humans

Environmental Research 151 (2016) 233–243

Contents lists available at ScienceDirect

Environmental Research journal homepage: www.elsevier.com/locate/envres

Review article

Transport phenomena of nanoparticles in plants and animals/humans Naser A. Anjum a,n,1, Miguel Angel Merlos Rodrigo b,c,1, Amitava Moulick b,c,1, Zbynek Heger b,c,1, Pavel Kopel b,c, Ondřej Zítka b,c,nn, Vojtech Adam b,c, Alexander S. Lukatkin d, Armando C. Duarte a, Eduarda Pereira a, Rene Kizek b,c,nn a

CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal Department of Chemistry and Biochemistry, Laboratory of Metallomics and Nanotechnologies, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic c Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno, Czech Republic d Department of Botany, Physiology and Ecology of Plants, N.P. Ogarev Mordovia State University, Bolshevistskaja Str., 68, Saransk 430005, Russia b

art ic l e i nf o

a b s t r a c t

Article history: Received 26 April 2016 Received in revised form 12 July 2016 Accepted 13 July 2016

The interaction of a plethora nanoparticles with major biota such as plants and animals/humans has been the subject of various multidisciplinary studies with special emphasis on toxicity aspects. However, reports are meager on the transport phenomena of nanoparticles in the plant-animal/human system. Since plants and animals/humans are closely linked via food chain, discussion is imperative on the main processes and mechanisms underlying the transport phenomena of nanoparticles in the plant-animal/ human system, which is the main objective of this paper. Based on the literature appraised herein, it is recommended to perform an exhaustive exploration of so far least explored aspects such as reproducibility, predictability, and compliance risks of nanoparticles, and insights into underlying mechanisms in context with their transport phenomenon in the plant-animal/human system. The outcomes of the suggested studies can provide important clues for fetching significant benefits of rapidly expanding nanotechnology to the plant-animal/human health-improvements and protection as well. & 2016 Elsevier Inc. All rights reserved.

Keywords: Nanoparticles Transport phenomena Plant Animal Human

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 Transport phenomena of nanoparticles in plants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 2.1. Nanoparticle-plant root interaction and its regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 2.2. Processes at root level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 2.3. Processes at cellular level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 2.4. Transport of the root-harbored nanoparticles to leaves and edible plant parts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 Transport phenomena of nanoparticles in animals/humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 3.1. Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 3.2. Lungs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 3.3. Gastro-intestinal tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 3.4. Nervous system-mediated uptake of nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 3.4.1. Uptake via blood-brain-barrier and olfactory nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 3.5. Cellular uptake. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

n

Corresponding author. Corresponding authors at: CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal (NAA); Department of Chemistry and Biochemistry, Laboratory of Metallomics and Nanotechnologies, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic (OZ and RK). E-mail addresses: [email protected] (N.A. Anjum), [email protected] (O. Zítka), [email protected] (R. Kizek). 1 These authors contributed equally to this work. nn

http://dx.doi.org/10.1016/j.envres.2016.07.018 0013-9351/& 2016 Elsevier Inc. All rights reserved.

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3.6. 3.7.

Phagocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 Pinocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 3.7.1. Macropinocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 3.7.2. Clathrin-dependent endocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 3.7.3. Clathrin-independent endocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 3.7.4. Caveolae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 4. Conclusions and major knowledge-gaps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

1. Introduction Rapid production and interdisciplinary applications of varied engineered nanoparticles (particulate matter with at least one dimension that is less than 100 nm) in everyday life are constantly increasing worldwide (Fig. 1). Varied nanoparticles may be released into different environmental compartments, such as soil, either during production processes, transport or by direct or indirect disposal of consumer products upon use. Therefore, organisms and especially those that strongly interact with their immediate environments, such as plants, microorganisms and edaphon have a greater chance to be exposed to and impacted with nanoparticles (Anjum et al., 2013, 2015). Thus, plants and animals/ humans are being significantly exposed to nanoparticles diversity through various pathways. Potential benefits of nanotechnologies have been welcomed in diverse sectors including plant healthimprovement (Seabra et al., 2013; Husen and Siddiqi, 2014; Iravani et al., 2015), animal/human health and medicine (Cooper et al., 2014; Bhavsar et al., 2015; Cheng et al., 2015), and environmental decontamination (Ram et al., 2011; Mohmood et al., 2013; Sharma et al., 2013; Perreault et al., 2015). However, owing to the existence of a close link between the components of the plant-animal/human system, the contamination of animal/human food with manufactured nanoparticles via plant and/or plant-based products has become a major challenge for life and environmental scientists. This situation can be further aggravated by a lack of discussion and poor understanding on the engineered nanoparticle-interaction with the plant-animal/human system (Fig. 2). Additionally, indiscriminate and multidisciplinary use without aftermath knowledge on the fate, behavior and consequences of nanoparticles in the environment and their interaction with the biological systems can help negative effects to surpass the nanoparticle-lead opportunities, thus undermining the sustainable development of rapidly growing field of nanotechnology (Fig. 3). Given the above, this note briefly discusses and interprets the facts related with the mainstay of ‘transport phenomenon’ of nanoparticles in the plant-animal/human system. The outcome of

Fig. 1. Different classes of nanoparticles according to their size (Modified afterNowack and Bucheli, 2007).

the discussion can provide clues important for the improvement of the plant-animal/human health as well as for their protection against potential toxic consequences on nanoparticles.

