메뉴 건너뛰기




Volumn 18, Issue 4, 1996, Pages 306-315

Arsenic-induced alterations in embryonic transcription factor gene expression: Implications for abnormal neural development

Author keywords

arsenic; birth defects; gene expression; murine embryos; neural tube defects; Transcription factors

Indexed keywords

ARSENIC; NERVE CELL ADHESION MOLECULE; RNA; TRANSCRIPTION FACTOR;

EID: 0029938713     PISSN: 0192253X     EISSN: None     Source Type: Journal    
DOI: 10.1002/(SICI)1520-6408(1996)18:4<306::AID-DVG4>3.0.CO;2-D     Document Type: Article
Times cited : (37)

References (70)
  • 1
    • 0024372629 scopus 로고
    • Quality of community drinking water and the occurrence of spontaneous abortion
    • Aaschengrau A, Zierler S, Cohen A (1989): Quality of community drinking water and the occurrence of spontaneous abortion. Arch Environ Health 44:283-290.
    • (1989) Arch Environ Health , vol.44 , pp. 283-290
    • Aaschengrau, A.1    Zierler, S.2    Cohen, A.3
  • 2
    • 0024592814 scopus 로고
    • Hox and HOM: Homologous gene clusters in insects and vertebrates
    • Akam M (1989): Hox and HOM: homologous gene clusters in insects and vertebrates. Cell 57:347-349.
    • (1989) Cell , vol.57 , pp. 347-349
    • Akam, M.1
  • 4
    • 0011282134 scopus 로고
    • Sur l'arret de developpement du borgeon caudal obtenu experimentalement chez l'embryon de poulet
    • Ancel P, Lallemande S (1941): Sur l'arret de developpement du borgeon caudal obtenu experimentalement chez l'embryon de poulet. Arch Physique Biol 15:27-29.
    • (1941) Arch Physique Biol , vol.15 , pp. 27-29
    • Ancel, P.1    Lallemande, S.2
  • 5
    • 0022448458 scopus 로고
    • Spatial restriction in expression of a mouse homeo box locus within the central nervous system
    • Awgulewitsch A, Utset MF, Hart CP, McGinnis W, Ruddle FH (1986): Spatial restriction in expression of a mouse homeo box locus within the central nervous system. Nature 320:328-335.
    • (1986) Nature , vol.320 , pp. 328-335
    • Awgulewitsch, A.1    Utset, M.F.2    Hart, C.P.3    McGinnis, W.4    Ruddle, F.H.5
  • 6
    • 0018051950 scopus 로고
    • The Ronnskar smelter-Occupational and environmental effects in and around a polluting industry in Northern Sweden
    • Beckman L (1978): The Ronnskar smelter-Occupational and environmental effects in and around a polluting industry in Northern Sweden. Ambio 7:226-231.
    • (1978) Ambio , vol.7 , pp. 226-231
    • Beckman, L.1
  • 7
    • 0026605567 scopus 로고
    • Multiple organ failure with adult respiratory distress syndrome in homicidal arsenic poisoning
    • Bolliger CT, Van Zigl P, Louw JA (1992): Multiple organ failure with adult respiratory distress syndrome in homicidal arsenic poisoning. Respiration 59:57-61.
    • (1992) Respiration , vol.59 , pp. 57-61
    • Bolliger, C.T.1    Van Zigl, P.2    Louw, J.A.3
  • 8
    • 0027378294 scopus 로고
    • Emx and Otx homeobox genes in the developing mouse brain
    • Boncinelli E, Gulisano M, Broccoli V (1993): Emx and Otx homeobox genes in the developing mouse brain. J Neurobiol 24:1356-1366.
    • (1993) J Neurobiol , vol.24 , pp. 1356-1366
    • Boncinelli, E.1    Gulisano, M.2    Broccoli, V.3
  • 9
    • 0026807056 scopus 로고
    • Epidemiologic studies on human subjects exposed to arsenic in drinking water in Southeast Hungary
    • Borzsonyi M, Bereczky A, Rudnai P, Csanady M, Horvath A (1992): Epidemiologic studies on human subjects exposed to arsenic in drinking water in Southeast Hungary. Arch Toxicol 66:77-78.
