concentrations. In comparison, in the case of NiNP, concentrations were tenfold higher before any toxicity was noted. AuNP, TiO2NP and Al2O3NP showed hardly any detrimental effects.

Table 4.   Effect of metal nanoparticles on embryo development in piscine species and molluscs
AuthorAnimal/ModelNanoparticleConcentrationSizeExposureResults
  1. AuNP, Gold nanoparticle; TiO2NP, Titanium dioxide nanoparticles; AgNP, Silver nanoparticles; NiNP, Nickel nanoparticles; CuNP, Copper nanoparticles; ZnONP, Zinc oxide nanoparticles; Al2O3NP, Aluminium oxide nanoparticles; N/A, no data.

Musee et al. (2010)Freshwater snail embryosTiO2NP0–0.5 g/kg11 nmSpiked aquarium sand, 96 h and 28 daysNo toxicity detected
Ringwood et al. (2010)Oyster embryosAgNP0.0016–1.6 μg/l15±6 nmSuspended in seawater, 48 hAt 1.6 μg/l normal embryo development dropped by 80%
Wu et al. (2010)Japanese medaka embryosAgNP100–2000 μg/l20–37 nmSuspended in water, 70 daysMorphological malformations even at low doses, LD50 = 1.03 mg/l
Bai et al. (2010a)Zebrafish embryosCuNPN/AN/ASuspended in E3 mediumMorphological malformations, death >0.1 μg/l
Bai et al. (2010b)Zebrafish embryosZnONP0–100 mg/l30 nmSuspended in E3 medium, 96 hDevelopmental abnormalities 1 mg/l, death 50 mg/l
Laban et al. (2010)Fathead minnow embryosAgNP0.625–25 mg/l21–280 nmSuspended in water, 96 hMorphological malformations 2.5 mg/l, LD50 = 1.3 mg/l
Ispas et al. (2009)Zebrafish embryosNiNP10–1000) mg/l30, 60, 100 nm + aggregatesSuspended in E3 medium, 4 daysDevelopmantal abnormalities, 30 nm: LD50 = 328 mg/l60 nm: LD50 = 361 mg/l100 nm: LD50 = 221 mg/l Aggregates: LD50 = 115 mg/l
Yeo and Kang (2009)Zebrafish embryosTiO2NP, TiO2NP + Cu10–20 ppt30–50 nmSuspended in water, 72 hDecreased hatch rate, developmental abnormalities, Induction of oxidative stress
Yeo and Yoon (2009)Zebrafish embryosAgNP10–20 ppt20–30 nmSuspended in water, 72 hDevelopmental abnormalities, increased apoptosis
Bar-Ilan et al. (2009)Zebrafish embryosAuNP, AgNP0.25–250 μm Au/Ag3, 10, 50, 100 nmSuspended in egg-water, 120 hNo appreciable toxicity of AuNP, developmental abnormalities at 25 μm Ag, Increased mortality at 100 μm Ag
Browning et al. (2009)Zebrafish embryosAuNP0.025–1.2 nm AuNP11.6 ± 0.9 nmSuspended in egg-water, 120 hSlight increase in deformities
Zhu et al. (2008)Zebrafish embryosZnONP, TiO2NP, Al2O3NP, in comparison with bulk counterpartsZnO: 0–50 mg/l TiO2: 0–500 mg/l Al2O3: 0–1000 mg/lZnO: 50–360 nm TiO2: 100–550 nm Al2O3: 285–2450 nmSuspended in water, 96 hToxicity only in Zno + ZnO bulk, 96 h LC50Nano = 1.7996 h LC50Bulk = 1.55
Lee et al. (2007)ZebrafishAgNP0–0.71 nm11.6 ± 3.5 nmSuspended in egg-water, 120 h>0.19 nm only dead or deformed embryos observed

Extensive research on nanoreprotoxicology has also been conducted on chicken embryos (Table 5). Interestingly, in this species, exposure to nanoparticles made of gold (Zielinska et al. 2009), silver (Grodzik and Sawosz 2006, Sikorska et al. 2010), silver–palladium alloy (Studnicka et al. 2009) and silver–copper alloy (Sawosz et al. 2009) by in vivo injection caused no abnormal development, except a slight indication of inflammation in the embryo liver after contact with AgCu alloy nanoparticles.