2. Transport phenomena of nanoparticles in plants Plants strongly interact with their surrounding environment often contaminated with hazardous substances, including nanoparticles, thus becoming vulnerable to their potential effects. Since metal-based nanoparticles (MNPs) have extensive applications due to their unique physico-chemical properties and multidisciplinary applications, potential exposure of plants to MNPs has been considered the highest priority study subject (Anjum et al., 2013, 2015; Peng et al., 2015). Nevertheless, interaction of widely developing genetically modified/transgenic crops with extensively synthesized and applied nanoparticles can also be not ignored (Le et al., 2014; Li et al., 2014). Notably, human and animal systems can be at great risk via nanoparticles-laden plants or plant-based food products. Despite the previous fact, literature is scarce primarily on nanoparticles-plant interaction and secondarily on the transport phenomena of nanoparticles in plants (Ma et al., 2010; Sabo-Attwood et al., 2012; Anjum et al., 2013, 2015; Deng et al., 2014). Hereunder, efforts are made to appraise recent literature available on the subject to briefly highlight potential processes and mechanisms underlying nanoparticle-uptake/accumulation and root-harbored nanoparticle transport to leaves and edible plant parts (Fig. 4a). 2.1. Nanoparticle-plant root interaction and its regulation Leaves can be one of the major routes for the entry of nanoparticles into the plant system via leaf spray, injection and atmospheric exposures (Corredor et al., 2009; Birbaum et al., 2010; Deng et al., 2014). However, roots can be both the primary plant organ close to the soils potentially contaminated with the types of nanoparticles, and also the major entry point of nanoparticles for other plant organs as well as for plant-based foods and human/ animal system (Anjum et al., 2013, 2015). Processes such as adsorption, translocation and accumulation of nanoparticles can be modulated by plant types and also by the size, type, chemical composition and stability of nanoparticles (Rico et al., 2011). Nevertheless, contingent to types of nanoparticles and plants, and also the experimental conditions, the bioavailability of nanoparticles to plants can be different. Additionally, a differential nanoparticle adsorption and absorption can also be possible in roots. Nevertheless, plants are being used for the synthesis of various nanoparticles in order to ascertain their benefits in plants, and also to confirm and understand important phenomena for nanoparticles-delivery in the target tissue/organs/cells/cell organelles (Narayanan and Sakthivel, 2010; Basavegowda et al., 2014; Rajasekharreddy and Rani, 2014; Mittal et al., 2013; Noruzi, 2015; Manivasagan et al., 2015; Kumari et al., 2015; Servin et al., 2015; Silva et al., 2015). However, reports thus far available in this regard

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Fig. 2. The fate of nanoparticle in the environment (Modified after Bakshi et al., 2015).

Fig. 3. Representative images in support of the role of the basic metal detoxification pathway in earthworm in the production of luminescent, water-soluble semiconductor cadmium telluride (CdTe) quantum dots. (A: The earthworm, Lumbricus rubellus; B: Cross-section of the posterior section of the earthworm, where the chloragogenous tissue surrounds the posterior alimentary canal (PAC, The gut section following the thickened glandular clitellum) (indicated by arrows); C: The chloragogenous tissue harvested for analyses is also the predominant location of metallothionein accumulation, as determined by immunoperoxidase histochemistry performed with an earthworm-specific metallothionein antibody (note that the metallothionein-positive choragogen cells are stained red, as indicated by arrows). (Reprinted by permission from Stuerzenbaum et al., 2013, Nature Nanotechnology, 8:57–60, Macmillan Publishers Ltd.).

remained conflicting and inconclusive (Rico et al., 2011; GardeaTorresdey et al., 2014; Anjum et al., 2015). Hence, a sound knowledge of similarities and patterns in nanoparticles-accumulation/uptake processes in plants is necessary to estimate potential

concerns in the consumers of nanoparticle-laden plants or plantbased foods.

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Fig. 4. Summarized scheme highlighting transport phenomena and fate of nanoparticles in the plant (A) and human (B) system.

