多壁碳纳米管对雌性小鼠生殖系统影响的研究
|
摘要
化学和材料科学的飞速发展使得大批新材料涌现,纳米材料作为新型材料的代表,目前已渗透到工业和人类日常生活的众多领域。随着纳米材料在生态环境中有意或无意暴露的增多,人们对纳米材料是否会影响人类的健康和生态环境这一问题的关注越来越多。2003年,Science和Nature相继发表文章,探讨了纳米材料的生物效应和对环境的影响。
碳纳米管凭借独特的电、磁、热和机械性能,成为纳米材料中的研究热点之一。碳纳米管目前已用于复合材料、电子和能源等领域,以生物医学应用为目标的探索研究也正迅速发展成为一个新的研究领域。碳纳米管在医药领域深入广泛应用的前提是其良好的生物相容性和无毒副作用等。碳纳米管可经血液循环在肝、脾、肺、肾和脑中积累,并产生不同程度的损伤,但是碳纳米管是否能转移至雌性生殖器官并造成脏器功能障碍进而损伤生殖力的研究目前尚无报道。
由于受到工业污染等方面的影响,人类女性生殖健康状况呈不断下降趋势。了解纳米材料对雌性生殖健康的影响,作为纳米材料安全性评价的重要部分势在必行。已有报道指出金纳米和磷酸钙纳米颗粒可进入卵巢颗粒细胞,诱发细胞凋亡,抑制雌激素的分泌。孕期暴露单壁碳纳米管可造成胎儿畸形等形态学上的损伤。然而,还未有报道对碳纳米管的非孕期雌性生殖系统的体内毒性进行全面的评价。
碳纳米管作为一种工业及医药应用前景非常广阔的纳米材料,且在实际生产、生活中主动或者被动进入人体的几率极高,研究其对雌性生殖健康的影响具有现实意义。本研究采用水溶性较好的羧基化多壁碳纳米管为研究对象,以雌性ICR小鼠为模型,首次评价了多壁碳纳米管对非孕期雌性生殖健康的影响。依据雌性生殖系统的内分泌调控轴(下丘脑-垂体-卵巢轴),系统研究了羧基化多壁碳纳米管在雌性生殖系统的分布和毒性,并初步进行了机制研究。实验结果表明,尾静脉单针注射64Cu标记的羧基化碳纳米管可在卵巢、子宫和脑中分布,并在24h内呈积累下降趋势。碳纳米管的暴露造成了小鼠动情周期的在给药期间的延长和血清性激素水平紊乱,说明在受试条件下,雌鼠的生殖内分泌功能受到了碳纳米管的干扰。然而,对第13天和第60天卵巢和子宫组织进行光镜观察发现,多次暴露碳纳米管并未造成明显的病理学改变,各级卵泡和黄体数目、子宫内膜和肌层厚度均无显著性变化。对雌性生殖功能进行的评价结果显示,羧基化多壁碳纳米管对怀孕期母鼠和子代发育中的各指标(交配率、怀孕率、生殖率、孕鼠体重和行为；仔鼠出生数目和性别比、第1天和第10天生存率、体重变化等)均未产生负面影响。毒性机制研究表明,实验组小鼠子宫和卵巢在第13天表现有免疫因子TNFα水平的明显升高,氧化应激指标MDA和GSH与对照组相比有显著改变。卵巢切除实验证实,多壁碳纳米管不能维持小鼠正常的动情周期和子宫变化,因此不具备类雌激素效应。
综上所述,多壁碳纳米管可进入雌性生殖系统并影响生殖相关激素的分泌,但组织结构和生殖力均未受到影响。多壁碳纳米管在体内并不具备类雌激素效应,因此对内分泌的影响与碳管与雌激素的拮抗作用无关,而可能是多壁碳纳米管在卵巢内产生过量的氧化应激的结果。碳纳米管可进入小鼠脑部,但是碳纳米管是否会对与生殖内分泌相关的下丘脑和垂体造成影响尚不明确。因此,我们推测过量的活性氧影响了激素产生相关酶的活性或者碳纳米管对生殖内分泌相关的其他靶器官的影响干扰了激素的产生和分泌。本研究拓宽了纳米毒理学的广度,为认识纳米材料的生殖安全提供评价,并对碳纳米管的广泛生物医学应用提供了重要的实验参考。
The rapid development of chemistry and materials science produced a large number of new materials, in which nanomaterials represent the most striking example have entered into many aspects of people's life. Nowadays, more and more people begin to concern the effects of nanomaterials on human health and ecological environment after intentional or unintentional exposure of nanoparticles. In2003, Science and Nature published articles one after another to explore the biological effects, environmental and healthy impacts cause by nanomaterials.
Carbon nanotubes (CNTs) are collections of induvidual or several concentric graphite cylinders, and have attracted the attention of many scientists worldwide. CNTs represent the ideal, perfect and ordered carbon fiber. The size, structure, and topology make them possess unique electrical, magnetic, thermal and mechanical properties, and fascinating in plastics and composite materials, electronics, energy. The exploration in biomedicine is also rapidly developed into a new research field. However, the promise of the wide use of CNTs in biomedicine is their good compatibility and no toxic or side effects. The research in biological toxicity have found that CNTs can translocate in liver, spleen, kidney, and brain through blood circulation, and produce different degrees of damage. However, the study on female reproductive toxicity caused by CNTs is rare and need further study.
The health of female reproduction shows a declining trend, due to various effects like industrial pollution. As an important part in safety evaluation of nanomaterials, it is imperative to understand the impact of nanomaterials on female reproductive system. Studies have been reported that gold nanopaticles and calcium phosphate nanoparticles can translocated into ovarian granulosa cell, and induced cell apoptosis and inhibited the secretion of estradiol. Prenatal exposure of single-walled carbon nanotubes caused fetal abnormalities such as morphology damage. Nevertheless, the effects of CNTs on female reproductiv system in non-pregnant period have not been investigated systematacially.
CNTs have extensive prospect in manufacture and medicine, and have high risk of entering the human body actively or passively. Study the effects of CNTs on female reproductive health has a realistic significance. In view of the above considerations, we use ICR mouse as the mammalian model to investigate the effects of carboxylic multi-walled carbon nanotubes (MWCNT-COOH) on female reproductive system. According to the regulatory mechanism of the female reproductive system (hypothalamus-pituitary-ovarian axis), we investigated the distribution and effects of MWCNT-COOH on female reproductive organs, and further discussed the toxic mechanisms. The results showed that64Cu-labelled MWCNT-COOH can translocate in ovary, uterus and brain through tail vein injection and the accumulation showed a decreased trend within24h. Repeated administration of MWCNT-COOH prolonged the estrous cycle during the exposure time and inhibited the secretion of hormones (FSH, LH, estradiol, progesterone), which indicated that MWCNT-COOH disturbed the endocrine system of female mice. However, histologic studies of ovary and uterus showed little alteration after exposure. The number of corpus luteum and each stage follicles, thickness of the endometrium and myometrium from treated mice were characterized no difference compared with control mice. Fertility studies at day13and day60showed that MWCNT-COOH do not have detrimental effect on successful conception and healthy growth of offspring (litter size, survival rate, gain of body weight). To explore the mechanism of toxicity, we found that MWCNT-COOH increased the level of TNFa and changed the level of MDA and GSH in ovary and uterus. Further more, MWCNT-COOH do not possess estrogen-like activity because they are unable to maintain normal estrous cycle and cyclical change of uterus in ovariectomized mice.
In conclusion, CNTs can translocate into the female reproductive organs and inhibite hormonal secretion, but leave the structure of organs and fertility not affected. CNTs do not possess estrogen-like effect in vivo, so their influence on endocrine system was not the antagonism effect with estrogen but may be the results of excessive reactive oxygen species caused on steroidogenic enzymes. Due to the complexity and importance of the female reproductive system, understanding of the impact of nanomaterials on reproductive health has a realistic significance. Our study has broadened the knowledge of nanotoxicology on female reproducive system and provided important experimental reference on safe application of carbon nanotubes in biological medicine.