    • (1992) Arch Toxicol , vol.66 , pp. 77-78
    • Borzsonyi, M.1    Bereczky, A.2    Rudnai, P.3    Csanady, M.4    Horvath, A.5
  • 10
    • 0024004132 scopus 로고
    • Primary structure and developmental expression pattern of Hox 3.1, a member of the murine Hox 3 homeobox gene cluster
    • Breier G, Dressler GR, Gruss P (1988): Primary structure and developmental expression pattern of Hox 3.1, a member of the murine Hox 3 homeobox gene cluster. EMBO J 7:1329-1336.
    • (1988) EMBO J , vol.7 , pp. 1329-1336
    • Breier, G.1    Dressler, G.R.2    Gruss, P.3
  • 11
    • 0028297206 scopus 로고
    • Gallium arsenide-induced increase in serum corticosterone is not responsible for suppression of the IgM antibody response
    • Burns LA, Spriggs TL, Fuchs BA, Munson AE (1994): Gallium arsenide-induced increase in serum corticosterone is not responsible for suppression of the IgM antibody response. J Pharmacol Exper Ther 268:740-746.
    • (1994) J Pharmacol Exper Ther , vol.268 , pp. 740-746
    • Burns, L.A.1    Spriggs, T.L.2    Fuchs, B.A.3    Munson, A.E.4
  • 12
    • 0025124577 scopus 로고
    • Embryotoxic effects of sodium arsenite and sodium arsenate on mouse embryos in culture
    • Chaineau E, Binet S, Pol D, Chatellier G, Meninger V (1990): Embryotoxic effects of sodium arsenite and sodium arsenate on mouse embryos in culture. Teratology 41:105-112.
    • (1990) Teratology , vol.41 , pp. 105-112
    • Chaineau, E.1    Binet, S.2    Pol, D.3    Chatellier, G.4    Meninger, V.5
  • 14
    • 0028587375 scopus 로고
    • Pax3 contains domains for transcription activation and transcription inhibition
    • Chalepakis G, Jones FS, Edelman GM, Gruss P (1994): Pax3 contains domains for transcription activation and transcription inhibition. Proc Natl Acad Sci USA 91:12745-12749.
    • (1994) Proc Natl Acad Sci USA , vol.91 , pp. 12745-12749
    • Chalepakis, G.1    Jones, F.S.2    Edelman, G.M.3    Gruss, P.4
  • 15
    • 0018939015 scopus 로고
    • Gene-teratogen interaction in insulin-induced mouse exencephaly
    • Cole WA, Trasler DG (1980): Gene-teratogen interaction in insulin-induced mouse exencephaly. Teratology 22:125-139.
    • (1980) Teratology , vol.22 , pp. 125-139
    • Cole, W.A.1    Trasler, D.G.2
  • 16
    • 8944250305 scopus 로고    scopus 로고
    • Screening for reproductive toxicity in Fundulus heteroclitus by genetic expression profiling
    • in press
    • Craig JC, Westerman ME, Bennett GD, DiMichele L, Finnell RH (1996): Screening for reproductive toxicity in Fundulus heteroclitus by genetic expression profiling. Biomarkers (in press).
    • (1996) Biomarkers
    • Craig, J.C.1    Westerman, M.E.2    Bennett, G.D.3    DiMichele, L.4    Finnell, R.H.5
  • 18
    • 0021032905 scopus 로고
    • Early morphological abnormalities in splotch mouse embryos and predisposition to gene- And retinoic acid-induced neural tube defects
    • Dempsey EE, Trasler DG (1983): Early morphological abnormalities in splotch mouse embryos and predisposition to gene- and retinoic acid-induced neural tube defects. Teratology 28:461-472.
    • (1983) Teratology , vol.28 , pp. 461-472
    • Dempsey, E.E.1    Trasler, D.G.2
  • 21
    • 0025817934 scopus 로고
    • Cell adhesion molecules: Implications for a molecular histology
    • Edelman GM, Crossin KL (1991): Cell adhesion molecules: Implications for a molecular histology. Ann Rev Biochem 60:155-190.
    • (1991) Ann Rev Biochem , vol.60 , pp. 155-190
    • Edelman, G.M.1    Crossin, K.L.2
  • 22
    • 0029654108 scopus 로고
    • Developmental control of N-CAM expression by Hox and Pax gene products
    • Edelman GM, Jones FS (1995): Developmental control of N-CAM expression by Hox and Pax gene products. Phil Trans R Soc Land B 349:305-312.