2.2. Processes at root level At whole root level, owing to their high specific surface and surface reactivity MNPs can be easily adsorbed on the general physical interface (Wang et al., 2005). Also, electrostatic adsorption, mechanical adhesion and hydrophobic affinity of certain engineered nano-materials can control the interaction of roots with nanoparticles, where their accumulation in epidermis or their adherence onto surficial tissues (as individual particles and/ or aggregates) can be accomplished (Lin and Xing, 2008; Wild and Jones, 2009; Zhang et al., 2011; Zhao et al., 2012; reviewed by Deng et al., 2014). In particular, adsorption of ZnO nanoparticles was reported on the Lolium perenne root surface (Lin and Xing, 2008). Literature related with nanoparticle-accumulation by roots reflects overestimation of their uptake/accumulation, where the effective quantitative analysis of their adsorption and uptake is usually ignored. Hence, distinguishing nanoparticle-adsorption and their actual uptake is very critical. To this end, based on chemical extractions, quantification of both the adsorption and uptake of CuO-nanoparticles was reported in Triticum aestivum root (Zhou et al., 2011). The authors were able to distinguish the uptake and adsorption of MNPs on the root surface, and concluded that the adsorption of nanoparticles on the root surface cannot be regarded as their uptake in plants (Zhou et al., 2011). However, the use of ions and surfactants that can potentially compete with and modulate nanoparticles, and their subsequent desorption from root surfaces is very decisive (Zhou et al., 2011; Deng et al., 2014). Nevertheless, instead of nanoparticles, accumulation of dissolved ions can be possible in plants. Hence, apart from employing

visualization (such as via electron microscopy) and metal speciation estimation techniques, efforts must be made to consider both ion and bulk particle in exposure experiments, and estimating their levels also in the tissues not in direct contact with exposure media (Deng et al., 2014). As the roots in the nutrient solution remain directly in contact with nanoparticles, their absorption and subsequent localization is possible mainly in the epidermis and exodermis (Peng et al., 2015). MNPs (such as nano-ZnO) can penetrate the root epidermis and the cortex, and finally pass to the endodermis (Zhao et al., 2012). Easy penetration of the root, entry into the vascular cylinder and access to the aerial parts of the plants via moving the xylem vessels using the transpiration stream can be possible for magnetic carbon-coated nanoparticles (Cifuentes et al., 2010). Accumulation of MNPs (such as nano-Ag) has been observed primarily in border cells followed by root cap, columella and columella initials (Geisler-Lee et al., 2013). The presence or absence of plant roots in nutrient solution can also substantially control the dissolution and subsequently uptake of nanoparticles (such as nano-CeO2) compared to plant-free medium (Schwabe et al., 2015). The role of a mixture of mucilage and root exudates (composed of a number of organic acids and amino acids), released by plant roots was reported for increased Cu content and the percentage of nano-CuO in Oryza sativa roots (Peng et al., 2015). Lateral roots can penetrate the root epidermis and reach the exterior of the vascular cylinder during the process of lateral root differentiation (Péret et al., 2009). It has been argued that the formation of lateral roots could create new absorbing surfaces and provides a possible pathway for nanoparticles to finally enter the

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stele (Peng et al., 2015). The role of lateral roots in nanoparticleabsorption and their subsequent transport into the central cylinder was also reported (Peng et al., 2015). 2.3. Processes at cellular level At cellular level in roots, before entering into the cell and their subsequent intracellular transportation, nanoparticles have to interact firstly with plant cell wall (Fig. 4a). Notably, cell wall has a network of cellulose microfibrils cross-linked with hemicellulose and lignin, and further impregnated by pectin in the size range from 5 to 20 nm (Carpita et al., 1979; Tepfer and Taylor, 1981; Serag et al., 2013). Thus, pores of the cell wall with the mentioned characteristics restrict the entry of large aggregates or agglomerates of nanoparticles (reviewed by Deng et al., 2014). However, entry of smaller clusters or individual particles into the apoplastic and/or symplastic flow can be possible after the diffusion of these particles through pores. Alternatively, interaction of nanoparticles with carrier proteins, aquaporins, ion channels, and organic chemicals can also facilitate their entry into plant cells under the symplastic route, an important and highly regulated pathway for the nanoparticle-transportation into major crops (Rico et al., 2011). However, significant involvement of endocytosis pathways in cellular penetration and the subsequent internalization of nanoparticles have also been considered as a convincing concept (reviewed by Miralles et al., 2012). The role of plasmodesmata (20– 50 nm diameter) has been highlighted in the efficient transport of the engineered nano-materials containing endosomes or engineered nano-material-protein complex to neighboring cells in Arabidopsis thaliana exposed to ultra-small TiO2 nanoparticles (Wang et al., 2011a, 2011b; Larue et al., 2012). Nevertheless, the role of passive uptake mechanisms in Nicotiana tabacum cells under carbon nanotubes-exposure (Khodakovskaya et al., 2012), and differential hydrophobic and hydrophilic effect in the control of nanoparticle-interaction with plant cell membranes (Li et al., 2008; Stark, 2011). In osmotic pressure- or capillary forces-regulated ‘apoplastic route’, diffusion of root-adsorbed-nanoparticles in the space between the cell wall and plasma membrane, and also their subsequent epidermal- and cortical cells-mediated access to the endodermis is accomplished (Lin et al., 2009; Deng et al., 2014). Casparian strip (composed of suberin and lignin, and located in the transverse and radial walls of the endodermis) acts as a final apoplastic barrier between the outside and vascular tissue, and can relatively be impervious to not only water and dissolved minerals but also to MNPs. Casparian strip was evidenced to hinder the MNPs-translocation in several plant species including nanomolybdenum octahedral clusters-exposed Brassica napus (Aubert et al., 2012), nano-CeO-exposed Phaseolus vulgaris (Majumdar et al., 2014), nano-CuO-exposed Zea mays (Wang et al., 2012), quantum dot-exposed Populus deltoides x nigra (Wang et al., 2014), and nano-CuO-exposed O. sativa (Peng et al., 2015). Additionally, involvement of the Casparian strip in the accumulation of aggregated nanoparticles in the endodermis was also reported in a number of earlier studies on plants including nano-TiO2 exposed T. aestivum (Larue et al., 2012) and nano-ZnO exposed Z. mays (Zhao et al., 2012). However, apoplastic transport of nano-Ag to the stele was possible when the Casparian strip is not yet fully formed at the root apex (Geisler-Lee et al., 2013). Additionally, the gaps in the Casparian strip at the emergence of secondary roots can also facilitate the entry of MNPs (such as nano-CeO2) into P. vulgaris roots (Majumdar et al., 2014). Entry of MNPs into plant cytoplasm can also be assisted by several ion transporters identified for elements, and carbon nanotubes (Wild and Jones, 2009; Rico et al., 2011). Capability of multi-walled carbon nanotubes (MWCNTs) to penetrate the cell

