流行病學研究顯示空氣中懸浮微粒的增加及所含之化學成分與心血管疾病之發病率和致死率有關，無論是短期或長期暴露於細懸浮微粒下，細懸浮微粒容易累積於體內並造成健康危害。而隨著奈米材料廣泛的應用在許多產品上，大量生產奈米微粒產品的過程中提高了暴露的機會。環境中的奈米微粒可經由吸入或攝入進入人體，進而分布並累積至各個器官。其中內分泌系統主要產生以及分泌荷爾蒙，用以調控身體各種生理功能的運作。因此除了關注奈米微粒對健康的效應外，探討奈米微粒可能的敏感性器官及相關毒理研究也具其重要性。
本研究欲探討短期暴露奈米微粒是否會影響肝臟、腎臟、甲狀腺及腎上腺功能以期望能發掘可作為奈米微粒暴露後之敏感性器官。使用Sprague-Dawley大鼠以口服暴露方式重複暴露奈米碳黑微粒、奈米銀、奈米二氧化鈦及奈米氧化鉻。每天暴露一次，每週五天，分別重複暴露一週及三週，於最後一次暴露後24小時內犧牲，採集血清利用自動生化分析儀分別量測血清中甲狀腺、腎臟及肝臟等功能指標進行評估，並以蘇木素-伊紅染色法進一步觀察功能異常之組織變化。
結果顯示大鼠口服一週8及64 mg/kg的四種奈米微粒後，其血清中三碘甲狀腺素與控制組相比皆有顯著上升的情形；而血清中四碘甲狀腺素於暴露64 mg/kg之奈米微粒亦有顯著上升。然而，在口服暴露奈米微粒三週後，甲狀腺激素及腎功能指標並未有顯著改變。組織切片染色，觀察到大鼠暴露奈米微粒一週後，皆會造成甲狀腺濾泡細胞肥大並隨著劑量的增加而呈現正相關，在暴露三週後甲狀濾泡上皮細胞增生、濾泡細胞脫落至濾泡內腔等情形嚴重，推斷因甲狀腺結構的破壞進而影響甲狀腺素之分泌。肝功能指標量測顯示大鼠暴露四種奈米微粒一週後造成血清中麩丙酮酸轉胺酶較控制組有顯著上升，而在暴露三週奈米二氧化鈦後發現天門冬胺酸轉胺酶顯著上升。體外培養大鼠腎上腺初代細胞後以促腎上腺皮質刺激素刺激，在高劑量64 mg/kg奈米銀及奈米鉻組別其皮質醇分泌減少，而8 mg/kg組別皮質醇分泌增加。然而組織切片的結果並未觀察到腎上腺、肝臟及腎臟有明顯的病理變化。綜合上述結果，甲狀腺可能是奈米微粒短期暴露較具感受性的器官。

The purpose of this study is to investigate whether short-term expose of nanoparticles would have impact on thyroid and adrenal cortical function. Sprague-Dawley rats were treated with the ultrafine carbon black (ufCB), titanium dioxide nanoparticles (nano-TiO2), nano silver (nano-Ag), or nano chromium (nano-CrO) by oral administration. After 24 hours of the last exposure, animals were sacrificed, and tissue and blood samples were collected. Serum biochemical parameters were measured using a biochemical blood analyzer. The results indicate that exposure to ufCB, nano-Ag, nano-TiO2 and nano-CrO caused significant increased of serum T3 levels in 2, 8 and 64 mg/kg exposed rats, compared with the control groups. T4 levels were significantly increased in 64 mg/kg exposed rats. However, T3, T4 and kidney function were not significantly altered following 3 weeks of exposure. Rats with increased T3 levels showed anomalous follicular epithelium cell hyperplasia, focal hypertrophy, exfoliated folicular epithelial cells and dramatic increasing in amount of follicles with irregular shape in thyroid gland. In addition, adrenocorticotropic hormone (ACTH) challenge caused aberrant productions of cortisol in freshly cultured primary adrenal gland cells from rats. Thus, our results demonstrate that exposure to ufCB, nano TiO2, nano-silver, nano Chromium by oral administration may affect the production of thyroid hormone. Thus, thyroid glands may be the most susceptible organ upon short-term exposure to nanoparticles.