Table 5.   Effect of metal nanoparticles on embryo development in chicken
AuthorAnimal/ModelNanoparticleConcentrationSizeExposureResults
  1. AuNP, Gold nanoparticle; AgNP, Silver nanoparticles; Ag/Cu alloy NP, Silver/Copper alloy nanoparticles; Ag/Pd alloy NP, Silver/Paladium alloy nanoparticles; N/A, no data.

Sikorska et al. (2010)Chicken, eggAgNP50 ppmN/AInjection in ovo (0.3 ml)No effect on bone structure
Sawosz et al. (2009)Chicken, eggAgNP, AuNP, Ag/Cu alloy NP50 ppm<100 nmInjection in ovo (0.3 ml), 18 daysNo toxic effects, Ag/Cu alloys caused increased NF-kappa B mRNA expression
Studnicka et al. (2009)Chicken, eggAg/Pd alloy NPN/AN/AInjection in ovoNo toxic effects
Zielinska et al. (2009)Chicken, eggAuNPN/AN/AInjection in ovoNo toxic effects
Sawosz et al. (2009)Chicken, eggAgNP, Ag/Cu alloy NP Ag/Pd alloy NP50 ppm2–6 nmInjection in ovo (0.3 ml), 48 h and 20 daysNo toxic effects
Grodzik and Sawosz (2006)Chicken, eggAgNP10 ppm Injection in ovo on day 5, 11 and 17No abnormal development, decrease in lymph follicular number and size

Studies exploring embryo toxicology of nanoparticles in mammals are not as abundant as those for fish and chickens (Table 6). However, worryingly, especially with regard to the widely used titanium dioxide nanoparticles, a considerable amount of evidence points to an effect on the development of the nervous system. In a study by Takeda et al. (2009), performed on mice, damage to genital and cranial nerve systems was observed in the pups after exposure of the mothers to titanium dioxide nanoparticles by subcutaneous injection. The presence of nanoparticles was confirmed in the damaged organs. Another study showed that comparable exposure increased levels of dopamine in the brains of offspring (Takahashi et al. 2010). Shimizu et al. (2009) injected titanium dioxide nanoparticles subcutaneously into pregnant mice, which affected in the offspring the expression of genes related to the development and function of the central nervous system. Hougaard et al. (2010) noted that offspring prenatally exposed to titanium dioxide nanoparticles, after maternal inhalation exposure, exhibited changes in activity and in sensory-motor processes. Gao et al. (2011) observed that titanium increased in the hippocampus along with attenuated synaptic plasticity in the hippocampus (associated with learning and memory) in the foetal brain after the oral administration of titanium dioxide nanoparticles to rats during gestation. Not only the nervous system was affected, as Fedulov et al. (2008) noted an increased risk of mouse pups developing respiratory disease if the mothers were exposed to titanium dioxide nanoparticles by intranasal installation.

Besides titanium dioxide, only very few other nanomaterials have been explored for their developmental toxicity in mammalian species. Li et al. (2010) investigated silver nanoparticles for their effect on blastocyst development after coculture in a mouse model. The authors observed increased apoptosis, decreased cell numbers and decreased implantation success rates. Contrary to these findings, Taylor et al. (2010b) found no detrimental effects with regard to embryo development after injecting two-cell stage mouse embryos with gold and silver nanoparticles. Interestingly, whereas the former used chemically derived nanoparticles, the latter worked with particles produced by laser ablation in liquids. This suggests a better biocompatibility of the laser-generated nanoparticles, which might be at least partially due to the complete lack of stabilizers and other potentially noxious agents used for the production of chemically derived particles. In another study, the effect of cobalt–chromium nanoparticles on human trophoblast choriocarcinoma cell lines and a layer of BeWo b30 cells was examined, and DNA damage in the fibroblasts was noted despite indirect exposure (Bhabra et al. 2009).

In summary, the listed findings highlight how various developing organisms react to nanoparticles. Besides the chemical modalities of the tested nanoparticles, the production method and especially the test system itself seems to play a major role in the outcome of the study. Even particles commonly viewed as rather noxious, like silver nanoparticles, did not always display the expected toxicity, which shows how difficult it is to extrapolate results from one species to another. Therefore, there is a pressing need for further studies of nanoreprotoxicity in animal models phylogenetically close to the human.