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membrane of plant protoplasts (plant cells devoid of their cell walls) and their internalization mechanism were studied (Serag et al., 2011). The authors identified an endosome-escaping uptake mode of MWCNTs by plant protoplasts, where short MWCNTs (o100 nm) were observed to target specific cellular substructures including the nucleus, plastids, and vacuoles. 2.4. Transport of the root-harbored nanoparticles to leaves and edible plant parts Animal/human food chain can be contaminated by nanoparticles harbored in pants that can be contributed primarily by nanoparticle-accumulation and -translocation within plant species. Thus, gathering information related with the accumulation of both nanoparticles and component metals in plant´s edible tissues or in seeds for the next generation is important for understanding nanomaterial fate and potential effects assessment. The sequence of nanoparticle-uptake was extensively reported to be from the plant seeds and roots to the stems and leaves (reviewed by Rico et al., 2011, 2013; Anjum et al., 2015). The distance from roots to mature leaves is much shorter than that from roots to young leaves, and the exposure time of mature leaves is also much longer than that of young leaves. Hence, mature leaves were argued as a major site of nanoparticles (such as nano-CuO) transported to shoots (Peng et al., 2015). Transmission of fullerene C70 to the progeny of O. sativa through seeds can also be possible (Lin et al., 2009). The translocation of root-harbored nanoparticles to aboveground plant parts can be facilitated by the absorption patterns of water and nutrients within the root (Lee et al., 2010), and the water transpiration (Schwabe et al., 2013). The uptake of water and nutrients in the xylem was advocated to be responsible for the transport of C70 from root to leaves/seeds via transpiration in stem's vascular system or evaporation of water from leaves (Lin et al., 2009). Exposure of seeds and already germinated seedlings (with intact roots) to nanoparticles can exhibit different trends of nanoparticle-levels in root, stem, and other plant parts. To this end, a high accumulation of nanoparticles (such as C70) was evidenced in the leaves than in the roots under the seed-root-exposure experiment; whereas, the ‘root exposure’ samples showed a different trend of nanoparticle-translocation possibly because C70 first entered the roots and then was transported to the stems and leaves (Lin et al., 2009). Also the distance between epidermis and the vascular system was reported to control the amount of C70-translocation (Lin et al., 2009). A parallel distribution of nanoparticles (such as nano-TiO2) to the longitudinal section of roots was reported (Antisari et al., 2015). However, translocation of nanoparticles (such as nano-CeO2) within plant can be plant species-specific (Schwabe et al., 2015). In this context, a higher accumulation of Ce-ion was evidenced in Helianthus annuus compared to insignificant difference-exhibiting Cucurbita maxima and T. aestivum when supplied with dissolved Ce ions (Schwabe et al., 2015). In fact, merging of nanoparticles in apoplastic flow into the symplast can promote the penetration of nanoparticle into vascular system and eventually facilitate effective translocation to the shoot system (Deng et al., 2014). The discussed above literature reflects that though inconclusive, the aspects associated with nanoparticle-translocation from root to shoot, especially leaves were extensively reported. However, information is scarce on these aspects in relation to nanoparticles in flowers (Khodakovskaya et al., 2013) fruits (Kole et al., 2013), and grains (Lin et al., 2009). Also, rare studies are available in the literature highlighting the trophic transfer and bio-magnification of nanoparticles through investigating potential consequences in the consumers of nanoparticle-laden plant produce (Holbrook et al., 2008; Hou et al., 2013; Judy et al., 2012; Unrine et al., 2012; Deng et al., 2014; Gardea-Torresdey et al., 2014).