    • (1995) Phil Trans R Soc Land B , vol.349 , pp. 305-312
    • Edelman, G.M.1    Jones, F.S.2
  • 23
    • 0022382368 scopus 로고
    • Expression of cell adhesion molecules during embryogenesis and regeneration
    • Edelman GM (1984): Expression of cell adhesion molecules during embryogenesis and regeneration. Exp Cell Res 161:1-16.
    • (1984) Exp Cell Res , vol.161 , pp. 1-16
    • Edelman, G.M.1
  • 24
    • 0022825561 scopus 로고
    • Cell adhesion molecules in the regulation of animal form and tissue pattern
    • Edelman GM (1986): Cell adhesion molecules in the regulation of animal form and tissue pattern. Ann Rev Cell Biol 2:81-116.
    • (1986) Ann Rev Cell Biol , vol.2 , pp. 81-116
    • Edelman, G.M.1
  • 25
    • 0027323660 scopus 로고
    • Interaction between splotch (Sp) and curly tail (ct) mouse mutants in the embryonic development of neural tube defects
    • Estibeiro JP, Brook FA, Copp AJ (1993): Interaction between splotch (Sp) and curly tail (ct) mouse mutants in the embryonic development of neural tube defects. Development 119:113-121.
    • (1993) Development , vol.119 , pp. 113-121
    • Estibeiro, J.P.1    Brook, F.A.2    Copp, A.J.3
  • 27
    • 0014342423 scopus 로고
    • Malformations induced by sodium arsenate
    • Ferm VH, Carpenter SJ (1968): Malformations induced by sodium arsenate. J Repro Fertil 17:199-201.
    • (1968) J Repro Fertil , vol.17 , pp. 199-201
    • Ferm, V.H.1    Carpenter, S.J.2
  • 29
    • 0023691642 scopus 로고
    • Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4-propyl-4-pentenoic acid metabolite
    • Finnell RH, Bennett GD, Karras SB, Mohl VK (1988): Common hierarchies of susceptibility to the induction of neural tube defects in mouse embryos by valproic acid and its 4-propyl-4-pentenoic acid metabolite. Teratology 38:313-320.
    • (1988) Teratology , vol.38 , pp. 313-320
    • Finnell, R.H.1    Bennett, G.D.2    Karras, S.B.3    Mohl, V.K.4
  • 30
    • 0025744986 scopus 로고
    • Genetic Differences in susceptibility to anticonvulsant drug induced developmental defects
    • Finnell RH (1991): Genetic Differences in susceptibility to anticonvulsant drug induced developmental defects. Pharmacol Toxicol 69:223-227.
    • (1991) Pharmacol Toxicol , vol.69 , pp. 223-227
    • Finnell, R.H.1
  • 32
    • 0023239424 scopus 로고
    • Homeo boxes in the study of development [review]
    • Gehring WJ (1987): Homeo boxes in the study of development [review]. Science 236:1245-1252.
    • (1987) Science , vol.236 , pp. 1245-1252
    • Gehring, W.J.1
  • 33
    • 0017762297 scopus 로고
    • Closure of the neural tube in the cephalic region of the mouse embryo
    • Geelen JG, Langman J (1977): Closure of the neural tube in the cephalic region of the mouse embryo. Anat Rec 189:625-640.
    • (1977) Anat Rec , vol.189 , pp. 625-640
    • Geelen, J.G.1    Langman, J.2
  • 34
    • 0027461863 scopus 로고
    • Intermittent pattern of neural tube closure in two strains of mice
    • Golden J, Chernoff G (1993): Intermittent pattern of neural tube closure in two strains of mice. Teratology 47:73-80.
    • (1993) Teratology , vol.47 , pp. 73-80
    • Golden, J.1    Chernoff, G.2
  • 35
    • 0025875226 scopus 로고
    • Pax-3, a novel murine DNA-binding protein expressed during early neurogenesis
    • Goulding MD, Chalepakis G, Deutsch U, Erselius JR, Gruss P (1991): Pax-3, a novel murine DNA-binding protein expressed during early neurogenesis. EMBO J 10:1135-1147.