Conclusion

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References

From the published data, it is rather difficult to depict clear trends regarding the biocompatibility of metal nanoparticles. However, most studies observed adverse effects under certain dosage conditions, regardless of the nanoparticles used.

Unfortunately, it is rather difficult to compare studies, particularly because the information given concerning the dosage of nanoparticles is very diverse. It would be useful if common nomenclature could be developed to express nanoparticle dose. One option would be to calculate the particle surface exposed to a certain number of cells or the exact mass of an organism, as suggested by Oberdorster et al. (2005), because it combines particle number and size with the amount of exposed biomass. This approach has been shown to fit very well with dose–response curves, allowing threshold limit values, given by nanoparticle surface per rat lung tissue in units of cm2/g, to be extracted. Additionally, resilient methods for particle quantification in the tested biological material, such as has been shown for gold nanoparticles in vitro using a conventional laser scanning confocal microscope (Klein et al. 2010), are still missing for many particle types.

Another weakness in the literature published so far is the almost purely descriptive nature of the toxic effects of nanoparticles. The mechanisms, which determine particle biocompatibility, are mostly elusive at the moment. Thus, it is recommended that future research explores the interactions between nanomaterials and biological matter on a molecular level. This might require several levels of interdisciplinary research. It would, for instance, be of major importance to understand the effect of nanoparticles on lipid bilayer membranes, with the aim of controlling the penetrating behaviour of nanoparticles. This could be studied in isolated systems on artificial membranes outside the cellular context. The knowledge gained from such experiments could then be transferred to studies in the more complex biological environment.

Furthermore, information is missing concerning the effect of nanomaterials on the overall reproductive outcome. To obtain this information, long-term studies would be required using animal models phylogenetically close to humans and exposure conditions that reflect realistic scenarios with regard to dosages and routes of admission. Similar studies also need to be conducted with indicator species for sensitive ecosystems to estimate the impact of nanoparticles after intended or unintended release into the environment.