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3. Transport phenomena of nanoparticles in animals/humans Nanoparticles entry into the animal/human body can be possible through a number of ports. Owing to their continuous contact with the environment the lungs, skin and the gastro-intestinal tract of animals/humans are used by natural or anthropogenic nanoparticles as three major points of their entry to the body. However, injections and implants can also be other possible routes of nanoparticle-entry (reviewed by Buzea et al., 2007; Janrao et al., 2014). Notably, the olfactory nerves and blood-brain-barrier may mediate the neuronal uptake of inhaled nanoparticles (Oberdörster et al., 2002). Translocation of interstitially injected particles via lymphatic system and their subsequent localization in the lymph nodes were also reported (Liu et al., 2006). Nanoparticles (especially of metallic type) have tendency to rapidly enter in the circulatory system (Oberdörster et al., 2005). Thus, once in the blood stream, the transportation of nano-materials can occur around the body and be taken up by organs and tissues including the brain, heart, liver, kidneys, spleen, bone marrow and also the nervous system (Oberdörster et al., 2005). Despite the above facts information is meager on the behavior of nanoparticles in the body (Janrao et al., 2014). Hereunder follows a brief discussion on the major ports of nanoparticles transport and underlying mechanisms in animals/humans. 3.1. Skin Skin-penetration of nanoparticles is possible, where accelerated skin uptake of nanomaterials can be possible in flexed skin and in the skin broken as a result of acne, eczema, shaving wounds or severe sunburn (Tinkle et al., 2003; Oberdörster et al., 2005; Ryman-Rasmussen et al., 2006; reviewed by Janrao et al., 2014). Details related with dermal penetration are not very clear. However, nanoparticle-penetration in the body through the skin may include three possible penetration pathways namely intercellular, intracellular, and follicular. Subcutaneous, dermis and epidermis are the three layers in human skin. The outer portion of the epidermis, stratum corneum is composed of a 10 mm thick keratinized layer of dead cells and is usually difficult to pass for ionic compounds and water soluble molecules. It can be found that the epidermis-surface is highly micro-structured, showing a scaly appearance with pores for sweat, sebaceous glands, and hair follicle sites. The potential of nanoparticle-penetration through the stratum corneum has also been revealed (Desai et al., 2010). Generally, hair follicles, and flexed and broken skin can be major entry routes for nanoparticles (Toll et al., 2003; reviewed by Janrao et al., 2014). Toxicological investigations are extensive on TiO2 due its significant use of in cosmetics industry. The largest amount of coated TiO2 was found localized in the upper part of the stratum corneum (Nohynek et al., 2007). Additionally, dermis is enriched with blood and macrophages, dendritic cells, nerve endings and lymph vessels. Hence, nanoparticles penetrating the stratum corneum, epidermis and dermis can effectively be recognized by the immune system of the body (Borm et al., 2006). 3.2. Lungs Nanoparticles can come into body also by inhalation and can be deposited throughout the entire respiratory tract, starting from nose and pharynx, and finally down to the lungs (Fröhlich and Salar-Behzadi, 2014). Human lungs consist of about 300 million alveoli with an internal surface area of 75–140 m2. This large surface area of the lung acts as the main entry portal for inhaled particles. Solid material can reach the gas exchange surfaces if it is in spherical shape with diameters smaller than 10 mm. The particles with a larger diameter can be deposited in the respiratory