碳纳米管凭借独特的电、磁、热和机械性能,成为纳米材料中的研究热点之一。碳纳米管目前已用于复合材料、电子和能源等领域,以生物医学应用为目标的探索研究也正迅速发展成为一个新的研究领域。碳纳米管在医药领域深入广泛应用的前提是其良好的生物相容性和无毒副作用等。碳纳米管可经血液循环在肝、脾、肺、肾和脑中积累,并产生不同程度的损伤,但是碳纳米管是否能转移至雌性生殖器官并造成脏器功能障碍进而损伤生殖力的研究目前尚无报道。
由于受到工业污染等方面的影响,人类女性生殖健康状况呈不断下降趋势。了解纳米材料对雌性生殖健康的影响,作为纳米材料安全性评价的重要部分势在必行。已有报道指出金纳米和磷酸钙纳米颗粒可进入卵巢颗粒细胞,诱发细胞凋亡,抑制雌激素的分泌。孕期暴露单壁碳纳米管可造成胎儿畸形等形态学上的损伤。然而,还未有报道对碳纳米管的非孕期雌性生殖系统的体内毒性进行全面的评价。
碳纳米管作为一种工业及医药应用前景非常广阔的纳米材料,且在实际生产、生活中主动或者被动进入人体的几率极高,研究其对雌性生殖健康的影响具有现实意义。本研究采用水溶性较好的羧基化多壁碳纳米管为研究对象,以雌性ICR小鼠为模型,首次评价了多壁碳纳米管对非孕期雌性生殖健康的影响。依据雌性生殖系统的内分泌调控轴(下丘脑-垂体-卵巢轴),系统研究了羧基化多壁碳纳米管在雌性生殖系统的分布和毒性,并初步进行了机制研究。实验结果表明,尾静脉单针注射64Cu标记的羧基化碳纳米管可在卵巢、子宫和脑中分布,并在24h内呈积累下降趋势。碳纳米管的暴露造成了小鼠动情周期的在给药期间的延长和血清性激素水平紊乱,说明在受试条件下,雌鼠的生殖内分泌功能受到了碳纳米管的干扰。然而,对第13天和第60天卵巢和子宫组织进行光镜观察发现,多次暴露碳纳米管并未造成明显的病理学改变,各级卵泡和黄体数目、子宫内膜和肌层厚度均无显著性变化。对雌性生殖功能进行的评价结果显示,羧基化多壁碳纳米管对怀孕期母鼠和子代发育中的各指标(交配率、怀孕率、生殖率、孕鼠体重和行为；仔鼠出生数目和性别比、第1天和第10天生存率、体重变化等)均未产生负面影响。毒性机制研究表明,实验组小鼠子宫和卵巢在第13天表现有免疫因子TNFα水平的明显升高,氧化应激指标MDA和GSH与对照组相比有显著改变。卵巢切除实验证实,多壁碳纳米管不能维持小鼠正常的动情周期和子宫变化,因此不具备类雌激素效应。
综上所述,多壁碳纳米管可进入雌性生殖系统并影响生殖相关激素的分泌,但组织结构和生殖力均未受到影响。多壁碳纳米管在体内并不具备类雌激素效应,因此对内分泌的影响与碳管与雌激素的拮抗作用无关,而可能是多壁碳纳米管在卵巢内产生过量的氧化应激的结果。碳纳米管可进入小鼠脑部,但是碳纳米管是否会对与生殖内分泌相关的下丘脑和垂体造成影响尚不明确。因此,我们推测过量的活性氧影响了激素产生相关酶的活性或者碳纳米管对生殖内分泌相关的其他靶器官的影响干扰了激素的产生和分泌。本研究拓宽了纳米毒理学的广度,为认识纳米材料的生殖安全提供评价,并对碳纳米管的广泛生物医学应用提供了重要的实验参考。
The rapid development of chemistry and materials science produced a large number of new materials, in which nanomaterials represent the most striking example have entered into many aspects of people's life. Nowadays, more and more people begin to concern the effects of nanomaterials on human health and ecological environment after intentional or unintentional exposure of nanoparticles. In2003, Science and Nature published articles one after another to explore the biological effects, environmental and healthy impacts cause by nanomaterials.
Carbon nanotubes (CNTs) are collections of induvidual or several concentric graphite cylinders, and have attracted the attention of many scientists worldwide. CNTs represent the ideal, perfect and ordered carbon fiber. The size, structure, and topology make them possess unique electrical, magnetic, thermal and mechanical properties, and fascinating in plastics and composite materials, electronics, energy. The exploration in biomedicine is also rapidly developed into a new research field. However, the promise of the wide use of CNTs in biomedicine is their good compatibility and no toxic or side effects. The research in biological toxicity have found that CNTs can translocate in liver, spleen, kidney, and brain through blood circulation, and produce different degrees of damage. However, the study on female reproductive toxicity caused by CNTs is rare and need further study.
The health of female reproduction shows a declining trend, due to various effects like industrial pollution. As an important part in safety evaluation of nanomaterials, it is imperative to understand the impact of nanomaterials on female reproductive system. Studies have been reported that gold nanopaticles and calcium phosphate nanoparticles can translocated into ovarian granulosa cell, and induced cell apoptosis and inhibited the secretion of estradiol. Prenatal exposure of single-walled carbon nanotubes caused fetal abnormalities such as morphology damage. Nevertheless, the effects of CNTs on female reproductiv system in non-pregnant period have not been investigated systematacially.
CNTs have extensive prospect in manufacture and medicine, and have high risk of entering the human body actively or passively. Study the effects of CNTs on female reproductive health has a realistic significance. In view of the above considerations, we use ICR mouse as the mammalian model to investigate the effects of carboxylic multi-walled carbon nanotubes (MWCNT-COOH) on female reproductive system. According to the regulatory mechanism of the female reproductive system (hypothalamus-pituitary-ovarian axis), we investigated the distribution and effects of MWCNT-COOH on female reproductive organs, and further discussed the toxic mechanisms. The results showed that64Cu-labelled MWCNT-COOH can translocate in ovary, uterus and brain through tail vein injection and the accumulation showed a decreased trend within24h. Repeated administration of MWCNT-COOH prolonged the estrous cycle during the exposure time and inhibited the secretion of hormones (FSH, LH, estradiol, progesterone), which indicated that MWCNT-COOH disturbed the endocrine system of female mice. However, histologic studies of ovary and uterus showed little alteration after exposure. The number of corpus luteum and each stage follicles, thickness of the endometrium and myometrium from treated mice were characterized no difference compared with control mice. Fertility studies at day13and day60showed that MWCNT-COOH do not have detrimental effect on successful conception and healthy growth of offspring (litter size, survival rate, gain of body weight). To explore the mechanism of toxicity, we found that MWCNT-COOH increased the level of TNFa and changed the level of MDA and GSH in ovary and uterus. Further more, MWCNT-COOH do not possess estrogen-like activity because they are unable to maintain normal estrous cycle and cyclical change of uterus in ovariectomized mice.
In conclusion, CNTs can translocate into the female reproductive organs and inhibite hormonal secretion, but leave the structure of organs and fertility not affected. CNTs do not possess estrogen-like effect in vivo, so their influence on endocrine system was not the antagonism effect with estrogen but may be the results of excessive reactive oxygen species caused on steroidogenic enzymes. Due to the complexity and importance of the female reproductive system, understanding of the impact of nanomaterials on reproductive health has a realistic significance. Our study has broadened the knowledge of nanotoxicology on female reproducive system and provided important experimental reference on safe application of carbon nanotubes in biological medicine.
引文
1. Fischer, H. C.; Chan, W. C., Nanotoxicity:the growing need for in vivo study. Current opinion in biotechnology 2007,18,565.
2. Reilly, R. M., Carbon nanotubes:potential benefits and risks of nanotechnology in nuclear medicine. Journal of Nuclear Medicine 2007,48, 1039-1042.
3. Endo, M.; Strano, M.; Ajayan, P., Potential applications of carbon nanotubes. Carbon Nanotubes 2008,13-61.
4. Cuenca, A. G.; Jiang, H.; Hochwald, S. N.; Delano, M.; Cance, W. G.; Grobmyer, S. R., Emerging implications of nanotechnology on cancer diagnostics and therapeutics. Cancer 2006,107,459-466.
5. Ferrari, M., Cancer nanotechnology:opportunities and challenges. Nature Reviews Cancer 2005,5,161-171.
6. Kam, N. W. S.; Dai, H., Carbon nanotubes as intracellular protein transporters: generality and biological functionality. Journal of the American Chemical Society 2005,127,6021-6026.
7. Kam, N. W. S.; Jessop, T. C.; Wender, P. A.; Dai, H., Nanotube molecular transporters:internalization of carbon nanotube-protein conjugates into mammalian cells. Journal of the American Chemical Society 2004,126, 6850-6851.
8. Pastorin, G.; Wu, W.; Wieckowski, S.; Briand, J.-P.; Kostarelos, K.; Prato, M.; Bianco, A., Double functionalisation of carbon nanotubes for multimodal drug delivery. Chemical Communications 2006,1182-1184.
9. Yinghuai, Z.; Peng, A. T.; Carpenter, K.; Maguire, J. A.; Hosmane, N. S.; Takagaki, M., Substituted carborane-appended water-soluble single-wall carbon nanotubes:new approach to boron neutron capture therapy drug delivery. Journal of the American Chemical Society 2005,127,9875-9880.