Agency for Toxic Substances and Disease Registry（ATSDR. Toxicological profile for Chromium. Atlanta: U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry; 2000.

Bateson T F, Schwartz J. Selection bias and confounding in case-crossover analyses of environmental time-series data. Epidemiology. 2001;12(6):654-61.

Brunekreef B, Holgate ST: Air pollution and health. Lancet. 2002,360:1233-1242.

Bermudez E, Mangum JB, Wong BA, Asgharian B, Hext PM, Warheit DB, Everitt JI. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol. Sci. 2004; 77 (2):347-357.

Berbel P, Mestre JL, Santamaria A, Palazon I, Franco A, Graells M, Gonzalez-Torga A, de Escobar GM. Delayed neurobehavioral development in children born to pregnant women with mild hypothyroxinemia during the first month of gestation: The importance of early iodine supplementation. Thyroid. 2009; 19:511-519.

Bergin Ingrid L, Witzmann Frank A. Nanoparticle toxicity by the gastrointestinal route:
evidence and knowledge gaps. Int. J. Biomedical Nanoscience and Nanotechnology. 2013; 3:163-210.

Chen H, Goldberg MS, Villeneuve PJ. A systematic review of the relation between long-term exposure to ambient air pollution and chronic diseases. Rev Environ Health. 2008; 23(4):243-297.

Choi HS, Ashitate Y, Lee JH, Kim SH, Matsui A, Insin N, et al. Rapid translocation of nanoparticles from the lung airspaces to the body. Nature biotechnology. 2010; 28: 1300-1304.

Cui Y, Liu H, Zhou M, Duan Y, Li N, Gong X, et al. Signaling pathway of inflammatory responses in the mouse liver caused by TiO2 nanoparticles. J Biomed Mater Res A. 2011; 96A:221-229.

Dockery DW, Pope CA 3rd, Xu X, Spengler JD, Ware JH, Fay ME, Ferris BG, Speizer FE.
An association between air pollution and mortality in six U.S. cities. New England Journal of Medicine. 1993; 329:1753-1759.

Dockery DW, Pope CA III, Xu X, Spengler JD, Ware JH, Fay ME, et al. An association between air pollution and mortality in six U.S. cities. N Engl J Med. 1993; 329:1753-1759

Donaldson K, Li XY, MacNee W. Ultrafine (nanometer) particle mediated lung injury. J Aerosol Sci. 1998; 29:553-560.

Duan Y, Liu J, Ma L, Na L, Liu H, Wang J, et al. Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials. 2010; 31:894-899.

Elder A, Gelein R, Silva V, Feikert T, Opanashuk L, Carter J, et al. Translocation of inhaled ultrafine manganese oxide particles to the central nervous system. Environ Health Perspect. 2006; 114:1172-1178.

Eyles JE, Bramwell VW, Williamson ED, Alpar HO. Microsphere translocation and immunopotentiation in systemic tissues following intranasal administration, Vaccine. 2001; 19, 32:4732-4742.

Ebabe ER, Gaillet S, Vide J, Romain C, Lauret C, Rugani N, et al. Dietary exposure to silver nanoparticles in Sprague–Dawley rats: Effects on oxidative stress and inflammation. Food Chem Toxicol. 2013; 60:297–301.

Ferin J, Oberdorster G, Penny D. Pulmonary retention of ultra-fine and fine particles in rats. Am J Respir Cell Mol Biol. 1992; 6:535-542.

Guyton AC, Hall JE. Human physiology and mechanisns of disease, 6th ed. Saunders, Philadelphua. 1997

Gaiser BK, Fernandes TF, Jepson M, Lead JR, Tyler CR, Stone V. Assessing exposure, uptake and toxicity of silver and cerium dioxide nanoparticles from contaminated environments. Environmental Health. 2009; 8, S1, 52-56.