tract as a result of gravitational settling, interception and impaction. Generally, particles having a smaller diameter can be more affected by diffusion and these can be accumulated in the alveoli and smaller airways. Smaller diameter fibres can penetrate deep into the lung but the fibres having very long aspect ratio remain in the upper airways. Nevertheless, straight long fibres can penetrate deeply into the alveolar region are retained there because of the much slower process of clearance by the alveolar macrophages (Hoet et al., 2004; Buzea et al., 2007; Roshchenko et al., 2011). After inhalation, nanoparticles first interact in the respiratory tract with the lining fluid that is composed of proteins and phospholipids (Wright et al., 1994; Konduru et al., 2015). Subsequently, the particles are wetted and displaced towards the epithelium by surface forces from the liquid-air interface (Peters et al., 2006). After contact, esophageal epithelial cells can uptake nanoparticles in the presence of preexistent inflammation. Using cilia, the bronchial epithelial cells help in moving the covering mucous layer with particles, away from the lungs and into the pharynx and generally this process takes several hours. The protective antioxidants of mucus layer can be depleted if a huge amount of oxidative compounds are inhaled. Finally, nanoparticles enter the gastro-intestinal tract (Semmler et al., 2004). 3.3. Gastro-intestinal tract The gastro-intestinal tract can be considered as a complex barrier-exchange system, and is the most significant pathway for the entry of macromolecules into the body. Nanoparticles can interact with gastro-intestinal tract from endogenous and exogenous sources including intestinal calcium and phosphate secretion, food pharmaceuticals or even water (Lomer et al., 2004; Uemura et al., 2010). People ingest each day high levels of nanoparticles and microparticles in the range of 0.1–3 mm (reviewed by Borm et al., 2006). The dietary consumption of nanoparticles (such as consisting mainly TiO2 and mixed silicates) in developed countries is estimated around 1012 particles/person/day (Oberdörster, 2004; Oberdörster, 2004). Nevertheless, some specific food products, like salad dressing (containing nano-TiO2 as whitening agent) can cause an increase of more than 40-fold of the daily average intake (Di Gioacchino et al., 2009). However, the size, surface chemistry and charge, length of administration, and dose of nanoparticles affect the level of absorption in the gastro-intestinal tract. After the penetration of mucus, the particles can reach enterocytes and further translocate to several organs (Hoet et al., 2004; Yuan et al., 2013). 3.4. Nervous system-mediated uptake of nanoparticles 3.4.1. Uptake via blood-brain-barrier and olfactory nerves The blood-brain-barrier is a physical barrier containing negative electrostatic charge between the brain and blood vessels. This barrier selectively helps in restricting the access of certain substances. This anionic barrier can also help to stop most anionic molecules, while the cationic molecules increase the permeability of the blood-brain-barrier through charge neutralization. Many researches have focused on this route for the purpose of drug delivery to the brain (Borm et al., 2006; Mikitsh and Chacko, 2014; Sela et al., 2015). Nanoparticles depend on their own charge to pass through the blood-brain-barrier. The blood-brain-barrier has been suggested to allow a larger number of cationic nanoparticles to pass compared to neutral or anionic particles, due to the disruption of its integrity (Lockman et al., 2004). Notably, different types of inflammation and some specific circulatory diseases (like hypertension) were argued to cause increase in the permeability of blood-brain-barrier, which could eventually allow the nanoparticles to access the nervous system (Peters et al., 2006). On the

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other, inhaled nanoparticles can also be internalized through the olfactory nerves. The nasal and tracheo-bronchial regions possess many sensory nerve endings. Extensive reports support the internalization of the inhaled nanoparticles from olfactory mucosa via the olfactory nerves in the olfactory bulb (Borm et al., 2006; Malhotra et al., 2014). In rat, inhalation of nano-magnesium oxide (30 nm; Elder et al., 2006) and nano-carbon (20–30 nm; Oberdörster et al., 2002) was reported. The translocation of the inhaled nanoparticles to the olfactory bulb was also evidenced (Elder et al., 2006). Additionally, nanoparticles can also be translocated into deeper brain structures (Malhotra et al., 2014). 3.5. Cellular uptake Nanoparticles are able to enter different types of cells and can interact with subcellular structures. However, the chemistry, size, and shape of nanoparticles can affect their cellular uptake, subcellular localization, and their ability to catalyze oxidative products (Kettler et al., 2014). Nanoparticles can penetrate cells using a possible mechanism/s of passive uptake and/or adhesive interaction. Van der Waals forces, electrostatic charges, steric interactions, or interfacial tension effects can initiate this uptake, which does not result in the formation of vesicles (Geiser et al., 2005; Peters et al., 2006). After such an uptake, nanoparticles need not to be placed within a phagosome. C60 molecules were reported to enter cells, where these can be found along the nuclear membrane and also within the nucleus (Porter et al., 2006). Non-phagocytic uptake and free movement within the cell can cause very dangerous situation by having direct access to cytoplasm proteins and organelles. At organelle level, nanoparticles can be found in several locations inside cell, such as the cytoplasm, outer-cell membrane, mitochondria, lipid vesicles, and also along the nuclear membrane or within the nucleus (Garcia-Garcia et al., 2005; Xia et al., 2006). Cells generally use two main endocytic pathways namely phagocytosis and pinocytosis. Phagocytosis is generally employed by neutrophils, dendritic cells, and macrophages; whereas, pinocytosis can be found in almost all types of cells. Pinocytosis can be further classified as clathrin-mediated endocytosis, caveolaemediated endocytosis, clathrin/caveolae-independent endocytosis, and micropinocytosis (reviewed by Yameen et al., 2014). 3.6. Phagocytosis Phagocytosis can be found in different cell types including fibroblasts, epithelial cells, specific phagocytic cells (monocyte, macrophages, and neutrophils), immune cells, natural killer cells and inflammatory mediator producing cells (basophils, eosinophils, and mast cells). This important endocytosis process is initiated either through two major ways. Firstly, there can be the contact of the receptors on cell-surface with particular ligands presented by the foreign agent or secondly, through the interaction of particular cell-surface receptors with soluble factors that recognize the foreign agent and enable phagocytosis. The internalization of nanoparticles via phagocytosis has been explored extensively (Kettler et al., 2014; Shang et al., 2014; Yameen et al., 2014). The geometry of the particle can help in the control of their cellular uptake via phagocytosis. Because of different shapes, particles can generate different angles between the membrane and then at the point of cell attachment. The angle of contact shows significant effects on the ability of macrophages to uptake particles via actin-driven movement of the membrane of macrophages (Champion and Mitragotri, 2006, 2009). Instead of the size, the shape of the particle plays a dominant role in phagocytosis, where elongated particles with higher aspect ratios can be less prone to phagocytosis (Champion and Mitragotri, 2006; Geng