    • (1991) EMBO J , vol.10 , pp. 1135-1147
    • Goulding, M.D.1    Chalepakis, G.2    Deutsch, U.3    Erselius, J.R.4    Gruss, P.5
  • 36
    • 0017658182 scopus 로고
    • Placental permeability of arsenate ion during early embryogenesis in the hamster
    • Hanlon DP, Ferm VH (1977): Placental permeability of arsenate ion during early embryogenesis in the hamster. Experientia 33:1221-1222.
    • (1977) Experientia , vol.33 , pp. 1221-1222
    • Hanlon, D.P.1    Ferm, V.H.2
  • 37
    • 0018826176 scopus 로고
    • Teratogenicity of disodium methanearsonate and sodium dimethylarsinate (sodium cacodylate) in mice
    • Harrison WP, Frazier JC, Mazzanti EM, Hood RD (1980): Teratogenicity of disodium methanearsonate and sodium dimethylarsinate (sodium cacodylate) in mice. Teratology 21:43A.
    • (1980) Teratology , vol.21
    • Harrison, W.P.1    Frazier, J.C.2    Mazzanti, E.M.3    Hood, R.D.4
  • 38
    • 0019426003 scopus 로고
    • Prenatal effects following exposure of hamsters to sodium arsenite by oral or intraperitoneal routes
    • Harrison WP, Hood ED (1981) Prenatal effects following exposure of hamsters to sodium arsenite by oral or intraperitoneal routes. Teratology 23:40A.
    • (1981) Teratology , vol.23
    • Harrison, W.P.1    Hood, E.D.2
  • 39
    • 0028048222 scopus 로고
    • Binding and activation of the promoter for the neural cell adhesion molecule by Pax-8
    • Holst BD, Goomer RS, Wood IC, Edelman GM, Jones FS (1994): Binding and activation of the promoter for the neural cell adhesion molecule by Pax-8. J Biol Chem 269(35):22245-22252.
    • (1994) J Biol Chem , vol.269 , Issue.35 , pp. 22245-22252
    • Holst, B.D.1    Goomer, R.S.2    Wood, I.C.3    Edelman, G.M.4    Jones, F.S.5
  • 41
    • 0019280034 scopus 로고
    • International Agency for Research on Cancer, Lyon
    • IRAC (1980): Arsenic and arsenic compounds. International Agency for Research on Cancer, Lyon 23:39-141.
    • (1980) Arsenic and Arsenic Compounds , vol.23 , pp. 39-141
  • 42
    • 0023936633 scopus 로고
    • Histological comparison of the effects of the splotch gene and retinoic acid on the closure of the mouse neural tube
    • Kapron-Bras CM, Trasler DG (1988): Histological comparison of the effects of the splotch gene and retinoic acid on the closure of the mouse neural tube. Teratology 37:389-399.
    • (1988) Teratology , vol.37 , pp. 389-399
    • Kapron-Bras, C.M.1    Trasler, D.G.2
  • 43
    • 0018581951 scopus 로고
    • Cephalic neurulation and optic vessel formation in the early mouse embryo
    • Kaufman MH (1979): Cephalic neurulation and optic vessel formation in the early mouse embryo. Am J Anat 155:425-444.
    • (1979) Am J Anat , vol.155 , pp. 425-444
    • Kaufman, M.H.1
  • 44
    • 0023101635 scopus 로고
    • Expression of Xenopus N-CAM RNA is an early response of ectoderm to induction
    • Kintner CR, Melton DM (1987): Expression of Xenopus N-CAM RNA is an early response of ectoderm to induction. Development 99:311-325.
    • (1987) Development , vol.99 , pp. 311-325
    • Kintner, C.R.1    Melton, D.M.2
  • 46
    • 0021241997 scopus 로고
    • Embryotoxicity of arsenite and arsenate: Distribution in pregnant mice and monkeys and effects on embryonic cells in vitro
    • Lindgren A, Danielsson BRG, Dencker L, Vahter M (1984): Embryotoxicity of arsenite and arsenate: Distribution in pregnant mice and monkeys and effects on embryonic cells in vitro. Acta Pharmacol Toxicol 54:311-320.