Gui S, Zhang Z, Zheng L, Cui Y, Liu X, Li N, et al. Molecular mechanism of kidney injury of mice caused by exposure to titanium dioxide nanoprticles. J Hazard Mater 2011; 195; 365– 370.

Gui S, Sang X, Zheng L, Ze Y, Zhao X, Sheng L, et al. Intragastric exposure to titanium dioxide nanoparticles induced nephrotoxicity in mice, assessed by physiological and gene expression modifications. Part Fibre Toxicol. 2013; 10: 4.

Gui S, Li B, Zhao X, Sheng L, Hong J, Yu X, et al. Renal injury and Nrf2 modulation in mouse kidney following chronic exposure to TiO2 nanoparticles. J Agr Food Chem. 2013; 61:8959-68.

Hu R, Gong X, Duan Y, Li N, Che Y, Cui Y, et al. Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials. 2010; 31:8043-8050.

Iavicoli I, Fontana L, Leso V, Bergamaschi. The Effects of Nanomaterials as Endocrine Disruptors. Int. J. Mol. Sci. 2013, 14:16732-16801.

Jeong GN, Jo UN, Ryu H Y, Kim YS, Song KS, Yu IJ. Histochemical study of intestinal mucins after administration of silver nanoparticles in Sprague–Dawley rats. Arch Toxicol. 2010; 84:63–69.

Kim YS, Kim JS, Cho HS, Rha DS, Kim JM, Park JD, et al. Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats. Inhal Toxicol. 2008; 20:575-83.

Kim WY, Kim J, Park JD, Ryu HY, Yu IJ. Histological Study of Gender Differences in Accumulation of Silver Nanoparticles in Kidneys of Fischer 344 Rats. J Toxicol Env Heal A. 2009; 72:1279-1284.

Kim YS, Song MY, Park JD, Song KS, Ryu HR, Chung YH, et al. Subchronic oral toxicity of silver nanoparticles. Part Fibre Toxicol. 2010; 7: 20.

Laden F, Schwartz J, Speizer FE, Dockery DW. Reduction in fine particulate air pollution and mortality: Extended follow-up of the Harvard Six Cities study. Am J Respir Crit Care Med. 2006; 173(6):667-672.

Liu H, Ma L, Zhao J, Liu J, Yan J, Ruan J, et al. Biochemical toxicity of nano-anatase TiO2 particles in mice. Biol Trace Elem Res. 2009; 129:170-180.

Li C, Taneda S, Taya K, Watanabe G, Li X, Fujitani Y, et al. Effects of inhaled nanoparticle-rich diesel exhaust on regulation of testicular function in adult male rats. Inhal Toxicol. 2009; 21:803-11.

Loeschne K, Hadrup N, Qvortrup K, Larsen A, Gao X, Vogel U, et al. Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate. Part Fibre Toxicol. 2011; 8: 18.

Li C, Li X, Jigami J, Hasegawa C, Suzuki AK, Zhang Y, et al. Effect of nanoparticle-rich diesel exhaust on testosterone biosynthesis in adult male mice. Inhal Toxicol. 2012; 24:599-608.

Li WQ, Wang F, Liu ZM, Wang YC, Wang J, Sun F. Gold nanoparticles elevate plasma testosterone levels in male mice without affecting fertility. Small. 2013; 2:1708-1714.

Lee JH, Kim YS, Song KS, Ryu HR, Sung JH, Park JD, et al. Biopersistence of silver nanoparticles in tissues from Sprague-Dawley rats. Part Fibre Toxicol. 2013; 10:36.

Lu X, Liu Y, Kong X, Lobie PE, Chen C, Zhu T. Nanotoxicity: A Growing Need for Study in the Endocrine System. Small. 2013; 9:1654-1671.

MacNee W and Donaldson K. Mechanism of lung injury caused by PM10 and ultrafine particles with special reference to COPD. Eur Respir J. 2003; 21:47-51.

Maraghi F, Macri C, Ricciardi C, Stazi A V, Rescia M, Mantovani A. Histological and histomorphometric alterations in thyroid and adrenals of CD rat pups exposed in utero to methyl thiophanate. Reproductive Toxicology. 2003; 17:617-623.

