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Express assessment of neurotoxicity of particles of planetary and interstellar dust

Express assessment of neurotoxicity of particles of planetary and interstellar dust www.nature.com/npjmgrav PERSPECTIVE OPEN Express assessment of neurotoxicity of particles of planetary and interstellar dust Tatiana Borisova Establishment of high-quality, consistent on-board assessment of the neurotoxicity of planetary, and interstellar dust particles will be required to predict their potential threat to human health during long-term space missions. This Perspective article proposes an approach for the rapid assessment of potential neurotoxicity of micro-sized and nano-sized dust particles based on experimental results with other neurotoxic particles. Capacity of particles to affect membrane potential, integrity of nerve terminals, and consequently key synaptic transmission characteristics can be assessed using a planar lipid bilayer technique by monitoring artificial membrane conductivity in the presence of particles. Preliminary neurotoxicity data of nanoparticles, including lunar and Martian dust simulants, obtained using a planar lipid bilayer technique, is compared with that acquired using more-established methodological approaches. Under space flight conditions, neurotoxicity assessments of particulate matter could be rapidly and reproducibly performed using a planar lipid bilayer technique, which does not require biological material. npj Microgravity (2019) 5:2 ; https://doi.org/10.1038/s41526-019-0062-7 INTRODUCTION the central nervous system (CNS). Accumulating evidences suggest that inhaled outdoor air pollutants may have a consider- Particles of planetary and interstellar dust might affect human able impact on health and disease of the CNS. More recently, health during long-term human space missions, so their toxicity environmental exposure to PM has been associated with autism, risk assessment is required for human planetary exploration. 2.5 children’s attention deficit/hyperactivity disorders, and neurode- Throughout several Apollo missions, lunar dust particles were generative diseases, including dementia in adults—although shown to adhere to space suits, thereafter getting into spacecraft evidence of causation has not been established for these and having a direct contact with the astronauts. These particles 9–12 disorders. caused irritation of eyes, the respiratory system, and skin. In 2016, exogenous magnetite nanoparticles were found Additionally, these dust simulants damaged alveolar macrophages present in the human brain, likely via uptake through the olfactory in vitro and elicited an increase in cytotoxicity. An acute bulb. Nanoparticles can accumulate in the nasal regions, where inflammatory response led to a chronic inflammatory lesion they are then transported along sensory axons of the olfactory during prolonged presence of lunar and Martian dust simulants in 14,15 nerve directly to the CNS. Titanium dioxide nanoparticles the lungs of mice. Expression of inducible nitric oxide synthase in intranasally instilled to mice can be translocated to the brain and a murine macrophage cell line was also enhanced by lunar dust cause potential lesions, with the hippocampus being the main simulant. It was shown evaluating the respiratory system of mice target. Further, a mouse study suggested that nanoparticles that lunar dust simulant was more toxic than titanium dioxide could be transferred from mother to child. Titanium dioxide particles, while the acute effects of Martian dust simulant were nanoparticles administrated subcutaneously to pregnant mice comparable with those of quartz dust. Assessments of biochem- ical and cellular markers of toxicity in lavage fluid and were registered in the brains of the offspring, had a severe histopathology of lungs and lymph nodes showed that the negative effect on fetal brain development and a risk of various highest Non-Observable-Adverse-Effect Level (NOAEL) was nervous system disorders. 6.8 mg/m for rats exposed during 4 weeks to lunar soil aerosols While the ability of micro-sized and nano-sized particles to collected during the Apollo 14 mission; an estimated human circumvent the blood–brain barrier is encouraging for nanome- 3 5 NOAEL was 2.3 mg/m . Other study on assessment of the dicine, this route presents problems regarding potential neuro- pulmonary toxicity of airborne lunar dust in rats exposed by toxic effects of planetary and interstellar dust for the safety of human space flight. A rapid and accurate system for toxicity nose-only inhalation showed safe exposure estimate values assessment of these dust particles under space flight conditions ranging from 0.6 to 0.9 mg/m , when benchmark dose was would be useful to address this concern. Dust particle toxicity extrapolated to humans. Notable, current air quality standards of should also be analyzed in situ as different planetary regions have the European Commission for air pollution particulate matter (PM) their own unique environmental factors (for example, ultraviolet are 25 μg/m for PM with an aerodynamic diameter below 2.5 μm 3 7 (PM ) and 40–50 μg/m for PM . and ionizing radiation) which, in turn, can significantly influence 