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et al., 2007). Nevertheless, a higher aspect ratio can be associated with preferential localization into endosomes and lysosomes (Harguindey et al., 2009). Hence, it was advocated to properly design the shape of particles in order to modulate intracellular targeting and phagocytosis (Yameen et al., 2014). 3.7. Pinocytosis 3.7.1. Macropinocytosis Macropinocytosis is an endocytic process regulated by actin. Using this process, cells can internalize significant volumes of extracellular fluid through macropinosomes, large vesicles with diameter of 0.5–10 mm (Falcone et al., 2006; Mailänder and Landfester, 2009; reviewed by Yameen et al., 2014). Notably, macropinosomes can undergo acidification and fusion events due to their sensitivity to cytoplasmic pH (West et al., 1989). Unlike receptor-mediated endocytosis and phagocytosis, the initiation of macropinocytosis is not controlled by the direct action of a receptor or cargo molecules (Kerr and Teasdale, 2009). Apart from their cellular internalization via more than one endocytic pathways, the cellular uptake of micron-size particles can also be possible through macropinocytosis (Gratton et al., 2008). The role of energy-dependent endocytosis (including clathrin-dependent pinocytosis and micropinocytosis) in the uptake of nanoparticles of size  62 nm and a zeta potential of 22.80 mV by BT-474 cells was reported (Zhang et al., 2014). 3.7.2. Clathrin-dependent endocytosis Eukaryotic cells use clathrin-mediated endocytosis (CME) for trafficking of materials, which includes intercellular signaling, membrane recycling, and uptake of nutrients (Kettler et al., 2014; Yameen et al., 2014). Different proteins are employed to initiate a curvature in the membrane and subsequently some vesicles are formed. The vesicles are released from the plasma membrane by the activity of GTPase dynamin, which is assembled as a ring around the neck of a newly formed invagination (Mettlen et al., 2009). After the release of coated vesicles, the clathrin pit can be disassembled with the help of auxilin and heat shock cognate 70 (HSC70)-dependent proteins (McMahon and Boucrot, 2011). After internalization, uncoated vesicles can be directed to early endosomes and; in some cases, they can be recycled to the plasma membrane surface also. The receptor-mediated cellular uptake of nanoparticles can be possible mostly by CME. Moreover, CME can also be involved in the exclusive internalization of the cationic nanoparticles (  100 nm) derived from polylactide-co-polyethylene glycol (PLA-PEG) (Harush-Frenkel et al., 2007). Poly(Llysine), a cationic polymer functionalized at the surface of poly (lactide-co-glycolide) (PLGA) Nanoparticles, can enhance cellular uptake significantly through CME (Vasir and Labhasetwar, 2008). 3.7.3. Clathrin-independent endocytosis Clathrin-independent endocytosis (CIE) pathway can be considered as an entry point for different cell-surface proteins and bacterial toxins (Sandvig et al., 2008). In this process, the vesicle formation and internalization do not need coat proteins; rather, CIE requires actin and actin-associated proteins for the formation of vesicles (Robertson et al., 2009). Through different types of pathways, CIE also involves various proteins including Arf-6, RhoA and Cdc42 (Sandvig et al., 2011). Generally, CIE delivers the cargos first to the early endosomes, and later to late endosomes and lysosomes. The cargos can also be moved to the trans-Golgi network or recycled back to the plasma membrane (Grant and Donaldson, 2009; reviewed by Yameen et al., 2014). CIE has been reported to help in the internalization of polyplexes of self-branched and trisaccharide-substituted chitosan oligomer nanoparticles (SBTCO) in order to deliver DNA (Garaiova et al., 2012). Delivery of cowpea