10. Pantarotto, D.; Singh, R.; McCarthy, D.; Erhardt, M.; Briand, J. P.; Prato, M.; Kostarelos, K.; Bianco, A., Functionalized carbon nanotubes for plasmid DNA gene delivery. Angewandte Chemie International Edition 2004,43, 5242-5246.
11. Pantarotto, D.; Partidos, C. D.; Hoebeke, J.; Brown, F.; Kramer, E.; Briand, J.-P.; Muller, S.; Prato, M.; Bianco, A., Immunization with peptide-functionalized carbon nanotubes enhances virus-specific neutralizing antibody responses. Chemistry & biology 2003,10,961-966.
12. Kam, N. W. S.; Liu, Z.; Dai, H., Carbon nanotubes as intracellular transporters for proteins and dna:an investigation of the uptake mechanism and pathway. Angewandte Chemie 2006,118,591-595.
13. Pantarotto, D.; Briand, J.-P.; Prato, M.; Bianco, A., Translocation of bioactive peptides across cell membranes by carbon nanotubes. Chemical Communications 2004,16-17.
14. McDevitt, M. R.; Chattopadhyay, D.; Kappel, B. J.; Jaggi, J. S.; Schiffman, S. R.; Antczak, C.; Njardarson, J. T.; Brentjens, R.; Scheinberg, D. A., Tumor targeting with antibody-functionalized, radiolabeled carbon nanotubes. Journal of Nuclear Medicine 2007,48,1180-1189.
15. Singh, R.; Pantarotto, D.; Lacerda, L.; Pastorin, G.; Klumpp, C.; Prato, M.; Bianco, A.; Kostarelos, K., Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proceedings of the National Academy of Sciences of the United States of America 2006,103, 3357-3362.
16. Bulte, J. W.; Douglas, T.; Witwer, B.; Zhang, S.-C.; Strable, E.; Lewis, B. K.; Zywicke, H.; Miller, B.; van Gelderen, P.; Moskowitz, B. M., Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nature biotechnology 2001,19,1141-1147.
17. Bulte, J.; Zhang, S.-C;. Van Gelderen, P.; Herynek, V.; Jordan, E.; Duncan, I.; Frank, J., Neurotransplantation of magnetically labeled oligodendrocyte progenitors:magnetic resonance tracking of cell migration and myelination. Proceedings of the National Academy of Sciences 1999,96,15256-15261.
18. Shi, D.; Lian, J.; Wang, W.; Liu, G.; He, P.; Dong, Z.; Wang, L. M.; Ewing, R. C., Luminescent carbon nanotubes by surface functionalization. Advanced Materials 2005,18,189-193.
19. Rochette, J.-F.; Sacher, E.; Meunier, M.; Luong, J., A mediatorless biosensor for putrescine using multiwalled carbon nanotubes. Analytical biochemistry 2005,336,305-311.
20. Kam, N. W. S.; O'Connell, M.; Wisdom, J. A.; Dai, H., Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proceedings of the National Academy of Sciences of the United States of America 2005,102,11600-11605.
21. Shi, X.; Sitharaman, B.; Pham, Q. P.; Liang, F.; Wu, K.; Edward Billups, W.; Wilson, L. J.; Mikos, A. G, Fabrication of porous ultra-short single-walled carbon nanotube nanocomposite scaffolds for bone tissue engineering. Biomaterials 2007,28,4078-4090.
22. Zanello, L. P.; Zhao, B.; Hu, H.; Haddon, R. C., Bone cell proliferation on carbon nanotubes. Nano letters 2006,6,562-567.
23. Cheng, Q.; Rutledge, K.; Jabbarzadeh, E., Carbon Nanotube-Poly (lactide-co-glycolide) Composite Scaffolds for Bone Tissue Engineering Applications. Annals of biomedical engineering 2013,1-13.
24. Ma, P.-C.; Siddiqui, N. A.; Marom, G.; Kim, J.-K., Dispersion and functionalization of carbon nanotubes for polymer-based nanocomposites:A review. Composites Part A:Applied Science and Manufacturing 2010,41, 1345-1367.
25. Zhao, Y.-L.; Stoddart, J. F., Noncovalent functionalization of single-walled carbon nanotubes. Accounts of chemical research 2009,42,1161-1171.
26. Wang, S.-F.; Shen, L.; Wei-De Zhang, and; Tong, Y.-J., Preparation and mechanical properties of chitosan/carbon nanotubes composites. Biomacromolecules 2005,6,3067-3072.
27. Zang, R.; Yang, S.-T., Multiwalled carbon nanotube-coated polyethylene terephthalate fibrous matrices for enhanced neuronal differentiation of mouse embryonic stem cells. Journal of Materials Chemistry B 2013,1,646-653.
28. MacDonald, R. A.; Laurenzi, B. F.; Viswanathan, G.; Ajayan, P. M.; Stegemann, J. P., Collagen-carbon nanotube composite materials as scaffolds in tissue engineering. Journal of Biomedical Materials Research Part A 2005, 74,489-496.
29. Hu, H.; Ni, Y.; Montana, V.; Haddon, R. C.; Parpura, V., Chemically functionalized carbon nanotubes as substrates for neuronal growth. Nano letters 2004,4,507-511.
30. Gabay, T.; Jakobs, E.; Ben-Jacob, E.; Hanein, Y., Engineered self-organization of neural networks using carbon nanotube clusters. Physica A:Statistical Mechanics and its Applications 2005,350,611-621.
31. Supronowicz, P.; Ajayan, P.; Ullmann, K.; Arulanandam, B.; Metzger, D.; Bizios, R., Novel current-conducting composite substrates for exposing osteoblasts to alternating current stimulation. Journal of biomedical materials research 2001,59,499-506.
32. Dvir, T.; Timko, B. P.; Kohane, D. S.; Langer, R., Nanotechnological strategies for engineering complex tissues. Nature nano technology 2010,6,13-22.
33. Gui, X.; Cao, A.; Wei, J.; Li, H.; Jia, Y.; Li, Z.; Fan, L.; Wang, K.; Zhu, H.; Wu, D., Soft, highly conductive nanotube sponges and composites with controlled compressibility. ACS nano 2010,4,2320-2326.
34. Besteman, K.; Lee, J.-O.; Wiertz, F. G.; Heering, H. A.; Dekker, C., Enzyme-coated carbon nanotubes as single-molecule biosensors. Nano letters 2003,3,727-730.
35. Cai, H.; Cao, X.; Jiang, Y.; He, P.; Fang, Y, Carbon nanotube-enhanced electrochemical DNA biosensor for DNA hybridization detection. Analytical and bioanalytical chemistry 2003,375,287-293.
36. Zhang, Y.; Guo, G.; Zhao, F.; Mo, Z.; Xiao, F.; Zeng, B., A novel glucose biosensor based on glucose oxidase immobilized on aupt nanoparticle-carbon nanotube-ionic liquid hybrid coated electrode. Electroanalysis 2010,22, 223-228.
37. Li, F.; Wang, Z.; Shan, C.; Song, J.; Han, D.; Niu, L., Preparation of gold nanoparticles/functionalized multiwalled carbon nanotube nanocomposites and its glucose biosensing application. Biosensors and Bioelectronics 2009,24, 1765-1770.
38. Leeuw, T. K.; Reith, R. M.; Simonette, R. A.; Harden, M. E.; Cherukuri, P.; Tsyboulski, D. A.; Beckingham, K. M.; Weisman, R. B., Single-walled carbon nanotubes in the intact organism:Near-IR imaging and biocompatibility studies in Drosophila. Nano letters 2007,7,2650-2654.
39. Welsher, K.; Liu, Z.; Daranciang, D.; Dai, H., Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. Nano letters 2008,8,586-590.
40. Wang, J.; Deng, X.; Yang, S.; Wang, H.; Zhao, Y; Liu, Y, Rapid translocation and pharmacokinetics of hydroxylated single-walled carbon nanotubes in mice. Nanotoxicology 2008,2,28-32.
41. Klumpp, C.; Kostarelos, K.; Prato, M.; Bianco, A., Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics. Biochimica et Biophysica Acta (BBA)-Biomembranes 2006,1758,404-412.
42. Shvedova, A. A.; Pietroiusti, A.; Fadeel, B.; Kagan, V. E., Mechanisms of carbon nanotube-induced toxicity:Focus on oxidative stress. Toxicology and applied pharmacology 2012.
43. Patel, H.; Kwon, S., Multi-walled carbon nanotube-induced inflammatory response and oxidative stress in a dynamic cell growth environment. Journal of biological engineering 2012,6,1-9.
44. Beamer, C. A.; Girtsman, T. A.; Seaver, B. P.; Finsaas, K. J.; Migliaccio, C. T.; Perry, V. K.; Rottman, J. B.; Smith, D. E.; Holian, A., IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology 2012, 1-12.