2.5 10 18–20 Toxicity assessment of engineered particles and environmen- particle properties. tally derived micro-sized (PM ) and nano-sized (PM )PMis The PM sensors currently used for Earth environmental 0.1–2.5 <0.1 a focus of research interest, particularly as it pertains to effects on monitoring detect PM (starting to be monitored), PM , and 1 2.5 Department of Neurochemistry, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovicha Street, Kiev 01030, Ukraine Correspondence: Tatiana Borisova (tborisov@biochem.kiev.ua) Received: 17 October 2017 Accepted: 15 January 2019 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA T. Borisova 7 26 PM , with no discrimination regarding chemical composition. components. Also, the study demonstrated the ability 3+ 27 Lead, cadmium, nickel, arsenic, and polycyclic aromatic hydro- of NaYF :Eu nanocrystals and maghemite nanoparticles 7 28,29 carbons are monitored separately. These monitoring techniques γ-Fe O to change neurotransmitter transport characteristics 2 3 can be useful to collect information during space exploration, but in synaptosomes, namely uptake and release of excitatory and they are not enough to predict the potential toxicity of planetary inhibitory neurotransmitters. Acquired experimental data define a and interstellar dust. Indeed, detailed investigation of toxicity representative parameter that is indicative of acute neurotoxicity requires laboratory testing, which can be performed using highly causing by nanoparticles (see below). sophisticated equipment (mass spectrometry , laser correlation 22 22 spectroscopy , electron , and confocal laser scanning micro- NERVE TERMINAL MEMBRANE POTENTIAL scopy ) and a variety of different cell culture types, tissue preparations, and animals. However, bulky equipment and The plasma membrane of nerve cells is directly involved in nerve biological material are not practical for on-board measurements signal transmission and simultaneously performs a classical barrier during space flight. function, which is interrupted during contact with dust particles. Therefore, the aims of this Perspective article are to first outline Changes of key neurotransmitter transport parameters (exocytotic, the potential for analysis and comparison of changes in the tonic, and Na -dependent neurotransmitter transporter-mediated 14 3 membrane potential of nerve terminals induced by different types release of L-[ C]glutamate and [ H]GABA; uptake and the ambient of micro-sized and nano-sized particles and consequent altera- level of these neurotransmitters) correlated with alterations of the tions of key synaptic transmission characteristics. In addition, this membrane potential (measured using fluorescent potential- Perspective describes an approach for rapid assessment of sensitive dye) during exposure of synaptosomes to carbon 24 25 3+ potential neurotoxicity of micro-sized and nano-sized dust nanodots, detonation nanodiamonds, NaYF :Eu nanocrys- 28,29 particles for use in space flight. tals, and γ-Fe O nanoparticles. Interestingly, simulated lunar 2 3 and Martian dusts did not affect the membrane potential and were inert regarding neurotransmitter transport modulation. NEUROTOXICITY OF DIFFERENT TYPES OF PARTICLES The increase in non-specific glutamate binding induced by Characterization of the neurotoxicity of engineered and envir- simulated lunar dust did not correlate with any change in onmentally derived micro-sized and nano-sized particles is membrane potential. The mixture of simulated Martian soil incredibly useful for designing an adequate approach that could particles and carbon nanoparticles depolarized the plasma 23–26 assess the potential toxicity of planetary and interstellar dust. membrane and consequently modulated neurotransmitter Experiments concerning neurotoxicity risk assessment have been transport. Thus, nanoparticle-induced changes in key synaptic performed at the neurochemical level of nervous system transmission characteristics and the neurotoxic features of organization and involved an analysis of neurotransmitter different types of particles examined in our experiments transport, functioning of ion channels, and other parameters corresponded to their ability to change the plasma membrane (according to Guidelines for Neurotoxicity Risk Assessment of US potential of synaptosomes (Fig. 1)(Table 1). These experimental Environmental Protection Agency, 1998, based on paragraph 3. data suggest that the plasma membrane potential of synapto- Hazard Characterization: 3.1.2. Animal Studies; 3.1.2.3. Neuro- somes can be used as a representative parameter to adequately chemical Endpoints of Neurotoxicity; 3.1.3.4. In Vitro Data in reflect acute nanoparticle-induced neurotoxicity. 