Morones JR, Elechiguerra JL, Yacaman MJ, Camacho A, Holt K, Kouri JB, Ramez JT. The bactericidal effect of silver nanoparticles. Nanotechnology. 2005; 16:2346-2353.

Ma L, Liu J, Li N, Wang J, Duan Y, Yan J, et al. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials. 2010; 31:99-105.

Mahmood T, Qureshi IZ, Iqbal MJ. Histopathological and biochemical changes in rat thyroid following acute exposure to hexavalent chromium. Histol Histopathol. 2010; 25:1355-1370.

Mahdy MME, Eldin TAS, Aly HS, Mohammed FF, Shaalan MI. Evaluation of hepatotoxic and genotoxic potential of silvernanoparticles in albino rats. Exp Toxicol Pathol. 2014; 67: 21-29.

Nemmar A, Vanbilloen H, Hoylaerts MF, Hoet PH, Verbruggen A, Nemery B: Passage of intratracheally instilled ultrafine particles from the lung into the systemic circulation in hamster.Am J Respir Crit Care Med. 2001, 164:1665-1668.

Nemmar A, Hoet PHM, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, et al. Passage of inhaled particles into blood circulation in humans. Circ. 2002; 105:411-414.

Nemmar A, Hoet PHM, Vanquickenborne B, Dinsdale D, Thomeer M, Hoylaerts MF, et al. Possible mechanisms of the cardiovascular effects of inhaled particles: systemic translocation and prothrombotic effects. Toxicol Letterc. 2004; 149:243-253.

Nemmar A, Holme JA, Rosas I, Schwarze PE, Alfaro-Moreno E. Recent advances in particulate matter and nanoparticle toxicology: A review of the in vivo and in vitro studies. Biomed Res Int. 2013; 279371.

Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Lunts A, et al. Extrapulmonary translocation of ultrafine carbon particles following whole-body inhalation exposure of rats. Journal of Toxicology and Environmental Health-Part A. 2002; 65:1531-1543.

Osornio-Vargas AR, Bonner JC, Alfaro-Moreno E, Martínez L, García-Cuellar C, Ponce-de-León Rosales S, et al. Proinflammatory and cytotoxic effects of Mexico City air pollution particulate matter in vitro are dependent on particle size and composition. Environ Health Perspect. 2003; 111:1289-1293.

Oberdörster G, Sharp Z, Atudorei V, Elder A, Gelein R, Kreyling W, et al. Translocation of inhaled ultrafine particles to the brain. Inhal Toxicol. 2004; 16(6–7):437-445.

Oberdörster G, Oberdo¨rster E, Oberdo¨rster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Env Health Perspect. 2005; 113:823-39.

Pope CA 3rd, Thun MJ, Namboodiri MM, Dockery DW, Evans JS, Speizer FE, Heath CW Jr. Particulate air pollution as a predictor of mortality in a prospective study of U.S.
adults. American Journal of Respiratory and Critical Care Medicine. 1995; 151:669-674.

Peters A., Dockery D.W., Muller J.E., Mittleman M.A. Increased particulate air pollution and triggering of myocardial infarction. Circulation. 2001; 103:2810-2815.

Pope CA 3rd, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, Thurston GD. Lung
cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. Journal of the American Medical Association. 2002; 287:1132-1141.

Park EJ, Bae E, Yi J, Kim Y, Choi K, Lee SH, et al. Repeated-dose toxicity and inflammatory responses in mice by oral administration of silver nanoparticles. Environ Toxicol Phar. 2010; 30:162-168.

Pope CA 3rd, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, Thurston GD. Lung cancer and cardiovascular disease mortality associated with ambient air pollution and cigarette smoke: shape of the exposure–response relationships. Env Health Perspect. 2011; 119:1616-621.

Park K, Park EJ, Chum IK, Choi K, Lee SH, Yoon J, et al. Bioavailability and Toxicokinetics of Citrate-coated Silver Nanoparticles in Rats. Arch Pharm Res. 2011; 34: 153-158.