References

  1. Top of page
  2. Contents
  3. Introduction
  4. Production of Metal Nanoparticles
  5. Influences on Nanoparticle Toxicity
  6. Translocation to Reproduction-Relevant Sites
  7. Effect of Nanoparticles on Male Gametes
  8. Effect of Nanoparticles on Female Gametes
  9. Embryo Development
  10. Conclusion
  11. Conflicts of interests
  12. Funding resources
  13. References
  • Antonini JM, 2003: Health effects of welding. Crit Rev Toxicol 33, 61103.
  • Araujo L, Sheppard M, Lobenberg R, Kreuter J, 1999: Uptake of PMMA nanoparticles from the gastrointestinal tract after oral administration to rats: modification of the body distribution after suspension in surfactant solutions and in oil vehicles. Int J Pharm 176, 209224.
  • Bai W, Tian W, Zhang Z, He X, Ma Y, Liu N, Chai Z, 2010a: Effects of copper nanoparticles on the development of zebrafish embryos. J Nanosci Nanotechnol 10, 86708676.
  • Bai W, Zhang ZY, Tian WJ, He X, Ma YH, Zhao YL, Chai ZF, 2010b: Toxicity of zinc oxide nanoparticles to zebrafish embryo: a physicochemical study of toxicity mechanism. J Nanopart Res 5, 16451654.
  • Balasubramanian SK, Jittiwat J, Manikandan J, Ong CN, Yu LE, Ong WY, 2010: Biodistribution of gold nanoparticles and gene expression changes in the liver and spleen after intravenous administration in rats. Biomaterials 31, 20342042.
  • Barcikowski S, Hahn A, Chichkov BN, 2007: Nanoparticles as potential risk during femtosecond laser ablation. J Laser Appl 19, 6573.
  • Barcikowski S, Hustedt M, Chichkov B, 2008: Nanocomposite manufacturing using ultrashort-pulsed laser ablation in solvents and monomers. Polimery-W 53, 657662.
  • Bar-Ilan O, Albrecht RM, Fako VE, Furgeson DY, 2009: Toxicity assessments of multisized gold and silver nanoparticles in zebrafish embryos. Small 5, 18971910.
  • Bhabra G, Sood A, Fisher B, Cartwright L, Saunders M, Evans WH, Surprenant A, Lopez-Castejon G, Mann S, Davis SA, Hails LA, Ingham E, Verkade P, Lane J, Heesom K, Newson R, Case CP, 2009: Nanoparticles can cause DNA damage across a cellular barrier. Nat Nanotechnol 4, 876883.
  • Braydich-Stolle L, Hussain S, Schlager JJ, Hofmann MC, 2005: In vitro cytotoxicity of nanoparticles in mammalian germline stem cells. Toxicol Sci 88, 412419.
  • Braydich-Stolle LK, Lucas B, Schrand A, Murdock RC, Lee T, Schlager J, Hussain S, Hofmann MC, 2010: Silver nanoparticles disrupt GDNF/Fyn kinase signaling in spermatogonial stem cells. Toxicol Sci 116, 577589.
  • Brown C, Fisher J, Ingham E, 2006: Biological effects of clinically relevant wear particles from metal-on-metal hip prostheses. Proc Inst Mech Eng H 220, 355369.
  • Browning LM, Lee KJ, Huang T, Nallathamby PD, Lowman JE, Xu XHN, 2009: Random walk of single gold nanoparticles in zebrafish embryos leading to stochastic toxic effects on embryonic developments. Nanoscale 1, 138152.
  • Case CP, Langkamer VG, James C, Palmer MR, Kemp AJ, Heap PF, Solomon L, 1994: Widespread dissemination of metal debris from implants. J Bone Joint Surg Br 76B, 701712.
  • Challier JC, Panigel M, Meyer E, 1973: Uptake of colloidal 198Au by fetal liver in rat, after direct intrafetal administration. Int J Nucl Med Biol 1, 103106.
  • Chu M, Wu Q, Yang H, Yuan R, Hou S, Yang Y, Zou Y, Xu S, Xu K, Ji A, Sheng L, 2010: Transfer of quantum dots from pregnant mice to pups across the placental barrier. Small 6, 670678.
  • Connor EE, Mwamuka J, Gole A, Murphy CJ, Wyatt MD, 2005: Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. Small 1, 325327.
  • Ding Y, Bian XC, Yao W, Li RT, Ding D, Hu Y, Jiang XQ, Hu YQ, 2010: Surface-potential-regulated transmembrane and cytotoxicity of chitosan/gold hybrid nanospheres. ACS Appl Mater Interfaces 2, 14561465.
  • Faux SP, Tran CL, Miller BG, Jones AD, vMontellier C, Donaldson K, 2003: In Vitro Determinants of Particulate Toxicity: The Dosemetric for Poorly Soluble Dusts. HSE Books, Sudbury/Suffolk.