22–29 Neurotoxicology). Nerve terminals isolated from rat brain (synaptosomes) have been used as models when exploring the PLANAR LIPID BILAYER TECHNIQUE relationship between the structure of synaptic proteins, their biochemical properties, and physiological roles. The effects of Importantly, the neurotoxicity of particles depends not only on different types of nanoparticles on the transport characteristics of their size but also on their composition, shape, charge, surface radiolabelled glutamate and γ-aminobutyric acid (GABA), which properties, aggregation state, and ability to absorb toxic are key excitatory and inhibitory neurotransmitters in the CNS, substances from the environment. Measurements of these 22–29 respectively, were examined using synaptosomes. Studies characteristics require complex and sophisticated equipment, have revealed three types of functional changes in synaptosomes complicated techniques, and the existence of well-functioning in response to application of different nanoparticles: (1) decreased biological models, for example cell culture, tissue preparations, exocytotic release and Na -dependent neurotransmitter and animals, which may not be readily amenable to direct testing 14 31 3 transporter-mediated uptake L-[ C]glutamate and [ H]GABA, in space flight. The complex characteristics of the particles (2) elevated tonic and transporter-mediated release, and ambient determine their capacity to affect integrity of the plasma 32 33,34 levels of these neurotransmitters, (3) attenuation of acidification membrane of nerve terminals, which can be examined using 22–29 of synaptic vesicles and resting membrane potential. Different corresponding membrane potential measurements. The capacity particles elicit varying combinations of these effects in synapto- of particles to affect the parameters previously described could be somes. For instance, the levels of L-[ C]glutamate binding to assessed using a planar lipid bilayer, a well-known technique for synaptosomes in low Na concentration media and at low investigation of ion-conducting properties of pore-forming 35–41 temperature increased in the presence of simulated lunar soil, molecules and proteins, ion channels, and transporters. whereas simulated Martian soil caused significantly less changes Single, stable lipid bilayers between two compartments filled under the same conditions (both simulated soils are composed of with saline were formed by Mueller et al., and the transverse natural volcanic ash). This suggests that lunar dust interacts with electrical properties were measured in controlled chemical the synaptosomal plasma membrane to increase non-specific investigations. Planar lipid bilayers are usually composed of 14 22 L-[ C]glutamate binding. Using the same methodological phosphatidylcholine and cholesterol at a weight ratio of 2:1; approaches, the neurotoxic and neuromodulatory properties of however, other lipid and protein components can be also 23 24 36 carbon nanodots synthesized from β-alanine, thiourea , and included. Bilayer membranes are usually painted across a round detonation nanodiamonds were predicted. The mixture of aperture with a small mm-sized diameter in a thin wall of a Teflon simulated Martian soil particles and carbon nanoparticles, cup held within a glass chamber. A high-resolution amplifier and potential components of native Martian dust, impaired uptake computer are used for voltage-clamp recordings of transmem- and release of excitatory and inhibitory neurotransmitters, and so brane current. Monitoring the membrane activity of micro-sized had a harmful effect on synaptic neurotransmission. This effect and nano-sized dust particles during long-term space flight could was determined by its carbon content, but not inorganic potentially be implemented using an adapted planar lipid bilayer npj Microgravity (2019) 2 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; T. Borisova * * 40 100 * * * Fig. 1 Correspondence of an increase in the ambient level of L-[ C]glutamate (a, b)reflecting the neurotoxic potential of nanoparticles and a decrease in the membrane potential registered using fluorescent dye rhodamine 6 G (a, c) in the preparations of nerve terminals without (b, c, columns # 1) and in the presence of micro- and nano-sized particles: simulated Martian soil, 2.0 mg/ml (b, c, columns # 2); Lunar soil 22 3+ 27 3 simulant, 2.0 mg/ml (b, c, columns # 3); nanocrystals NaYF :Eu -PEG, 7.5 mg/ml (b); 3.5 mg/ml (c) (columns # 4); nanocrystals NaYF :Eu- 4 4 + 27 28 OH, 3.5 mg/ml (b); 1.5 mg/ml (c) (columns # 5); maghemite nanoparticles, 0.75 mg/ml (b, c, columns # 6); nanodiamonds, 1.0 mg/ml (b, c, 25 24 columns # 7); carbon nanodots synthesized from thiourea, 1.0 mg/ml (b); 0.5 mg/ml (c) (columns # 8). Data are mean ± SEM of six independent experiments. *p < 0.05, as compared to the control; Student t-test technique through registration of artificial membrane conductivity particles did not affect the membrane potential of nerve in the presence of particles. Ion conductance of the planar lipid terminals and also did not influence the conductance of the bilayer might correlate with the capacity of the acquired planetary planar lipid bilayer. The principal similarity of effects obtained dust particles, once added to the operation cuvette, to affect the using neurochemical methods with those using the planar lipid membrane integrity. The planar lipid bilayer technique has already bilayer technique was also found in preliminary experiments with been proposed for investigation of the gravitational vector effects carbon nanodots and nanodiamonds. Preliminary verification of on action of antibiotic alamethicin. the experimental data on particle neurotoxicity obtained using 14 3 Initial feasibility