45. Liu, Y.; Zhao, Y.; Sun, B.; Chen, C., Understanding the Toxicity of Carbon Nanotubes. Accounts of chemical research 2012.
46. Oberdorster, G.; Maynard, A.; Donaldson, K.; Castranova, V.; Fitzpatrick, J.; Ausman, K.; Carter, J.; Karn, B.; Kreyling, W.; Lai, D., Principles for characterizing the potential human health effects from exposure to nanomaterials:elements of a screening strategy. Particle and Fibre Toxicology 2005,2,8.
47. Donaldson, K.; Stone, V.; Tran, C.; Kreyling, W.; Borm, P., Nanotoxicology. Occupational and Environmental Medicine 2004,61,727-728.
48. Oberdorster, G; Oberdorster, E.; Oberdorster, J., Nanotoxicology:an emerging discipline evolving from studies of ultrafine particles. Environmental health perspectives 2005,113,823.
49. Huczko, A.; Lange, H.; Calko, E.; Grubek-Jaworska, H.; Droszcz, P., Physiological testing of carbon nanotubes:are they asbestos-like? Fullerene science and technology 2001,9,251-254.
50. Lam, C.-W.; James, J. T.; McCluskey, R.; Hunter, R. L., Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicological Sciences 2004,77,126-134.
51. Warheit, D. B.; Laurence, B.; Reed, K. L.; Roach, D.; Reynolds, G.; Webb, T., Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicological Sciences 2004,77,117-125.
52. Huczko, A.; Lange, H.; Bystrzejewski, M.; Baranowski, P.; Grubek-Jaworska, H.; Nejman, P.; Przybylowski, T.; Czuminska, K.; Glapinski, J.; Walton, D., Pulmonary Toxicity of 1-D Nanocarbon Materials. Fullerenes, nanotubes, and carbon nanostructures 2005, 13,141-145.
53. Muller, J.; Huaux, F.; Moreau, N.; Misson, P.; Heilier, J.-F.; Delos, M.; Arras, M.; Fonseca, A.; Nagy, J. B.; Lison, D., Respiratory toxicity of multi-wall carbon nanotubes. Toxicology and applied pharmacology 2005,207,221-231.
54. Simeonova, P. P.; Erdely, A., Engineered nanoparticle respiratory exposure and potential risks for cardiovascular toxicity:predictive tests and biomarkers. Inhalation toxicology 2009,21,68-73.
55. Patlolla, A. K.; Berry, A.; Tchounwou, P. B., Study of hepatotoxicity and oxidative stress in male Swiss-Webster mice exposed to functionalized multi-walled carbon nanotubes. Molecular and cellular biochemistry 2011, 358,189-199.
56. Smith, C. J.; Shaw, B. J.; Handy, R. D., Toxicity of single walled carbon nanotubes to rainbow trout,(Oncorhynchus mykiss):Respiratory toxicity, organ pathologies, and other physiological effects. Aquatic toxicology 2007, 52,94-109.
57. Huczko, A.; Lange, H., Carbon nanotubes:experimental evidence for a null risk of skin irritation and allergy. Fullerene science and technology 2001,9, 247-250.
58. Monteiro-Riviere, N. A.; Nemanich, R. J.; Inman, A. O.; Wang, Y. Y.; Riviere, J. E., Multi-walled carbon nanotube interactions with human epidermal keratinocytes. Toxicology letters 2005,155,377-384.
59. Ding, L.; Stilwell, J.; Zhang, T.; Elboudwarej, O.; Jiang, H.; Selegue, J. P.; Cooke, P. A.; Gray, J. W; Chen, F. F., Molecular characterization of the cytotoxic mechanism of multiwall carbon nanotubes and nano-onions on human skin fibroblast. Nano letters 2005,5,2448-2464.
60. Maynard, A. D.; Baron, P. A.; Foley, M.; Shvedova, A. A.; Kisin, E. R.; Castranova, V., Exposure to carbon nanotube material:aerosol release during the handling of unrefined single-walled carbon nanotube material. Journal of Toxicology and Environmental Health, Part A 2004,67,87-107.
61. Blum, J. L.; Xiong, J. Q.; Hoffman, C.; Zelikoff, J. T., Cadmium Associated With Inhaled Cadmium Oxide Nanoparticles Impacts Fetal and Neonatal Development and Growth. Toxicological Sciences 2012,126,478-486.
62. Yamashita, K.; Yoshioka, Y.; Higashisaka, K.; Mimura, K.; Morishita, Y.; Nozaki, M.; Yoshida, T.; Ogura, T.; Nabeshi, H.; Nagano, K., Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nature nanotechnology 2011,6,321-328.
63. Semmler-Behnke, M.; Fertsch, S.; Schmid, G.; Wenk, A.; Kreyling, W. G, Uptake of 1.4 nm versus 18 nm gold nanoparticles in secondary target organs is size dependent in control and pregnant rats after intratracheal or intravenous application. EuroNanoForum 2007 2007,102.
64. Takeda, K.; Suzuki, K.-i.; Ishihara, A.; Kubo-Irie, M; Fujimoto, R.; Tabata, M.; Oshio, S.; Nihei, Y.; Ihara, T.; Sugamata, M., Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. Journal of Health Science 2009,55,95-102.
65. Refuerzo, J. S.; Godin, B.; Bishop, K.; Srinivasan, S.; Shah, S. K.; Amra, S.; Ramin, S. M.; Ferrari, M, Size of the nanovectors determines the transplacental passage in pregnancy:study in rats. American journal of obstetrics andgynecology 2011,204,546. e545-546. e549.
66. Tian, F.; Razansky, D.; Estrada, G. G.; Semmler-Behnke, M.; Beyerle, A.; Kreyling, W.; Ntziachristos, V.; Stoeger, T., Surface modification and size dependence in particle translocation during early embryonic development. Inhalation toxicology 2009,21,92-96.
67. Chu, M.; Wu, Q.; Yang, H.; Yuan, R.; Hou, S.; Yang, Y; Zou, Y; Xu, S.; Xu, K.; Ji, A.; Sheng, L., Transfer of Quantum Dots from Pregnant Mice to Pups Across the Placental Barrier. Small 2010,6,670-678.
68. Sumner, S. C.; Fennell, T. R.; Snyder, R. W.; Taylor, G. F.; Lewin, A. H., Distribution of carbon-14 labeled C60 ([14C] C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine. Journal of Applied Toxicology 2010,30,354-360.
69. Morgan, K., Development of a preliminary framework for informing the risk analysis and risk management of nanoparticles. Risk Analysis 2005,25, 1621-1635.
70. Wick, P.; Malek, A.; Manser, P.; Meili, D.; Maeder-Althaus, X.; Diener, L Diener, P.-A.; Zisch, A.; Krug, H. F.; Von Mandach, U., Barrier capacity of human placenta for nanosized materials. Environmental health perspectives 2010,118,432.
71. Pietroiusti, A.; Massimiani, M.; Fenoglio, I.; Colonna, M.; Valentini, F.; Palleschi, G.; Camaioni, A.; Magrini, A.; Siracusa, G.; Bergamaschi, A., Low doses of pristine and oxidized single-wall carbon nanotubes affect mammalian embryonic development. ACS nano 2011,5,4624-4633.
72. Philbrook, N. A.; Walker, V. K.; Afrooz, A.; Saleh, N. B.; Winn, L. M, Investigating the effects of functionalized carbon nanotubes on reproduction and development in Drosophila melanogaster and CD-I mice. Reproductive Toxicology 2011.
73. Lim, J. H.; Kim, S. H.; Shin, I. S.; Park, N. H.; Moon, C.; Kang,.S. S.; Kim, S. H.; Park, S. C.; Kim, J. C., Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats. Birth Defects Research Part B:Developmental and Reproductive Toxicology 2011, 92,69-76.
74. Ono, N.; Oshio, S.; Niwata, Y.; Yoshida, S.; Tsukue, N.; Sugawara, I.; Takano, H.; Takeda, K., Prenatal exposure to diesel exhaust impairs mouse spermatogenesis. Inhalation toxicology 2007,19,275-281.
75. Kubo-Irie, M.; Oshio, S.; Niwata, Y.; Ishihara, A.; Sugawara, I.; Takeda, K., Pre-and postnatal exposure to low-dose diesel exhaust impairs murine spermatogenesis. Inhalation toxicology 2011,23,805-813.
76. Hemmingsen, J. G.; Hougaard, K. S.; Talsness, C.; Wellejus, A.; Loft, S.; Wallin, H.; M(?)ller, P., Prenatal exposure to diesel exhaust particles and effect on the male reproductive system in mice. Toxicology 2009,264,61-68.
77. Li, C.; Taneda, S.; Taya, K.; Watanabe, G.; Li, X.; Fujitani, Y.; Nakajima, T.; Suzuki, A. K., Effects of in utero exposure to nanoparticle-rich diesel exhaust on testicular function in immature male rats. Toxicology letters 2009,185,1-8.