  • Fedulov AV, Leme A, Yang Z, Dahl M, Lim R, Mariani TJ, Kobzik L, 2008: Pulmonary exposure to particles during pregnancy causes increased neonatal asthma susceptibility. Am J Respir Cell Mol Biol 38, 5767.
  • Fu W, Shenoy D, Li J, Crasto C, Jones G, DiMarzio C, Sridhar S, Amiji M, 2005: Biomedical applications of gold nanoparticles functionalized using hetero-bifunctional poly (ethylene glycol) spacer. Proceedings of Material Research Symposium, pp. 845.
  • Gannon CJ, Patra CR, Bhattacharya R, Mukherjee P, Curley SA, 2008: Intracellular gold nanoparticles enhance non-invasive radiofrequency thermal destruction of human gastrointestianal cancer cells. J Nanobiotechnology 6, 2.
  • Gao X, Yin S, Tang M, Chen J, Yang Z, Zhang W, Chen L, Yang B, Li Z, Zha Y, Ruan D, Wang M, 2011: Effects of developmental exposure to TiO2 nanoparticles on synaptic plasticity in hippocampal dentate gyrus area: an in vivo study in anesthetized rats. Biol Trace Elem Res 143, 16161628.
  • Gopalan R, Osman I, de Matas M, Anderson D, 2009: The effect of zinc oxide and titanium dioxide nanoparticles in the comet assay with UVA photoactivation of human sperm and lymphocytes. Environ Mol Mutagen 50, 541541.
  • Grodzik M, Sawosz E, 2006: The influence of silver nanoparticles on chicken embryo development and bursa of Fabricius morphology. J Anim Feed Sci 15, 111114.
  • Guo DD, Wu CH, Li XM, Jiang H, Wang XM, Chen BA, 2008: In vitro cellular uptake and cytotoxic effect of functionalized nickel nanoparticles on leukemia cancer cells. J Nanosci Nanotechnol 8, 23012307.
  • Han G, You CC, Kim BJ, Turingan RS, Forbes NS, Martin CT, Rotello VM, 2006: Light-regulated release of DNA and its delivery to nuclei by means of photolabile gold nanoparticles. Angew Chem Int Edit 118, 32373241.
  • Henglein A, 1993: Physicochemical properties of small metal particles in solution – microelectrode reactions, chemisorption, composite metal particles, and the atom-to-metal transition. J Phys Chem 97, 54575471.
  • Hougaard KS, Jackson P, Jensen KA, Sloth JJ, Loschner K, Larsen EH, Birkedal RK, Vibenholt A, Boisen AM, Wallin H, Vogel U, 2010: Effects of prenatal exposure to surface-coated nanosized titanium dioxide (UV-Titan). A study in mice. Part Fibre Toxicol 7, 16.
  • Hsieh MS, Shiao NH, Chan WH, 2009: Cytotoxic effects of CdSe quantum dots on maturation of mouse oocytes, fertilization, and fetal development. Int J Mol Sci 10, 21222135.
  • Ispas C, Andreescu D, Patel A, Goia DV, Andreescu S, Wallace KN, 2009: Toxicity and developmental defects of different sizes and shape nickel nanoparticles in Zebrafish. Environ Sci Technol 43, 63496356.
  • Johnston HJ, Hutchison G, Christensen FM, Peters S, Hankin S, Stone V, 2010: A review of the in vivo and in vitro toxicity of silver and gold particulates: Particle attributes and biological mechanisms responsible for the observed toxicity. Crit Rev Toxicol 40, 328346.
  • Kim JS, Yoon TJ, Kim BG, Park SJ, Kim HW, Lee KH, Park SB, Lee JK, Cho MH, 2006: Toxicity and tissue distribution of magnetic nanoparticles in mice. Toxicol Sci 89, 338347.
  • Klein S, Petersen S, Taylor U, Barcikowski S, Rath D, 2010: Visualisation of gold nanoparticles down to single particle level in intra- and extracellular environments. Biomed Opt 15, 036015.
  • Laban G, Nies LF, Turco RF, Bickham JW, Sepulveda MS, 2010: The effects of silver nanoparticles on fathead minnow (Pimephales promelas) embryos. Ecotoxicology 19, 185195.
  • Lee KJ, Nallathamby PD, Browning LM, Osgood CJ, Xu XH, 2007: In vivo imaging of transport and biocompatibility of single silver nanoparticles in early development of zebrafish embryos. ACS Nano 1, 133143.
  • Li PW, Kuo TH, Chang JH, Yeh JM, Chan WH, 2010: Induction of cytotoxicity and apoptosis in mouse blastocysts by silver nanoparticles. Toxicol Lett 197, 8287.