of the planar lipid bilayer technique was shown radiolabelled L-[ C]glutamate and [ H]GABA and fluorescence in experiments with macrocycle calix[4]arene-bis-hydroxymethyl- methods using fluorescent potential-sensitive dye with data on phosphonic acid (calix[4]arene C-99) that demonstrated parallel the membrane conductance measured using planar lipid bilayer 22–29,33,34,36,38,41 calixarene-induced changes in the planar lipid membrane equipment has been completed. However, exten- conductance and in the membrane potential of blood platelets. sive validation is required to have appropriate assessment Polysaccharide-coated magnetite nanoparticles were inert regard- algorithms and the parameter relations for different types of ing changes in the synaptosomal membrane potential and also particles. Moreover, the lipid composition of the planar membrane demonstrated an absence of effects on the planar lipid membrane can be easily varied (protein compounds might also be included conductance. The vitamin B1 (thiamine) structural analogue 3- to improve performance) and different parameters, e.g., mem- decyloxycarbonylmethyl-4-methyl-5-(β-hydroxyethyl) thiazole brane conductance and capacitance, can be analyzed. chloride changed the membrane potential of nerve terminals, It is difficult to make a predictive model for particle and its sequential additions to the planar lipid bilayer membrane neurotoxicity without experimental measurements because of decreased the membrane stability and led to its eventual rupture the huge diversity of particle characteristics and their unknown at high concentrations. Simulated lunar and Martian dust effects. Furthermore, even a small variation of particle size, charge, Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 2 Ambient level of L- [ C]glutamate, % of total synaptosomal label The synaptosomal membrane potenal, % T. Borisova Table 1. Comparison of the ambient level of L-[ C]glutamate in the preparations of nerve terminals and their membrane potential registered as an increase in fluorescence (F = F /F ) of the dye rhodamine 6 G in the presence of different types of micro- and nano-sized particles t 0 Various types of micro- and nano-sized The ambient level of L-[ C]glutamate An increase in rhodamine 6 G fluorescence, References particles (nmol/mg of protein) in the synaptosomal (arb. units) in synaptosomes, reflecting preparations membrane depolarization Control synaptosomes without micro- 0.193 ± 0.013 0.015 ± 0.005 Krisanova et al. and nano-sized particles 2013; Pozdnyakova et al. 2017; Soika et al. 2017; Pozdnyakova et al. 2016; Borisova et al. 2017 Martial soil simulant JSC, Mars-1A 0.208 ± 0.021 0.017 ± 0.005 Krisanova et al. (2.0 mg/ml) 2013; Pozdnyakova et al. Lunar soil simulant JSC-1a (2.0 mg/ml) 0.214 ± 0.029 0.020 ± 0.005 Krisanova et al. 2013 3+ 27 Nanocrystals NaYF :Eu -PEG (0.5; 3.5; ‒ 0.02 ± 0.008; Soika et al. 2017 7.5 mg/ml, respectively) ‒ 0.05 ± 0.014; 0.268 ± 0.017 0.11 ± 0.015 3+ 27 Nanocrystals NaYF :Eu- OH (0.5; 1.5; ‒ 0.04 ± 0.006; Soika et al. 2017 3.5 mg/ml, respectively) ‒ 0.06 ± 0.014; 0.298 ± 0.012 0.14 ± 0.01 Maghemite nanoparticles γ-Fe O 0.30 ± 0.02 0.10 ± 0.01 Horak et al. 2017; 2 3 (0.75 mg/ml) Borisova et al. 2014 Nanodiamonds (1.0 mg/ml) 0.383 ± 0.022 0.10 ± 0.01 Pozdnyakova et al. Carbon nanodots synthesized from 0.216 ± 0.01; 0.07 ± 0.01 Borisova et al. 2017 thiourea (0.5 mg/ml; 1.0 mg/ml, 0.364 ± 0.02 ‒ respectively) shape, and functional group exposure can unpredictably alter AUTHOR CONTRIBUTIONS their neuroactive properties. In this context, the results from Data analysis and paper writing were performed by Т.B. planar lipid bilayer measurements might supplement data obtained by other techniques. To support experimentation in ADDITIONAL INFORMATION space, the planar lipid bilayer technique would need to be Supplementary information accompanies the paper on the npj Microgravity website adapted to be portable, automated, vibration-resistant, and (https://doi.org/10.1038/s41526-019-0062-7). suitable to perform measurements in a simple manner, thereby making the monitoring process manageable for those on board. Competing interests: The author declares no competing interests. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims CONCLUSIONS in published maps and institutional affiliations. With successful further optimization, it is possible that the planar lipid bilayer technique could be used for the rapid assessment of potential neurotoxicity of planetary and interstellar dust micro- REFERENCES sized and nano-sized particles during long-term space missions. If 1. Gaier, J. R. 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Effect of O-methyl-β-cyclodextrin-modified magnetic nano- article’s Creative Commons license and your intended use is not permitted by statutory particles on the uptake and extracellular level of L-glutamate in brain nerve regulation or exceeds the permitted use, you will need to obtain permission directly terminals. Colloids Surf. B Biointerfaces 149,64–71 (2017). from the copyright holder. To view a copy of this license, visit http://creativecommons. 29. Borisova, T. et al. Manipulation of isolated brain nerve terminals by an external org/licenses/by/4.0/. magnetic field using D-mannose-coated γ-Fe O nano-sized particles and 2 3 assessment of their effects on glutamate transport. Beilstein J. Nanotechnol. 5, © The Author(s) 2019 778–788 (2014). Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 2 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Microgravity Springer Journals