78. Watanabe, N., Decreased number of sperms and Sertoli cells in mature rats exposed to diesel exhaust as fetuses. Toxicology letters 2005,155,51-58.
79. Sugamata, M.; Ihara, T.; Takano, H.; Oshio, S.; Takeda, K., Maternal diesel exhaust exposure damages newborn murine brains. Journal of Health Science 2006,52,82-84.
80. Sugamata, M.; Ihara, T.; Umezawa, M.; Takeda, K., P-999-Maternal exposure to nanoparticles enhances the risk of mental neurological disorders in offspring. European Psychiatry 2012,27,1.
81. Yokota, S.; Mizuo, K.; Moriya, N.; Oshio, S.; Sugawara, I.; Takeda, K., Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Nenrosci. Lett.2009,449,38-41.
82. Hougaard, K. S.; Jensen, K. A.; Nordly, P.; Taxvig, C; Vogel, U.; Saber, A. T. Wallin, H., Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice. Part Fibre Toxicol 2008,5,3.
83. Li, P.-W.; Kuo, T.-H.; Chang, J.-H.; Yen, J.-M.; Chan, W.-H., Induction of cytotoxicity and apoptosis in mouse blastocysts by silver nanoparticles. Toxicology letters 2010,197,82-87.
84. CHAN, W. h.; SHIAO, N. h., Cytotoxic effect of CdSe quantum dots on mouse embryonic development. Acta Pharmacologica Sinica 2008,29, 259-266.
85. STELZER, R.; HUTZ, R. J., Gold nanoparticles enter rat ovarian granulosa cells and subcellular organelles, and alter in-vitro estrogen accumulation. Journal of Reproduction and Development 2009,55,685-690.
86. Liu, X.; Qin, D.; Cui, Y.; Chen, L.; Li, H.; Chen, Z.; Gao, L.; Li, Y.; Liu, J., Research The effect of calcium phosphate nanoparticles on hormone production and apoptosis in human granulosa cells.2010.
87. Lovekamp-Swan, T.; Davis, B. J., Mechanisms of phthalate ester toxicity in the female reproductive system. Environmental health perspectives 2003,111, 139.
88. Gloire, G; Legrand-Poels, S.; Piette, J., NF-κB activation by reactive oxygen species:fifteen years later. Biochemical pharmacology2006,72,1493-1505.
89. Jomova, K.; Jenisova, Z.; Feszterova, M.; Baros, S.; Liska, J.; Hudecova, D.; Rhodes, C; Valko, M., Arsenic:toxicity, oxidative stress and human disease. Journal of Applied Toxicology 2011,31,95-107.
90. Halliwell, B.; Gutteridge, J. M., Free radicals in biology and medicine. Oxford university press Oxford:1999; Vol.3.
91. Schoonbroodt, S.; Piette, J., Oxidative stress interference with the nuclear factor-kappa B activation pathways. Biochemical pharmacology 2000,60, 1075.
92. Wang, X.; Martindale, J. L.; Liu, Y.; Holbrook, N. J., The cellular response to oxidative stress:influences of mitogen-activated protein kinase signalling pathways on cell survival. BiochemicalJournal 1998,333,291.
93. Nel, A.; Xia, T.; Madler, L.; Li, N., Toxic potential of materials at the nanolevel. Science 2006,311,622-627.
94. Wells, P. G.; Bhuller, Y.; Chen, C. S.; Jeng, W.; Kasapinovic, S.; Kennedy, J. C; Kim, P. M.; Laposa, R. R.; McCallum, G. P.; Nicol, C. J., Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicology and applied pharmacology 2005,207,354-366.
95. Park, E.-J.; Kim, H.; Kim, Y; Park, K., Effects of platinum nanoparticles on the postnatal development of mouse pups by maternal exposure. Environmental Health and Toxicology 2010,25,279-286.
96. Meyer, U.; Feldon, J.; Fatemi, S. H., In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neuroscience& Biobehavioral Reviews 2009,55,1061-1079.
97. Zhu, L.; Chang, D. W.; Dai, L.; Hong, Y, DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano letters 2007,7,3592-3597.
98. Crain, D. A.; Janssen, S. J.; Edwards, T. M.; Heindel, J.; Ho, S.-m.; Hunt, P.; Iguchi, T.; Juul, A.; McLachlan, J. A.; Schwartz, J., Female reproductive disorders:the roles of endocrine-disrupting compounds and developmental timing. Fertility and sterility 2008,90,911-940.
99. Bai, Y.; Zhang, Y.; Zhang, J.; Mu, Q.; Zhang, W.; Butch, E. R.; Snyder, S. E.; Yan, B., Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nature nanotechnology 2010,5,683-689.
100. Marcondes, F.; Bianchi, F.; Tanno, A., Determination of the estrous cycle phases of rats:some helpful considerations. Brazilian Journal of Biology 2002, 62,609-614.
101. Rubin, B. S.; Murray, M. K.; Damassa, D. A.; King, J. C.; Soto, A. M., Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environmental health perspectives 2001,109,675.
102. Li, X.; Johnson, D. C.; Rozman, K. K., Reproductive effects of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in female rats:ovulation, hormonal regulation, and possible mechanism (s). Toxicology and applied pharmacology 1995,755,321-327.
103. Baligar, P. N.; Kaliwal, B. B., Reproductive toxicity of carbofuran to the female mice:effects on estrous cycle and follicles. Industrial health 2002,40, 345-352.
104. Spona, J.; Feichtinger, W.; Kindermann, C.; Moore, C.; Mellinger, U.; Walter, F.; Graser, T., Modulation of ovarian function by an oral contraceptive containing 30 μg ethinyl estradiol in combination with 2.00 mg dienogest. Contraception 1997,56,185-191.
105. Sullivan, H.; Furniss, H.; Spona, J.; Elstein, M., Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity. Fertility and sterility 1999,72,115.
106. Bolon, B.; Bucci, T. J.; Warbritton, A. R.; Chen, J. J.; Mattison, D. R.; Heindel, J. J., Differential follicle counts as a screen for chemically induced ovarian toxicity in mice:results from continuous breeding bioassays. Toxicological Sciences 1997,39,1-10.
107. Wong, J. S.; Gill, S. S., Gene expression changes induced in mouse liver by di (2-ethylhexyl) phthalate. Toxicology and applied pharmacology 2002,755, 180-196.
108. Park, E.-J.; Cho, W.-S.; Jeong, J.; Yi, J.; Choi, K.; Park, K., Pro-inflammatory and potential allergic responses resulting from B cell activation in mice treated with multi-walled carbon nanotubes by intratracheal instillation. Toxicology 2009,259,113-121.
109. Gao, N.; Zhang, Q.; Mu, Q.; Bai, Y.; Li, L.; Zhou, H.; Butch, E. R.; Powell, T. B.; Snyder, S. E.; Jiang, G, Steering carbon nanotubes to scavenger receptor recognition by nanotube surface chemistry modification partially alleviates NFκB activation and reduces its immunotoxicity. ACS nano 2011,5, 4581-4591.
110. Ryan, B. C; Hotchkiss, A. K.; Crofton, K. M.; Gray, L. E., In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats. Toxicol. Sci.2010,114,133-148.
2. Reilly, R. M., Carbon nanotubes:potential benefits and risks of nanotechnology in nuclear medicine. Journal of Nuclear Medicine 2007,48, 1039-1042.
3. Endo, M.; Strano, M.; Ajayan, P., Potential applications of carbon nanotubes. Carbon Nanotubes 2008,13-61.
4. Cuenca, A. G.; Jiang, H.; Hochwald, S. N.; Delano, M.; Cance, W. G.; Grobmyer, S. R., Emerging implications of nanotechnology on cancer diagnostics and therapeutics. Cancer 2006,107,459-466.
5. Ferrari, M., Cancer nanotechnology:opportunities and challenges. Nature Reviews Cancer 2005,5,161-171.
6. Kam, N. W. S.; Dai, H., Carbon nanotubes as intracellular protein transporters: generality and biological functionality. Journal of the American Chemical Society 2005,127,6021-6026.
7. Kam, N. W. S.; Jessop, T. C.; Wender, P. A.; Dai, H., Nanotube molecular transporters:internalization of carbon nanotube-protein conjugates into mammalian cells. Journal of the American Chemical Society 2004,126, 6850-6851.
8. Pastorin, G.; Wu, W.; Wieckowski, S.; Briand, J.-P.; Kostarelos, K.; Prato, M.; Bianco, A., Double functionalisation of carbon nanotubes for multimodal drug delivery. Chemical Communications 2006,1182-1184.