  • Makhluf SBD, Qasem R, Rubinstein S, Gedanken A, Breitbart H, 2006: Loading magnetic nanoparticles into sperm cells does not affect their functionality. Langmuir 22, 94809482.
  • Massich MD, Giljohann DA, Schmucker AL, Patel PC, Mirkin CA, 2010: Cellular response of polyvalent oligonucleotide-gold nanoparticle conjugates. ACS Nano 4, 56415646.
  • Musee N, Oberholster PJ, Sikhwivhilu L, Botha AM, 2010: The effects of engineered nanoparticles on survival, reproduction, and behaviour of freshwater snail, Physa acuta (Draparnaud, 1805). Chemosphere 81, 11961203.
  • Myllynen PK, Loughran MJ, Howard CV, Sormunen R, Walsh AA, Vahakangas KH, 2008: Kinetics of gold nanoparticles in the human placenta. Reprod Toxicol 26, 130137.
  • Nel AE, Madler L, Velegol D, Xia T, Hoek EMV, Somasundaran P, Klaessig F, Castranova V, Thompson M, 2009: Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8, 543557.
  • Oberdorster G, Oberdorster E, Oberdorster J, 2005: Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 113, 823839.
  • Pan Y, Neuss S, Leifert A, Fischler M, Wen F, Simon U, Schmid G, Brandau W, Jahnen-Dechent W, 2007: Size-dependent cytotoxicity of gold nanoparticles. Small 3, 19411949.
  • Patra HK, Banerjee S, Chaudhuri U, Lahiri P, Dasgupta AK, 2007: Cell selective response to gold nanoparticles. Nanomedicine 3, 111119.
  • Pohlmann G, Koch W, Holzinger K, Dilthey U, 2008: Vergleichende Untersuchungen bezüglich der Charakterisierung der ultrafeinen Partikel in Schweißrauchen beim Schweißen und bei verwandten Verfahren, final report. Vereinigung der Metall-Berufsgenossenschaften – VMBG, Düsseldorf.
  • Qian W, Huang X, Kang B, El-Sayed MA, 2008: Dark-field light scattering imaging of living cancer cell component from birth through division using bioconjugated gold nanoprobes. J Biomed Opt 15, 046025.
  • Ringwood AH, McCarthy M, Bates TC, Carroll DL, 2010: The effects of silver nanoparticles on oyster embryos. Mar Environ Res 69(Suppl), S49S51.
  • Sadauskas E, Wallin H, Stoltenberg M, Vogel U, Doering P, Larsen A, Danscher G, 2007: Kupffer cells are central in the removal of nanoparticles from the organism. Part Fibre Toxicol 4, 10.
  • Salmaso S, Caliceti P, Amendola V, Meneghetti M, Magnusson JP, Pasparakis G, Alexander C, 2009: Cell up-take control of gold nanoparticles functionalized with a thermoresponsive polymer. J Mater Chem 19, 16081615.
  • Sawosz E, Grodzik M, Zielinska M, Niemiec T, Olszanka B, Chwalibog A, 2009: Nanoparticles of silver do not affect growth, development and DNA oxidative damage in chicken embryos. Arch Geflugelkd 73, 208213.
  • Semmler-Behnke M, Fertsch S, Schmid G, Wenk A, Kreyling W, 2007: Uptake of 1.4 nm versus 18 nm gold nanoparticles by secondary target organs is size dependent in control and pregnant rats after intertracheal or intravenous application. EuroNanoForum 2007, 102104.
  • Shenoy D, Fu W, Li J, Crasto C, Jones G, DiMarzio C, Sridhar S, Amiji M, 2006: Surface functionalization of gold nanoparticles using hetero-bifunctional poly(ethylene glycol) spacer for intracellular tracking and delivery. Int J Nanomed 1, 5157.
  • Shimizu M, Tainaka H, Oba T, Mizuo K, Umezawa M, Takeda K, 2009: Maternal exposure to nanoparticulate titanium dioxide during the prenatal period alters gene expression related to brain development in the mouse. Part Fibre Toxicol 6, 20.
  • Sikorska J, Szmidt M, Sawosz E, Niemiec T, Grodzik M, Chwalibog A, 2010: Can silver nanoparticles affect the mineral content, structure and mechanical properties of chicken embryo bones? J Anim Feed Sci 2, 286291.
  • Singh N, Manshian B, Jenkins GJS, Griffiths SM, Williams PM, Maffeis TGG, Wright CJ, Doak SH, 2009: NanoGenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials 30, 38913914.
  • Studnicka A, Sawosz E, Grodzik M, Chwalibog A, Balcerak M, 2009: Influence of nanoparticles of silver/palladium alloy on chicken embryos’ development. Annals of Warsaw University of Life Sciences – SGGW, Animal Science, pp. 237242.