Express assessment of neurotoxicity of particles of planetary and interstellar dust

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Life Sciences; Life Sciences, general; Classical and Continuum Physics; Biotechnology; Immunology; Space Sciences (including Extraterrestrial Physics, Space Exploration and Astronautics) ; Applied Microbiology
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Abstract

www.nature.com/npjmgrav PERSPECTIVE OPEN Express assessment of neurotoxicity of particles of planetary and interstellar dust Tatiana Borisova Establishment of high-quality, consistent on-board assessment of the neurotoxicity of planetary, and interstellar dust particles will be required to predict their potential threat to human health during long-term space missions. This Perspective article proposes an approach for the rapid assessment of potential neurotoxicity of micro-sized and nano-sized dust particles based on experimental results with other neurotoxic particles. Capacity of particles to affect membrane potential, integrity of nerve terminals, and consequently key synaptic transmission characteristics can be assessed using a planar lipid bilayer technique by monitoring artificial membrane conductivity in the presence of particles. Preliminary neurotoxicity data of nanoparticles, including lunar and Martian dust simulants, obtained using a planar lipid bilayer technique, is compared with that acquired using more-established methodological approaches. Under space flight conditions, neurotoxicity assessments of particulate matter could be rapidly and reproducibly performed using a planar lipid bilayer technique, which does not require biological material. npj Microgravity (2019) 5:2 ; https://doi.org/10.1038/s41526-019-0062-7 INTRODUCTION the central nervous system (CNS). Accumulating evidences suggest that inhaled outdoor air pollutants may have a consider- Particles of planetary and interstellar dust might affect human able impact on health and disease of the CNS. More recently, health during long-term human space missions, so their toxicity environmental exposure to PM has been associated with autism, risk assessment is required for human planetary exploration. 2.5 children’s attention deficit/hyperactivity disorders, and neurode- Throughout several Apollo missions, lunar dust particles were generative diseases, including dementia in adults—although shown to adhere to space suits, thereafter getting into spacecraft evidence of causation has not been established for these and having a direct contact with the astronauts. These particles 9–12 disorders. caused irritation of eyes, the respiratory system, and skin. In 2016, exogenous magnetite nanoparticles were found Additionally, these dust simulants damaged alveolar macrophages present in the human brain, likely via uptake through the olfactory in vitro and elicited an increase in cytotoxicity. An acute bulb. Nanoparticles can accumulate in the nasal regions, where inflammatory response led to a chronic inflammatory lesion they are then transported along sensory axons of the olfactory during prolonged presence of lunar and Martian dust simulants in 14,15 nerve directly to the CNS. Titanium dioxide nanoparticles the lungs of mice. Expression of inducible nitric oxide synthase in intranasally instilled to mice can be translocated to the brain and a murine macrophage cell line was also enhanced by lunar dust cause potential lesions, with the hippocampus being the main simulant. It was shown evaluating the respiratory system of mice target. Further, a mouse study suggested that nanoparticles that lunar dust simulant was more toxic than titanium dioxide could be transferred from mother to child. Titanium dioxide particles, while the acute effects of Martian dust simulant were nanoparticles administrated subcutaneously to pregnant mice comparable with those of quartz dust. Assessments of biochem- ical and cellular markers of toxicity in lavage fluid and were registered in the brains of the offspring, had a severe histopathology of lungs and lymph nodes showed that the negative effect on fetal brain development and a risk of various highest Non-Observable-Adverse-Effect Level (NOAEL) was nervous system disorders. 