9. Yinghuai, Z.; Peng, A. T.; Carpenter, K.; Maguire, J. A.; Hosmane, N. S.; Takagaki, M., Substituted carborane-appended water-soluble single-wall carbon nanotubes:new approach to boron neutron capture therapy drug delivery. Journal of the American Chemical Society 2005,127,9875-9880.
10. Pantarotto, D.; Singh, R.; McCarthy, D.; Erhardt, M.; Briand, J. P.; Prato, M.; Kostarelos, K.; Bianco, A., Functionalized carbon nanotubes for plasmid DNA gene delivery. Angewandte Chemie International Edition 2004,43, 5242-5246.
11. Pantarotto, D.; Partidos, C. D.; Hoebeke, J.; Brown, F.; Kramer, E.; Briand, J.-P.; Muller, S.; Prato, M.; Bianco, A., Immunization with peptide-functionalized carbon nanotubes enhances virus-specific neutralizing antibody responses. Chemistry & biology 2003,10,961-966.
12. Kam, N. W. S.; Liu, Z.; Dai, H., Carbon nanotubes as intracellular transporters for proteins and dna:an investigation of the uptake mechanism and pathway. Angewandte Chemie 2006,118,591-595.
13. Pantarotto, D.; Briand, J.-P.; Prato, M.; Bianco, A., Translocation of bioactive peptides across cell membranes by carbon nanotubes. Chemical Communications 2004,16-17.
14. McDevitt, M. R.; Chattopadhyay, D.; Kappel, B. J.; Jaggi, J. S.; Schiffman, S. R.; Antczak, C.; Njardarson, J. T.; Brentjens, R.; Scheinberg, D. A., Tumor targeting with antibody-functionalized, radiolabeled carbon nanotubes. Journal of Nuclear Medicine 2007,48,1180-1189.
15. Singh, R.; Pantarotto, D.; Lacerda, L.; Pastorin, G.; Klumpp, C.; Prato, M.; Bianco, A.; Kostarelos, K., Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers. Proceedings of the National Academy of Sciences of the United States of America 2006,103, 3357-3362.
16. Bulte, J. W.; Douglas, T.; Witwer, B.; Zhang, S.-C.; Strable, E.; Lewis, B. K.; Zywicke, H.; Miller, B.; van Gelderen, P.; Moskowitz, B. M., Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nature biotechnology 2001,19,1141-1147.
17. Bulte, J.; Zhang, S.-C;. Van Gelderen, P.; Herynek, V.; Jordan, E.; Duncan, I.; Frank, J., Neurotransplantation of magnetically labeled oligodendrocyte progenitors:magnetic resonance tracking of cell migration and myelination. Proceedings of the National Academy of Sciences 1999,96,15256-15261.
18. Shi, D.; Lian, J.; Wang, W.; Liu, G.; He, P.; Dong, Z.; Wang, L. M.; Ewing, R. C., Luminescent carbon nanotubes by surface functionalization. Advanced Materials 2005,18,189-193.
19. Rochette, J.-F.; Sacher, E.; Meunier, M.; Luong, J., A mediatorless biosensor for putrescine using multiwalled carbon nanotubes. Analytical biochemistry 2005,336,305-311.
20. Kam, N. W. S.; O'Connell, M.; Wisdom, J. A.; Dai, H., Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proceedings of the National Academy of Sciences of the United States of America 2005,102,11600-11605.
21. Shi, X.; Sitharaman, B.; Pham, Q. P.; Liang, F.; Wu, K.; Edward Billups, W.; Wilson, L. J.; Mikos, A. G, Fabrication of porous ultra-short single-walled carbon nanotube nanocomposite scaffolds for bone tissue engineering. Biomaterials 2007,28,4078-4090.
22. Zanello, L. P.; Zhao, B.; Hu, H.; Haddon, R. C., Bone cell proliferation on carbon nanotubes. Nano letters 2006,6,562-567.
23. Cheng, Q.; Rutledge, K.; Jabbarzadeh, E., Carbon Nanotube-Poly (lactide-co-glycolide) Composite Scaffolds for Bone Tissue Engineering Applications. Annals of biomedical engineering 2013,1-13.
24. Ma, P.-C.; Siddiqui, N. A.; Marom, G.; Kim, J.-K., Dispersion and functionalization of carbon nanotubes for polymer-based nanocomposites:A review. Composites Part A:Applied Science and Manufacturing 2010,41, 1345-1367.
25. Zhao, Y.-L.; Stoddart, J. F., Noncovalent functionalization of single-walled carbon nanotubes. Accounts of chemical research 2009,42,1161-1171.
26. Wang, S.-F.; Shen, L.; Wei-De Zhang, and; Tong, Y.-J., Preparation and mechanical properties of chitosan/carbon nanotubes composites. Biomacromolecules 2005,6,3067-3072.
27. Zang, R.; Yang, S.-T., Multiwalled carbon nanotube-coated polyethylene terephthalate fibrous matrices for enhanced neuronal differentiation of mouse embryonic stem cells. Journal of Materials Chemistry B 2013,1,646-653.
28. MacDonald, R. A.; Laurenzi, B. F.; Viswanathan, G.; Ajayan, P. M.; Stegemann, J. P., Collagen-carbon nanotube composite materials as scaffolds in tissue engineering. Journal of Biomedical Materials Research Part A 2005, 74,489-496.
29. Hu, H.; Ni, Y.; Montana, V.; Haddon, R. C.; Parpura, V., Chemically functionalized carbon nanotubes as substrates for neuronal growth. Nano letters 2004,4,507-511.
30. Gabay, T.; Jakobs, E.; Ben-Jacob, E.; Hanein, Y., Engineered self-organization of neural networks using carbon nanotube clusters. Physica A:Statistical Mechanics and its Applications 2005,350,611-621.
31. Supronowicz, P.; Ajayan, P.; Ullmann, K.; Arulanandam, B.; Metzger, D.; Bizios, R., Novel current-conducting composite substrates for exposing osteoblasts to alternating current stimulation. Journal of biomedical materials research 2001,59,499-506.
32. Dvir, T.; Timko, B. P.; Kohane, D. S.; Langer, R., Nanotechnological strategies for engineering complex tissues. Nature nano technology 2010,6,13-22.
33. Gui, X.; Cao, A.; Wei, J.; Li, H.; Jia, Y.; Li, Z.; Fan, L.; Wang, K.; Zhu, H.; Wu, D., Soft, highly conductive nanotube sponges and composites with controlled compressibility. ACS nano 2010,4,2320-2326.
34. Besteman, K.; Lee, J.-O.; Wiertz, F. G.; Heering, H. A.; Dekker, C., Enzyme-coated carbon nanotubes as single-molecule biosensors. Nano letters 2003,3,727-730.
35. Cai, H.; Cao, X.; Jiang, Y.; He, P.; Fang, Y, Carbon nanotube-enhanced electrochemical DNA biosensor for DNA hybridization detection. Analytical and bioanalytical chemistry 2003,375,287-293.
36. Zhang, Y.; Guo, G.; Zhao, F.; Mo, Z.; Xiao, F.; Zeng, B., A novel glucose biosensor based on glucose oxidase immobilized on aupt nanoparticle-carbon nanotube-ionic liquid hybrid coated electrode. Electroanalysis 2010,22, 223-228.
37. Li, F.; Wang, Z.; Shan, C.; Song, J.; Han, D.; Niu, L., Preparation of gold nanoparticles/functionalized multiwalled carbon nanotube nanocomposites and its glucose biosensing application. Biosensors and Bioelectronics 2009,24, 1765-1770.
38. Leeuw, T. K.; Reith, R. M.; Simonette, R. A.; Harden, M. E.; Cherukuri, P.; Tsyboulski, D. A.; Beckingham, K. M.; Weisman, R. B., Single-walled carbon nanotubes in the intact organism:Near-IR imaging and biocompatibility studies in Drosophila. Nano letters 2007,7,2650-2654.
39. Welsher, K.; Liu, Z.; Daranciang, D.; Dai, H., Selective probing and imaging of cells with single walled carbon nanotubes as near-infrared fluorescent molecules. Nano letters 2008,8,586-590.
40. Wang, J.; Deng, X.; Yang, S.; Wang, H.; Zhao, Y; Liu, Y, Rapid translocation and pharmacokinetics of hydroxylated single-walled carbon nanotubes in mice. Nanotoxicology 2008,2,28-32.
41. Klumpp, C.; Kostarelos, K.; Prato, M.; Bianco, A., Functionalized carbon nanotubes as emerging nanovectors for the delivery of therapeutics. Biochimica et Biophysica Acta (BBA)-Biomembranes 2006,1758,404-412.
42. Shvedova, A. A.; Pietroiusti, A.; Fadeel, B.; Kagan, V. E., Mechanisms of carbon nanotube-induced toxicity:Focus on oxidative stress. Toxicology and applied pharmacology 2012.