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mosaic virus (CPMV), a strategy for vaccine development, in vivo vascular imaging, and tissue-targeted delivery also involve CIE (Plummer and Manchester, 2013). Nanoparticles resulting from trisaccharide-substituted chitosan oligomers (SBTCO) were reported to exhibit a higher uptake and better transfection efficacy than nanoparticles derived from a linear chitosan (LCO) (Garaiova et al., 2012). 3.7.4. Caveolae Caveolae, flask-shaped invaginations of cell membrane with 60–80 nm size-range are involved in different cellular processes like endocytosis of proteins, cholesterol homeostasis, and signal transduction (Parton and Simons, 2007). Though caveolae can be found in different kind of cells e.g., adipocytes (occupying around 50%), fibroblasts, endothelial (occupying around 70%) and smoothmuscle cells, they are absent in neurons and leukocytes (Thorn et al., 2003; Wang et al., 2011a, 2011b). Caveolin (CAV1, CAV2 and CAV3) is the main protein constituent of caveolae, where about 140–150 CAV1 protein molecules may occur in each caveola (Pelkmans and Zerial, 2005). Working as coat protein, cavins (1–4) work together with caveolins to regulate the formation of caveolae, and also participate in the signals involved in the control caveolae-fate (Parton and del Pozo, 2013). Endothelial cells-associated caveolae perform transendothelial transport, which can be exploited for the release of nanoparticles in sub-endothelial tissues (Oh et al., 2007). Negative surface charges can trigger the cellular internalization via caveolae (Sahay et al., 2010). Mechanisms involving a combination of clathrin- and caveolae-mediated energy-dependent endocytosis and the GABAB receptor and the potential of RVG29-conjugated nanoparticles for crossing bloodbrain barrier were argued as a main strategy for delivering drugs to the brain (Lafon, 2005; Liu et al., 2009; reviewed by Yameen et al., 2014; Mikitsh and Chacko, 2014).

synthesized and applied different nanoparticles cannot be ignored. Hence, getting insights into unpredictable results of development and application of varied nanoparticles in transgenic plants need to be clarified before the extension of this technology. In the plant system, xylem(sap) can facilitate the transport of a number of nanoparticles from roots to shoots and edible plant parts and produce. Notably, in the animal/human system, apart from the nervous system uptake of nanoparticles, the lungs, skin and the gastro-intestinal tract of animals are in continuous contact with the environment. Hence, these organs can be the major points of nanoparticle-entry to the body and be the major cause of their toxic consequences therein (Buzea et al., 2007; Janrao et al., 2014; Yameen et al., 2014). Information is also scarce on the moleculargenetic mechanisms underlying the interaction of nanoparticles with biological compounds within the animal/human system those are bound to control both toxic consequences and benefits (such as disease control) of nanoparticles. Apoplastic or symplastic inter- and intra-cellular transportation of cell-harbored nanoparticles seem common in both plant and animal/human systems. However, exact mechanism underlying previous processes is inconclusive in the previous systems. Literature is available on the transport phenomena in plants, animals and humans; however, the plant-animal/human system has rarely been considered in this context. Thus, so far least explored aspects such as reproducibility, predictability, and compliance risks of nanoparticles, and insights into underlying mechanisms in regard with previous system must be considered in future research. If performed, the studies on the suggested above least explored aspects can provide important clues for fetching significant benefits of rapidly expanding nanotechnology to the plant-animal health-improvement and protection as well.

Acknowledgements 4. Conclusions and major knowledge-gaps Both components of the ‘plant-animal/human system’ are closely linked in terms of their exposure, and responses to a myriad of nanoparticles (Fig. 2). Herein, literature available on the mainstay of ‘transport phenomenon’ of nanoparticles in the plant-animal/ human system was briefly discussed and interpreted. Being at the base in the food chain, plants can interact, accumulate and transfer their nanoparticle-burden to the other biota at higher trophic levels, and can also be the cause of the nanoparticle-bioaccumulation and toxic consequences in animals/humans. However, exhaustive cross-talks on the components of the ‘plant-animal/human’ system are very rare. This may be due to complexity and unpredictability of nanoparticle behavior and fate in the ‘plantanimal/human’ system. Experiments considering possible pathways (such as root and atmospheric/foliar) of nanoparticle-entry into plant system can help to clarify all possible nanoparticle-exposure routes and underlying mechanisms (Deng et al., 2014). Much has been achieved regarding uptake and accumulation through various routes, and their subsequent intracellular transportation of MNPs via an apoplastic or symplastic pathway (Rico et al., 2011, 2013; Deng et al., 2014). Despite alteration in their fate, transport, and bio/toxicity of MNPs can be possible as a result of their (bio)transformation (Lowry et al., 2012; Cui et al., 2014; Rui et al., 2015), information is scarce on the (bio)transformation of MNPs within the plant system. If done, these studies and also that on metal speciation in plants can provide clues for unveiling phytotoxicity mechanisms, trophic transfer, and also for accurate health risk assessment of plant-harbored nanoparticles to human/animal system. Potential interaction of genetically modified crops with the extensively

NAA (SFRH/BPD/84671/2012), ACD and EP are grateful to the Portuguese Foundation for Science and Technology (FCT) and the Aveiro University Research Institute/Centre for Environmental and Marine Studies (CESAM) (UID/AMB/50017/2013) for partial financial supports. MAMR, AM, ZH, PK, OZ, VA, and RK gratefully acknowledge Czech Republic for research grant (CEITEC CZ.1.05/ 1.1.00/02.0068). ASL thanks to the Ministry of Education and Science of Russia for financing his present research through project number 6.783.2014K.

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