6.8 mg/m for rats exposed during 4 weeks to lunar soil aerosols While the ability of micro-sized and nano-sized particles to collected during the Apollo 14 mission; an estimated human circumvent the blood–brain barrier is encouraging for nanome- 3 5 NOAEL was 2.3 mg/m . Other study on assessment of the dicine, this route presents problems regarding potential neuro- pulmonary toxicity of airborne lunar dust in rats exposed by toxic effects of planetary and interstellar dust for the safety of human space flight. A rapid and accurate system for toxicity nose-only inhalation showed safe exposure estimate values assessment of these dust particles under space flight conditions ranging from 0.6 to 0.9 mg/m , when benchmark dose was would be useful to address this concern. Dust particle toxicity extrapolated to humans. Notable, current air quality standards of should also be analyzed in situ as different planetary regions have the European Commission for air pollution particulate matter (PM) their own unique environmental factors (for example, ultraviolet are 25 μg/m for PM with an aerodynamic diameter below 2.5 μm 3 7 (PM ) and 40–50 μg/m for PM . and ionizing radiation) which, in turn, can significantly influence 2.5 10 18–20 Toxicity assessment of engineered particles and environmen- particle properties. tally derived micro-sized (PM ) and nano-sized (PM )PMis The PM sensors currently used for Earth environmental 0.1–2.5 <0.1 a focus of research interest, particularly as it pertains to effects on monitoring detect PM (starting to be monitored), PM , and 1 2.5 Department of Neurochemistry, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, 9 Leontovicha Street, Kiev 01030, Ukraine Correspondence: Tatiana Borisova (tborisov@biochem.kiev.ua) Received: 17 October 2017 Accepted: 15 January 2019 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA T. Borisova 7 26 PM , with no discrimination regarding chemical composition. components. Also, the study demonstrated the ability 3+ 27 Lead, cadmium, nickel, arsenic, and polycyclic aromatic hydro- of NaYF :Eu nanocrystals and maghemite nanoparticles 7 28,29 carbons are monitored separately. These monitoring techniques γ-Fe O to change neurotransmitter transport characteristics 2 3 can be useful to collect information during space exploration, but in synaptosomes, namely uptake and release of excitatory and they are not enough to predict the potential toxicity of planetary inhibitory neurotransmitters. Acquired experimental data define a and interstellar dust. Indeed, detailed investigation of toxicity representative parameter that is indicative of acute neurotoxicity requires laboratory testing, which can be performed using highly causing by nanoparticles (see below). sophisticated equipment (mass spectrometry , laser correlation 22 22 spectroscopy , electron , and confocal laser scanning micro- NERVE TERMINAL MEMBRANE POTENTIAL scopy ) and a variety of different cell culture types, tissue preparations, and animals. However, bulky equipment and The plasma membrane of nerve cells is directly involved in nerve biological material are not practical for on-board measurements signal transmission and simultaneously performs a classical barrier during space flight. function, which is interrupted during contact with dust particles. Therefore, the aims of this Perspective article are to first outline Changes of key neurotransmitter transport parameters (exocytotic, the potential for analysis and comparison of changes in the tonic, and Na -dependent neurotransmitter transporter-mediated 14 3 membrane potential of nerve terminals induced by different types release of L-[ C]glutamate and [ H]GABA; uptake and the ambient of micro-sized and nano-sized particles and consequent altera- level of these neurotransmitters) correlated with alterations of the tions of key synaptic transmission characteristics. In addition, this membrane potential (measured using fluorescent potential- Perspective describes an approach for rapid assessment of sensitive dye) during exposure of synaptosomes to carbon 24 25 3+ potential neurotoxicity of micro-sized and nano-sized dust nanodots, detonation nanodiamonds, NaYF :Eu nanocrys- 28,29 particles for use in space flight. tals, and γ-Fe O nanoparticles. Interestingly, simulated lunar 2 3 and Martian dusts did not affect the membrane potential and were inert regarding neurotransmitter transport modulation. NEUROTOXICITY OF DIFFERENT TYPES OF PARTICLES The increase in non-specific glutamate binding induced by Characterization of the neurotoxicity of engineered and envir- simulated lunar dust did not correlate with any change in onmentally derived micro-sized and nano-sized particles is membrane potential. The mixture of simulated Martian soil incredibly useful for designing an adequate approach that could particles and carbon nanoparticles depolarized the plasma 23–26 assess the potential toxicity of planetary and interstellar dust. membrane and consequently modulated neurotransmitter Experiments concerning neurotoxicity risk assessment have been transport. Thus, nanoparticle-induced changes in key synaptic performed at the neurochemical level of nervous system transmission characteristics and the neurotoxic features of organization and involved an analysis of neurotransmitter different types of particles examined in our experiments transport, functioning of ion channels, and other parameters corresponded to their ability to change the plasma membrane (according to Guidelines for Neurotoxicity Risk Assessment of US potential of synaptosomes (Fig. 1)(Table 1). These experimental Environmental Protection Agency, 1998, based on paragraph 3. data suggest that the plasma membrane potential of synapto- Hazard Characterization: 3.1.2. Animal Studies; 3.1.2.3. Neuro- somes can be used as a representative parameter to adequately chemical Endpoints of Neurotoxicity; 3.1.3.4. In Vitro Data in reflect acute nanoparticle-induced neurotoxicity. 