  • Takahashi S, Matsuoka O, 1981: Cross placental-transfer of Au-198-colloid in near term rats. J Radiat Res 22, 242249.
  • Takahashi Y, Mizuo K, Shinkai Y, Oshio S, Takeda K, 2010: Prenatal exposure to titanium dioxide nanoparticles increases dopamine levels in the prefrontal cortex and neostriatum of mice. J Toxicol Sci 35, 749756.
  • Takeda K, Suzuki KI, Ishihara A, Kubo-Irie M, Fujimoto R, Tabata M, Oshio S, Nihei Y, Ihara T, Sugamata M, 2009: Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci 55, 95102.
  • Taylor U, Garrels W, Petersen S, Barcikowski S, Klein S, Kues W, Lucas-Hahn A, Niemann H, Rath D, 2010a: Development of murine embryos after injection of uncoated gold and silver nanoparticles. Reprod Fertil Dev 22, 240241.
  • Taylor U, Klein S, Petersen S, Kues W, Barcikowski S, Rath D, 2010b: Nonendosomal cellular uptake of ligand-free, positively charged gold nanoparticles. Cytometry A 77, 439446.
  • Taylor U, Petersen S, Barchanski A, Mittag A, Barcikowski S, Rath D, 2010c: Influence of gold nanoparticles on vitality parameters of bovine spermatozoa. Reprod Domest Anim 45, 6060.
  • Thomas M, Klibanov AM, 2003: Conjugation to gold nanoparticles enhances polyethylenimine’s transfer of plasmid DNA into mammalian cells. Proc Natl Acad Sci USA 100, 91389143.
  • Tkachenko AG, Xie H, Liu YL, Coleman D, Ryan J, Glomm WR, Shipton MK, Franzen S, Feldheim DL, 2004: Cellular trajectories of peptide-modified gold particle complexes: comparison of nuclear localization signals and peptide transduction domains. Bioconjug Chem 15, 482490.
  • Wang Z, Ma L, 2009: Gold nanoparticle probes. Coord Chem Rev 253, 16071618.
  • Watzky MA, Finke RG, 1997: Transition metal nanocluster formation kinetic and mechanistic studies. A new mechanism when hydrogen is the reductant: slow, continuous nucleation and fast autocatalytic surface growth. J Am Chem Soc 119, 1038210400.
  • Wick P, Malek A, Manser P, Meili D, Maeder-Althaus X, Diener L, Diener PA, Zisch A, Krug HF, von Mandach U, 2010: Barrier capacity of human placenta for nanosized materials. Environ Health Perspect 118, 432436.
  • Wiwanitkit V, Sereemaspun A, Rojanathanes R, 2009: Effect of gold nanoparticles on spermatozoa: the first world report. Fertil Steril 91, e7e8.
  • Wu Y, Zhou Q, Li H, Liu W, Wang T, Jiang G, 2010: Effects of silver nanoparticles on the development and histopathology biomarkers of Japanese medaka (Oryzias latipes) using the partial-life test. Aquat Toxicol 100, 160167.
  • Yamashita K, Yoshioka Y, Higashisaka K, Mimura K, Morishita Y, Nozaki M, Yoshida T, Ogura T, Nabeshi H, Nagano K, Abe Y, Kamada H, Monobe Y, Imazawa T, Aoshima H, Shishido K, Kawai Y, Mayumi T, Tsunoda S, Itoh N, Yoshikawa T, Yanagihara I, Saito S, Tsutsumi Y, 2011: Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat Nanotechnol 6, 321328.
  • Yeo MK, Kang M, 2009: Effects of Cu (x) TiO (y) nanometer particles on biological toxicity during zebrafish embryogenesis. Korean J Chem Eng 3, 711718.
  • Yeo MK, Yoon JW, 2009: Comparison of the effects of nano-silver antibacterial coatings and silver ions on Zebrafish embryogenesis. Mol Cell Toxicol 5, 2331.
  • Zakhidov ST, Marshak TL, Malolina EA, Kulibin AY, Zelenina IA, Pavluchenkova SM, Rudoy VM, Dement’eva OV, Skuridin SG, Evdokimov YM, 2010: Gold nanoparticles disturb nuclear chromatin decondensation in mouse sperm in vitro. Biol Membr 4, 349353.
  • Zhu XS, Zhu L, Duan ZH, Qi RQ, Li Y, Lang YP, 2008: Comparative toxicity of several metal oxide nanoparticle aqueous suspensions to Zebrafish (Danio rerio) early developmental stage. J Environ Sci Health A Tox Hazard Subst Environ Eng 43, 278284.
  • Zielinska AK, Sawosz E, Grodzik M, Chwalibog A, Kamaszewski M, 2009: Influence of nanoparticles of gold on chicken embryos’ development. Annals of Warsaw University of Life Sciences – SGGW, Animal Science, pp. 249253.