    • (1984) Acta Pharmacol Toxicol , vol.54 , pp. 311-320
    • Lindgren, A.1    Danielsson, B.R.G.2    Dencker, L.3    Vahter, M.4
  • 47
    • 0014481143 scopus 로고
    • Acute maternal arsenic intoxication with neonatal death
    • Lugo G, Cassady G, Palmisano P (1969): Acute maternal arsenic intoxication with neonatal death. Am J Dis Child 117:328-330.
    • (1969) Am J Dis Child , vol.117 , pp. 328-330
    • Lugo, G.1    Cassady, G.2    Palmisano, P.3
  • 48
    • 0024539888 scopus 로고
    • Developmental study of neural tube closure in a mouse stock with a high incidence of exencephaly
    • Macdonald KB, Juriloff DM, Harris MJ (1989): Developmental study of neural tube closure in a mouse stock with a high incidence of exencephaly. Teratology 39:195-213.
    • (1989) Teratology , vol.39 , pp. 195-213
    • Macdonald, K.B.1    Juriloff, D.M.2    Harris, M.J.3
  • 49
    • 0021255982 scopus 로고
    • A conserved DNA sequence in homeotic genes of the Drosophila Antennapedia × and bithorax complexes
    • McGinnis W, Levine MS, Hafen E, Kuroiwa A, Gehring WJ (1984): A conserved DNA sequence in homeotic genes of the Drosophila Antennapedia × and bithorax complexes. Nature 308:428-433.
    • (1984) Nature , vol.308 , pp. 428-433
    • McGinnis, W.1    Levine, M.S.2    Hafen, E.3    Kuroiwa, A.4    Gehring, W.J.5
  • 50
    • 0026668655 scopus 로고
    • A comparison of sodium arsenite- And hyperthermia-induced stress responses and abnormal development in post implantation rat embryos
    • Mirkes PE, Cornel L (1992): A comparison of sodium arsenite- and hyperthermia-induced stress responses and abnormal development in post implantation rat embryos. Teratology 46:251-259.
    • (1992) Teratology , vol.46 , pp. 251-259
    • Mirkes, P.E.1    Cornel, L.2
  • 52
    • 0026052275 scopus 로고
    • N-CAM alterations in splotch neural tube defect mouse embryos
    • Moase CE, Trasler DG (1991): N-CAM alterations in splotch neural tube defect mouse embryos. Development 113:1049-1058.
    • (1991) Development , vol.113 , pp. 1049-1058
    • Moase, C.E.1    Trasler, D.G.2
  • 53
    • 0022869260 scopus 로고
    • Toxicity of sodium arsenate in mouse embryos in-vitro and its influence on radiation risk
    • Muller WU, Streffer C, Fischer-Lahdo C (1986): Toxicity of sodium arsenate in mouse embryos in-vitro and its influence on radiation risk. Arch Toxicol 59:172-175.
    • (1986) Arch Toxicol , vol.59 , pp. 172-175
    • Muller, W.U.1    Streffer, C.2    Fischer-Lahdo, C.3
  • 54
    • 0028131139 scopus 로고
    • Early sialylation on N-CAM in Splotch neural tube defect mouse embryos
    • Neale SA, Trasler DG (1994): Early sialylation on N-CAM in Splotch neural tube defect mouse embryos. Teratology 50:118-124.
    • (1994) Teratology , vol.50 , pp. 118-124
    • Neale, S.A.1    Trasler, D.G.2
  • 55
    • 0024351657 scopus 로고
    • Localization of mRNA for neural cell adhesion molecule (N-CAM) polypeptides in neural and nonneural tissues by in situ hybridization
    • Prieto AL, Crossin KL, Cunningham BA, Edelman GM (1989): Localization of mRNA for neural cell adhesion molecule (N-CAM) polypeptides in neural and nonneural tissues by in situ hybridization. Proc Natl Acad Sci USA 86:9579-9583.
    • (1989) Proc Natl Acad Sci USA , vol.86 , pp. 9579-9583
    • Prieto, A.L.1    Crossin, K.L.2    Cunningham, B.A.3    Edelman, G.M.4
  • 57
    • 0030016415 scopus 로고    scopus 로고
    • The role of arsenic as a reproductive toxin with particular attention to neural tube defects
    • Shalat SL, Walker DB, Finnell RH (1996): The role of arsenic as a reproductive toxin with particular attention to neural tube defects. J Toxicol Environ Hlth 48:101-120.