22–29 Neurotoxicology). Nerve terminals isolated from rat brain (synaptosomes) have been used as models when exploring the PLANAR LIPID BILAYER TECHNIQUE relationship between the structure of synaptic proteins, their biochemical properties, and physiological roles. The effects of Importantly, the neurotoxicity of particles depends not only on different types of nanoparticles on the transport characteristics of their size but also on their composition, shape, charge, surface radiolabelled glutamate and γ-aminobutyric acid (GABA), which properties, aggregation state, and ability to absorb toxic are key excitatory and inhibitory neurotransmitters in the CNS, substances from the environment. Measurements of these 22–29 respectively, were examined using synaptosomes. Studies characteristics require complex and sophisticated equipment, have revealed three types of functional changes in synaptosomes complicated techniques, and the existence of well-functioning in response to application of different nanoparticles: (1) decreased biological models, for example cell culture, tissue preparations, exocytotic release and Na -dependent neurotransmitter and animals, which may not be readily amenable to direct testing 14 31 3 transporter-mediated uptake L-[ C]glutamate and [ H]GABA, in space flight. The complex characteristics of the particles (2) elevated tonic and transporter-mediated release, and ambient determine their capacity to affect integrity of the plasma 32 33,34 levels of these neurotransmitters, (3) attenuation of acidification membrane of nerve terminals, which can be examined using 22–29 of synaptic vesicles and resting membrane potential. Different corresponding membrane potential measurements. The capacity particles elicit varying combinations of these effects in synapto- of particles to affect the parameters previously described could be somes. For instance, the levels of L-[ C]glutamate binding to assessed using a planar lipid bilayer, a well-known technique for synaptosomes in low Na concentration media and at low investigation of ion-conducting properties of pore-forming 35–41 temperature increased in the presence of simulated lunar soil, molecules and proteins, ion channels, and transporters. whereas simulated Martian soil caused significantly less changes Single, stable lipid bilayers between two compartments filled under the same conditions (both simulated soils are composed of with saline were formed by Mueller et al., and the transverse natural volcanic ash). This suggests that lunar dust interacts with electrical properties were measured in controlled chemical the synaptosomal plasma membrane to increase non-specific investigations. Planar lipid bilayers are usually composed of 14 22 L-[ C]glutamate binding. Using the same methodological phosphatidylcholine and cholesterol at a weight ratio of 2:1; approaches, the neurotoxic and neuromodulatory properties of however, other lipid and protein components can be also 23 24 36 carbon nanodots synthesized from β-alanine, thiourea , and included. Bilayer membranes are usually painted across a round detonation nanodiamonds were predicted. The mixture of aperture with a small mm-sized diameter in a thin wall of a Teflon simulated Martian soil particles and carbon nanoparticles, cup held within a glass chamber. A high-resolution amplifier and potential components of native Martian dust, impaired uptake computer are used for voltage-clamp recordings of transmem- and release of excitatory and inhibitory neurotransmitters, and so brane current. Monitoring the membrane activity of micro-sized had a harmful effect on synaptic neurotransmission. This effect and nano-sized dust particles during long-term space flight could was determined by its carbon content, but not inorganic potentially be implemented using an adapted planar lipid bilayer npj Microgravity (2019) 2 Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA 1234567890():,; T. Borisova * * 40 100 * * * Fig. 1 Correspondence of an increase in the ambient level of L-[ C]glutamate (a, b)reflecting the neurotoxic potential of nanoparticles and a decrease in the membrane potential registered using fluorescent dye rhodamine 6 G (a, c) in the preparations of nerve terminals without (b, c, columns # 1) and in the presence of micro- and nano-sized particles: simulated Martian soil, 2.0 mg/ml (b, c, columns # 2); Lunar soil 22 3+ 27 3 simulant, 2.0 mg/ml (b, c, columns # 3); nanocrystals NaYF :Eu -PEG, 7.5 mg/ml (b); 3.5 mg/ml (c) (columns # 4); nanocrystals NaYF :Eu- 4 4 + 27 28 OH, 3.5 mg/ml (b); 1.5 mg/ml (c) (columns # 5); maghemite nanoparticles, 0.75 mg/ml (b, c, columns # 6); nanodiamonds, 1.0 mg/ml (b, c, 25 24 columns # 7); carbon nanodots synthesized from thiourea, 1.0 mg/ml (b); 0.5 mg/ml (c) (columns # 8). Data are mean ± SEM of six independent experiments. *p < 0.05, as compared to the control; Student t-test technique through registration of artificial membrane conductivity particles did not affect the membrane potential of nerve in the presence of particles. Ion conductance of the planar lipid terminals and also did not influence the conductance of the bilayer might correlate with the capacity of the acquired planetary planar lipid bilayer. The principal similarity of effects obtained