43. Patel, H.; Kwon, S., Multi-walled carbon nanotube-induced inflammatory response and oxidative stress in a dynamic cell growth environment. Journal of biological engineering 2012,6,1-9.
44. Beamer, C. A.; Girtsman, T. A.; Seaver, B. P.; Finsaas, K. J.; Migliaccio, C. T.; Perry, V. K.; Rottman, J. B.; Smith, D. E.; Holian, A., IL-33 mediates multi-walled carbon nanotube (MWCNT)-induced airway hyper-reactivity via the mobilization of innate helper cells in the lung. Nanotoxicology 2012, 1-12.
45. Liu, Y.; Zhao, Y.; Sun, B.; Chen, C., Understanding the Toxicity of Carbon Nanotubes. Accounts of chemical research 2012.
46. Oberdorster, G.; Maynard, A.; Donaldson, K.; Castranova, V.; Fitzpatrick, J.; Ausman, K.; Carter, J.; Karn, B.; Kreyling, W.; Lai, D., Principles for characterizing the potential human health effects from exposure to nanomaterials:elements of a screening strategy. Particle and Fibre Toxicology 2005,2,8.
47. Donaldson, K.; Stone, V.; Tran, C.; Kreyling, W.; Borm, P., Nanotoxicology. Occupational and Environmental Medicine 2004,61,727-728.
48. Oberdorster, G; Oberdorster, E.; Oberdorster, J., Nanotoxicology:an emerging discipline evolving from studies of ultrafine particles. Environmental health perspectives 2005,113,823.
49. Huczko, A.; Lange, H.; Calko, E.; Grubek-Jaworska, H.; Droszcz, P., Physiological testing of carbon nanotubes:are they asbestos-like? Fullerene science and technology 2001,9,251-254.
50. Lam, C.-W.; James, J. T.; McCluskey, R.; Hunter, R. L., Pulmonary toxicity of single-wall carbon nanotubes in mice 7 and 90 days after intratracheal instillation. Toxicological Sciences 2004,77,126-134.
51. Warheit, D. B.; Laurence, B.; Reed, K. L.; Roach, D.; Reynolds, G.; Webb, T., Comparative pulmonary toxicity assessment of single-wall carbon nanotubes in rats. Toxicological Sciences 2004,77,117-125.
52. Huczko, A.; Lange, H.; Bystrzejewski, M.; Baranowski, P.; Grubek-Jaworska, H.; Nejman, P.; Przybylowski, T.; Czuminska, K.; Glapinski, J.; Walton, D., Pulmonary Toxicity of 1-D Nanocarbon Materials. Fullerenes, nanotubes, and carbon nanostructures 2005, 13,141-145.
53. Muller, J.; Huaux, F.; Moreau, N.; Misson, P.; Heilier, J.-F.; Delos, M.; Arras, M.; Fonseca, A.; Nagy, J. B.; Lison, D., Respiratory toxicity of multi-wall carbon nanotubes. Toxicology and applied pharmacology 2005,207,221-231.
54. Simeonova, P. P.; Erdely, A., Engineered nanoparticle respiratory exposure and potential risks for cardiovascular toxicity:predictive tests and biomarkers. Inhalation toxicology 2009,21,68-73.
55. Patlolla, A. K.; Berry, A.; Tchounwou, P. B., Study of hepatotoxicity and oxidative stress in male Swiss-Webster mice exposed to functionalized multi-walled carbon nanotubes. Molecular and cellular biochemistry 2011, 358,189-199.
56. Smith, C. J.; Shaw, B. J.; Handy, R. D., Toxicity of single walled carbon nanotubes to rainbow trout,(Oncorhynchus mykiss):Respiratory toxicity, organ pathologies, and other physiological effects. Aquatic toxicology 2007, 52,94-109.
57. Huczko, A.; Lange, H., Carbon nanotubes:experimental evidence for a null risk of skin irritation and allergy. Fullerene science and technology 2001,9, 247-250.
58. Monteiro-Riviere, N. A.; Nemanich, R. J.; Inman, A. O.; Wang, Y. Y.; Riviere, J. E., Multi-walled carbon nanotube interactions with human epidermal keratinocytes. Toxicology letters 2005,155,377-384.
59. Ding, L.; Stilwell, J.; Zhang, T.; Elboudwarej, O.; Jiang, H.; Selegue, J. P.; Cooke, P. A.; Gray, J. W; Chen, F. F., Molecular characterization of the cytotoxic mechanism of multiwall carbon nanotubes and nano-onions on human skin fibroblast. Nano letters 2005,5,2448-2464.
60. Maynard, A. D.; Baron, P. A.; Foley, M.; Shvedova, A. A.; Kisin, E. R.; Castranova, V., Exposure to carbon nanotube material:aerosol release during the handling of unrefined single-walled carbon nanotube material. Journal of Toxicology and Environmental Health, Part A 2004,67,87-107.
61. Blum, J. L.; Xiong, J. Q.; Hoffman, C.; Zelikoff, J. T., Cadmium Associated With Inhaled Cadmium Oxide Nanoparticles Impacts Fetal and Neonatal Development and Growth. Toxicological Sciences 2012,126,478-486.
62. Yamashita, K.; Yoshioka, Y.; Higashisaka, K.; Mimura, K.; Morishita, Y.; Nozaki, M.; Yoshida, T.; Ogura, T.; Nabeshi, H.; Nagano, K., Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nature nanotechnology 2011,6,321-328.
63. Semmler-Behnke, M.; Fertsch, S.; Schmid, G.; Wenk, A.; Kreyling, W. G, Uptake of 1.4 nm versus 18 nm gold nanoparticles in secondary target organs is size dependent in control and pregnant rats after intratracheal or intravenous application. EuroNanoForum 2007 2007,102.
64. Takeda, K.; Suzuki, K.-i.; Ishihara, A.; Kubo-Irie, M; Fujimoto, R.; Tabata, M.; Oshio, S.; Nihei, Y.; Ihara, T.; Sugamata, M., Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. Journal of Health Science 2009,55,95-102.
65. Refuerzo, J. S.; Godin, B.; Bishop, K.; Srinivasan, S.; Shah, S. K.; Amra, S.; Ramin, S. M.; Ferrari, M, Size of the nanovectors determines the transplacental passage in pregnancy:study in rats. American journal of obstetrics andgynecology 2011,204,546. e545-546. e549.
66. Tian, F.; Razansky, D.; Estrada, G. G.; Semmler-Behnke, M.; Beyerle, A.; Kreyling, W.; Ntziachristos, V.; Stoeger, T., Surface modification and size dependence in particle translocation during early embryonic development. Inhalation toxicology 2009,21,92-96.
67. Chu, M.; Wu, Q.; Yang, H.; Yuan, R.; Hou, S.; Yang, Y; Zou, Y; Xu, S.; Xu, K.; Ji, A.; Sheng, L., Transfer of Quantum Dots from Pregnant Mice to Pups Across the Placental Barrier. Small 2010,6,670-678.
68. Sumner, S. C.; Fennell, T. R.; Snyder, R. W.; Taylor, G. F.; Lewin, A. H., Distribution of carbon-14 labeled C60 ([14C] C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine. Journal of Applied Toxicology 2010,30,354-360.
69. Morgan, K., Development of a preliminary framework for informing the risk analysis and risk management of nanoparticles. Risk Analysis 2005,25, 1621-1635.
70. Wick, P.; Malek, A.; Manser, P.; Meili, D.; Maeder-Althaus, X.; Diener, L Diener, P.-A.; Zisch, A.; Krug, H. F.; Von Mandach, U., Barrier capacity of human placenta for nanosized materials. Environmental health perspectives 2010,118,432.
71. Pietroiusti, A.; Massimiani, M.; Fenoglio, I.; Colonna, M.; Valentini, F.; Palleschi, G.; Camaioni, A.; Magrini, A.; Siracusa, G.; Bergamaschi, A., Low doses of pristine and oxidized single-wall carbon nanotubes affect mammalian embryonic development. ACS nano 2011,5,4624-4633.
72. Philbrook, N. A.; Walker, V. K.; Afrooz, A.; Saleh, N. B.; Winn, L. M, Investigating the effects of functionalized carbon nanotubes on reproduction and development in Drosophila melanogaster and CD-I mice. Reproductive Toxicology 2011.
73. Lim, J. H.; Kim, S. H.; Shin, I. S.; Park, N. H.; Moon, C.; Kang,.S. S.; Kim, S. H.; Park, S. C.; Kim, J. C., Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats. Birth Defects Research Part B:Developmental and Reproductive Toxicology 2011, 92,69-76.