    • (1996) J Toxicol Environ Hlth , vol.48 , pp. 101-120
    • Shalat, S.L.1    Walker, D.B.2    Finnell, R.H.3
  • 58
    • 0026759308 scopus 로고
    • Nested expression domains of four homeobox genes in developing rostral brain
    • Simeone A, Acampora D, Gulisano M, Stornaiuolo A, Boncinelli E (1992): Nested expression domains of four homeobox genes in developing rostral brain. Nature 358:687-690.
    • (1992) Nature , vol.358 , pp. 687-690
    • Simeone, A.1    Acampora, D.2    Gulisano, M.3    Stornaiuolo, A.4    Boncinelli, E.5
  • 60
    • 0001912208 scopus 로고
    • The relation of mating, ovulation and the estrus smear in the house mouse to the time of day
    • Snell GD, Fekete E, Hummel KP (1948): The relation of mating, ovulation and the estrus smear in the house mouse to the time of day. Anat Rec 76:30-54.
    • (1948) Anat Rec , vol.76 , pp. 30-54
    • Snell, G.D.1    Fekete, E.2    Hummel, K.P.3
  • 62
    • 0026497015 scopus 로고
    • Isolation of a stem cell for neurons and glia from the mammalian neural crest
    • Stemple DL, Anderson DJ (1992): Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 71:973-985.
    • (1992) Cell , vol.71 , pp. 973-985
    • Stemple, D.L.1    Anderson, D.J.2
  • 63
    • 0028929844 scopus 로고
    • Altered gene expression in murine branchial arches following in utero exposure to retinoic acid
    • Taylor LE, Bennett GD, Finnell RH (1995): Altered gene expression in murine branchial arches following in utero exposure to retinoic acid. J Cranio Genet Devel Biol 15:13-25.
    • (1995) J Cranio Genet Devel Biol , vol.15 , pp. 13-25
    • Taylor, L.E.1    Bennett, G.D.2    Finnell, R.H.3
  • 64
    • 2642613766 scopus 로고
    • Cell adhesion in morphogenesis
    • Cell to Cell Signals in Mammalian Development Berlin-Heidelberg: Springer
    • Thiery J-P (1989): Cell adhesion in morphogenesis. In: Cell to Cell Signals in Mammalian Development. NATO ASI series. Berlin-Heidelberg: Springer, pp. 109-128.
    • (1989) NATO ASI Series , pp. 109-128
    • Thiery, J.-P.1
  • 66
    • 0019468454 scopus 로고
    • Embryolethal and teratogenic effects of sodium arsenite in rats
    • Umpierre C (1981): Embryolethal and teratogenic effects of sodium arsenite in rats. Teratology 23:66A.
    • (1981) Teratology , vol.23
    • Umpierre, C.1
  • 67
    • 0021188795 scopus 로고
    • Prenatal and developmental toxicology of arsenicals
    • Willhite CC, Ferm VH (1984): Prenatal and developmental toxicology of arsenicals. Adv Exp Med Biol 177:205-228.
    • (1984) Adv Exp Med Biol , vol.177 , pp. 205-228
    • Willhite, C.C.1    Ferm, V.H.2
  • 68
    • 0002835328 scopus 로고
    • Current status of teratology-General principles and mechanisms derived from animal studies
    • Wilson JG, Fraser FC (eds): New York: Plenum Press
    • Wilson JG (1977): Current status of teratology-General principles and mechanisms derived from animal studies. In Wilson JG, Fraser FC (eds): "Handbook of Teratology," vol. 1. New York: Plenum Press, pp. 47-74.
    • (1977) Handbook of Teratology , vol.1 , pp. 47-74
    • Wilson, J.G.1
  • 70
    • 0023811439 scopus 로고
    • Chemical quality of maternal drinking water and congenital heart disease
    • Zierler S, Theodore M, Cohen A, Rothman KJ (1988): Chemical quality of maternal drinking water and congenital heart disease. Int J Epidemiol 17:589-594.
    • (1988) Int J Epidemiol , vol.17 , pp. 589-594
    • Zierler, S.1    Theodore, M.2    Cohen, A.3    Rothman, K.J.4


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.