dust particles, once added to the operation cuvette, to affect the using neurochemical methods with those using the planar lipid membrane integrity. The planar lipid bilayer technique has already bilayer technique was also found in preliminary experiments with been proposed for investigation of the gravitational vector effects carbon nanodots and nanodiamonds. Preliminary verification of on action of antibiotic alamethicin. the experimental data on particle neurotoxicity obtained using 14 3 Initial feasibility of the planar lipid bilayer technique was shown radiolabelled L-[ C]glutamate and [ H]GABA and fluorescence in experiments with macrocycle calix[4]arene-bis-hydroxymethyl- methods using fluorescent potential-sensitive dye with data on phosphonic acid (calix[4]arene C-99) that demonstrated parallel the membrane conductance measured using planar lipid bilayer 22–29,33,34,36,38,41 calixarene-induced changes in the planar lipid membrane equipment has been completed. However, exten- conductance and in the membrane potential of blood platelets. sive validation is required to have appropriate assessment Polysaccharide-coated magnetite nanoparticles were inert regard- algorithms and the parameter relations for different types of ing changes in the synaptosomal membrane potential and also particles. Moreover, the lipid composition of the planar membrane demonstrated an absence of effects on the planar lipid membrane can be easily varied (protein compounds might also be included conductance. The vitamin B1 (thiamine) structural analogue 3- to improve performance) and different parameters, e.g., mem- decyloxycarbonylmethyl-4-methyl-5-(β-hydroxyethyl) thiazole brane conductance and capacitance, can be analyzed. chloride changed the membrane potential of nerve terminals, It is difficult to make a predictive model for particle and its sequential additions to the planar lipid bilayer membrane neurotoxicity without experimental measurements because of decreased the membrane stability and led to its eventual rupture the huge diversity of particle characteristics and their unknown at high concentrations. Simulated lunar and Martian dust effects. Furthermore, even a small variation of particle size, charge, Published in cooperation with the Biodesign Institute at Arizona State University, with the support of NASA npj Microgravity (2019) 2 Ambient level of L- [ C]glutamate, % of total synaptosomal label The synaptosomal membrane potenal, % T. Borisova Table 1. Comparison of the ambient level of L-[ C]glutamate in the preparations of nerve terminals and their membrane potential registered as an increase in fluorescence (F = F /F ) of the dye rhodamine 6 G in the presence of different types of micro- and nano-sized particles t 0 Various types of micro- and nano-sized The ambient level of L-[ C]glutamate An increase in rhodamine 6 G fluorescence, References particles (nmol/mg of protein) in the synaptosomal (arb. units) in synaptosomes, reflecting preparations membrane depolarization Control synaptosomes without micro- 0.193 ± 0.013 0.015 ± 0.005 Krisanova et al. and nano-sized particles 2013; Pozdnyakova et al. 2017; Soika et al. 2017; Pozdnyakova et al. 2016; Borisova et al. 2017 Martial soil simulant JSC, Mars-1A 0.208 ± 0.021 0.017 ± 0.005 Krisanova et al. (2.0 mg/ml) 2013; Pozdnyakova et al. Lunar soil simulant JSC-1a (2.0 mg/ml) 0.214 ± 0.029 0.020 ± 0.005 Krisanova et al. 2013 3+ 27 Nanocrystals NaYF :Eu -PEG (0.5; 3.5; ‒ 0.02 ± 0.008; Soika et al. 2017 7.5 mg/ml, respectively) ‒ 0.05 ± 0.014; 0.268 ± 0.017 0.11 ± 0.015 3+ 27 Nanocrystals NaYF :Eu- OH (0.5; 1.5; ‒ 0.04 ± 0.006; Soika et al. 2017 3.5 mg/ml, respectively) ‒ 0.06 ± 0.014; 0.298 ± 0.012 0.14 ± 0.01 Maghemite nanoparticles γ-Fe O 0.30 ± 0.02 0.10 ± 0.01 Horak et al. 2017; 2 3 (0.75 mg/ml) Borisova et al. 2014 Nanodiamonds (1.0 mg/ml) 0.383 ± 0.022 0.10 ± 0.01 Pozdnyakova et al. Carbon nanodots synthesized from 0.216 ± 0.01; 0.07 ± 0.01 Borisova et al. 2017 thiourea (0.5 mg/ml; 1.0 mg/ml, 0.364 ± 0.02 ‒ respectively) shape, and functional group exposure can unpredictably alter AUTHOR CONTRIBUTIONS their neuroactive properties. In this context, the results from Data analysis and paper writing were performed by Т.B. planar lipid bilayer measurements might supplement data obtained by other techniques. To support experimentation in ADDITIONAL INFORMATION space, the planar lipid bilayer technique would need to be Supplementary information accompanies the paper on the npj Microgravity website adapted to be portable, automated, vibration-resistant, and (https://doi.org/10.1038/s41526-019-0062-7). suitable to perform measurements in a simple manner, thereby making the monitoring process manageable for those on board. Competing interests: The author declares no competing interests. Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims CONCLUSIONS in published maps and institutional affiliations. With successful further optimization, it is possible that the planar lipid bilayer technique could be used for the rapid assessment of potential neurotoxicity of planetary and interstellar dust micro- REFERENCES sized and nano-sized particles during long-term space missions. If 1. Gaier, J. R. 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