74. Ono, N.; Oshio, S.; Niwata, Y.; Yoshida, S.; Tsukue, N.; Sugawara, I.; Takano, H.; Takeda, K., Prenatal exposure to diesel exhaust impairs mouse spermatogenesis. Inhalation toxicology 2007,19,275-281.
75. Kubo-Irie, M.; Oshio, S.; Niwata, Y.; Ishihara, A.; Sugawara, I.; Takeda, K., Pre-and postnatal exposure to low-dose diesel exhaust impairs murine spermatogenesis. Inhalation toxicology 2011,23,805-813.
76. Hemmingsen, J. G.; Hougaard, K. S.; Talsness, C.; Wellejus, A.; Loft, S.; Wallin, H.; M(?)ller, P., Prenatal exposure to diesel exhaust particles and effect on the male reproductive system in mice. Toxicology 2009,264,61-68.
77. Li, C.; Taneda, S.; Taya, K.; Watanabe, G.; Li, X.; Fujitani, Y.; Nakajima, T.; Suzuki, A. K., Effects of in utero exposure to nanoparticle-rich diesel exhaust on testicular function in immature male rats. Toxicology letters 2009,185,1-8.
78. Watanabe, N., Decreased number of sperms and Sertoli cells in mature rats exposed to diesel exhaust as fetuses. Toxicology letters 2005,155,51-58.
79. Sugamata, M.; Ihara, T.; Takano, H.; Oshio, S.; Takeda, K., Maternal diesel exhaust exposure damages newborn murine brains. Journal of Health Science 2006,52,82-84.
80. Sugamata, M.; Ihara, T.; Umezawa, M.; Takeda, K., P-999-Maternal exposure to nanoparticles enhances the risk of mental neurological disorders in offspring. European Psychiatry 2012,27,1.
81. Yokota, S.; Mizuo, K.; Moriya, N.; Oshio, S.; Sugawara, I.; Takeda, K., Effect of prenatal exposure to diesel exhaust on dopaminergic system in mice. Nenrosci. Lett.2009,449,38-41.
82. Hougaard, K. S.; Jensen, K. A.; Nordly, P.; Taxvig, C; Vogel, U.; Saber, A. T. Wallin, H., Effects of prenatal exposure to diesel exhaust particles on postnatal development, behavior, genotoxicity and inflammation in mice. Part Fibre Toxicol 2008,5,3.
83. Li, P.-W.; Kuo, T.-H.; Chang, J.-H.; Yen, J.-M.; Chan, W.-H., Induction of cytotoxicity and apoptosis in mouse blastocysts by silver nanoparticles. Toxicology letters 2010,197,82-87.
84. CHAN, W. h.; SHIAO, N. h., Cytotoxic effect of CdSe quantum dots on mouse embryonic development. Acta Pharmacologica Sinica 2008,29, 259-266.
85. STELZER, R.; HUTZ, R. J., Gold nanoparticles enter rat ovarian granulosa cells and subcellular organelles, and alter in-vitro estrogen accumulation. Journal of Reproduction and Development 2009,55,685-690.
86. Liu, X.; Qin, D.; Cui, Y.; Chen, L.; Li, H.; Chen, Z.; Gao, L.; Li, Y.; Liu, J., Research The effect of calcium phosphate nanoparticles on hormone production and apoptosis in human granulosa cells.2010.
87. Lovekamp-Swan, T.; Davis, B. J., Mechanisms of phthalate ester toxicity in the female reproductive system. Environmental health perspectives 2003,111, 139.
88. Gloire, G; Legrand-Poels, S.; Piette, J., NF-κB activation by reactive oxygen species:fifteen years later. Biochemical pharmacology2006,72,1493-1505.
89. Jomova, K.; Jenisova, Z.; Feszterova, M.; Baros, S.; Liska, J.; Hudecova, D.; Rhodes, C; Valko, M., Arsenic:toxicity, oxidative stress and human disease. Journal of Applied Toxicology 2011,31,95-107.
90. Halliwell, B.; Gutteridge, J. M., Free radicals in biology and medicine. Oxford university press Oxford:1999; Vol.3.
91. Schoonbroodt, S.; Piette, J., Oxidative stress interference with the nuclear factor-kappa B activation pathways. Biochemical pharmacology 2000,60, 1075.
92. Wang, X.; Martindale, J. L.; Liu, Y.; Holbrook, N. J., The cellular response to oxidative stress:influences of mitogen-activated protein kinase signalling pathways on cell survival. BiochemicalJournal 1998,333,291.
93. Nel, A.; Xia, T.; Madler, L.; Li, N., Toxic potential of materials at the nanolevel. Science 2006,311,622-627.
94. Wells, P. G.; Bhuller, Y.; Chen, C. S.; Jeng, W.; Kasapinovic, S.; Kennedy, J. C; Kim, P. M.; Laposa, R. R.; McCallum, G. P.; Nicol, C. J., Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species. Toxicology and applied pharmacology 2005,207,354-366.
95. Park, E.-J.; Kim, H.; Kim, Y; Park, K., Effects of platinum nanoparticles on the postnatal development of mouse pups by maternal exposure. Environmental Health and Toxicology 2010,25,279-286.
96. Meyer, U.; Feldon, J.; Fatemi, S. H., In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neuroscience& Biobehavioral Reviews 2009,55,1061-1079.
97. Zhu, L.; Chang, D. W.; Dai, L.; Hong, Y, DNA damage induced by multiwalled carbon nanotubes in mouse embryonic stem cells. Nano letters 2007,7,3592-3597.
98. Crain, D. A.; Janssen, S. J.; Edwards, T. M.; Heindel, J.; Ho, S.-m.; Hunt, P.; Iguchi, T.; Juul, A.; McLachlan, J. A.; Schwartz, J., Female reproductive disorders:the roles of endocrine-disrupting compounds and developmental timing. Fertility and sterility 2008,90,911-940.
99. Bai, Y.; Zhang, Y.; Zhang, J.; Mu, Q.; Zhang, W.; Butch, E. R.; Snyder, S. E.; Yan, B., Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nature nanotechnology 2010,5,683-689.
100. Marcondes, F.; Bianchi, F.; Tanno, A., Determination of the estrous cycle phases of rats:some helpful considerations. Brazilian Journal of Biology 2002, 62,609-614.
101. Rubin, B. S.; Murray, M. K.; Damassa, D. A.; King, J. C.; Soto, A. M., Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environmental health perspectives 2001,109,675.
102. Li, X.; Johnson, D. C.; Rozman, K. K., Reproductive effects of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in female rats:ovulation, hormonal regulation, and possible mechanism (s). Toxicology and applied pharmacology 1995,755,321-327.
103. Baligar, P. N.; Kaliwal, B. B., Reproductive toxicity of carbofuran to the female mice:effects on estrous cycle and follicles. Industrial health 2002,40, 345-352.
104. Spona, J.; Feichtinger, W.; Kindermann, C.; Moore, C.; Mellinger, U.; Walter, F.; Graser, T., Modulation of ovarian function by an oral contraceptive containing 30 μg ethinyl estradiol in combination with 2.00 mg dienogest. Contraception 1997,56,185-191.
105. Sullivan, H.; Furniss, H.; Spona, J.; Elstein, M., Effect of 21-day and 24-day oral contraceptive regimens containing gestodene (60 microg) and ethinyl estradiol (15 microg) on ovarian activity. Fertility and sterility 1999,72,115.
106. Bolon, B.; Bucci, T. J.; Warbritton, A. R.; Chen, J. J.; Mattison, D. R.; Heindel, J. J., Differential follicle counts as a screen for chemically induced ovarian toxicity in mice:results from continuous breeding bioassays. Toxicological Sciences 1997,39,1-10.
107. Wong, J. S.; Gill, S. S., Gene expression changes induced in mouse liver by di (2-ethylhexyl) phthalate. Toxicology and applied pharmacology 2002,755, 180-196.
108. Park, E.-J.; Cho, W.-S.; Jeong, J.; Yi, J.; Choi, K.; Park, K., Pro-inflammatory and potential allergic responses resulting from B cell activation in mice treated with multi-walled carbon nanotubes by intratracheal instillation. Toxicology 2009,259,113-121.
109. Gao, N.; Zhang, Q.; Mu, Q.; Bai, Y.; Li, L.; Zhou, H.; Butch, E. R.; Powell, T. B.; Snyder, S. E.; Jiang, G, Steering carbon nanotubes to scavenger receptor recognition by nanotube surface chemistry modification partially alleviates NFκB activation and reduces its immunotoxicity. ACS nano 2011,5, 4581-4591.
110. Ryan, B. C; Hotchkiss, A. K.; Crofton, K. M.; Gray, L. E., In utero and lactational exposure to bisphenol A, in contrast to ethinyl estradiol, does not alter sexually dimorphic behavior, puberty, fertility, and anatomy of female LE rats. Toxicol. Sci.2010,114,133-148.