Park K. Toxicokinetic differences and toxicities of silver nanoparticles and silver ions in rats after single oral administration. J Toxicol Env Heal A. 2013; 76:1246-1260.

Rahman Q, Lohani M, Dopp E, Pemsel H, Jonas L, Weiss DG, Schiffmann D. Evidence that ultrafine titanium dioxide induces micronuclei and apoptosis in Syrian hamster embryo fibroblasts. Environ. Health Perspect. 2002; 110 (8):797-800.

Seaton A., MacNee W., Donaldson K., Godden D. Particulate air pollution and acute health effects. Lancet. 1995; 345:176-178.

Stearns RC, Paulauskis JD, Godleski JJ. Endocytosis of ultrafine particles by A549 cells. Am J Respir Cell Mol Biol. 2001; 24:108-115.

Sharma RP, Flora SJ, Drown DB, Oberg SG. Persistence of vanadium compounds in lungs after intratracheal instillation in rats. Toxicol Ind Health. 1987; 3:321-329.

Takeda K, Suzuki KI, Ishihara A, Kubo-Irie M, Fujimoto R, Tabata M, et al. Nanoparticles transferred from pregnant mice to their offspring can damage the genital and cranial nerve systems. J Health Sci. 2009; 55:95-102.

Trouiller B, Reliene R, Westbrook A, Solaimani P, Schiestl RH. Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res. 2009; 69(22):8784-8789.

Tassinari R, Cubadda F, Moracci G, Aureli F, D'Amato M, Valeri M, et al. Oral, short-term exposure to titanium dioxide nanoparticles in Sprague-Dawley rat: focus on reproductive and endocrine systems and spleen. Nanotoxicology. 2014; 8:654-62.

Völker C, Oetken M, Oehlman J. The biological effects and possible modes of action of nanosilver. Rev Environ Contam Toxicol. 2013; 223:81-106.

Villeneuve PJ, Goldberg MS, Krewski D, Burnett RT, Chen Y. Fine particulate air pollution and all-cause mortality within the Harvard Six-Cities Study: variations in risk by period of exposure. Ann Epidemiol. 2002; 12(8):568-576.

Weir A, Westerhoff P, Fabricius L, Hristovski K, Goetz NV. Titanium dioxide nanoparticles in food and personal care products. Environ. Sci. Technol. 2012; 46(4):2242-2250.

Wise JP, Sr., Goodale BC, Wise SS, Craig GA, Pongan AF, Walter RB, Thompson WD, Ng AK, Aboueissa AM, Mitani H, Spalding MJ, Mason MD. Silver nanospheres are cytotoxic and genotoxic to fish cells. Aquat Toxicol. 2010; 97:34-41.

Wang J, Zhou G, Chen C, Yu H, Wang T, Ma Y, rt al. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett. 2007; 176-185.

Yoshida S, Hiyosgi K, Oshio S, Takano H, Takeda K, Ichinose T, et al. Effects of fetal exposure to carbon nanoparticles on reproductive function in male offspring. Fertility and Sterility. 2010; 93:1695-1699.

YousefiBabadiVahid, AmraeaiEsmaiil, SalehhHojatollah, SadeghiLeila, Najafi Leila. Evaluation of Iron Oxide nanoparticles effects on tissue and Enzymes of Thyroid in Rats International Research Journal of Biological Sciences. 2013; 2(7):67-69.

Zha L, Zeng J, Sun S, Deng H, Luo H, Li W. Chromium(III) nanoparticles affect hormone and immune responses in heat-stressed rats. Biol Trace Elem Res. 2009; 129:157-69.

Zhang R, Niu Y, Li Y, Zhao C, Song B, Li Y, et al. Acute toxicity study of the interaction between titanium dioxide nanoparticles and lead acetate in mice. Environ Toxicol Phar. 2010; 30:52-60.

Zande M, Vandebrie RJ, Groot MJ, Kramer E, Rivera ZEH, Rasmussen K, et al. Sub-chronic toxicity study in rats orally exposed to nanostructured silica. Part Fibre Toxicol. 2014; 11: 8.