The use of micronucleus assay in exfoliated oral cells in patients undergoing fixed orthodontic therapy: a systematic review with meta-analysis

SOUZA, Daniel Vitor de; TAKESHITA, Wilton Mitsunari; CASTRO, Glaucia Monteiro de; RENNO, Ana Claudia Muniz; SANTOS, Jean Nunes dos; RIBEIRO, Daniel Araki

doi:10.1590/1807-3107bor-2023.vol37.0116

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Systematic Review, Orthodontics • Braz. oral. res. 37 • 2023 • https://doi.org/10.1590/1807-3107bor-2023.vol37.0116 copy

The use of micronucleus assay in exfoliated oral cells in patients undergoing fixed orthodontic therapy: a systematic review with meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The aim of this systematic review was to evaluate published papers regarding the micronucleus assay in oral mucosal cells of patients undergoing orthodontic therapy (OT). A search of the scientific literature was made in the PubMed, Scopus, and Web of Science databases for all data published until November, 2021 using the combination of the following keywords: “fixed orthodontic therapy,” “genetic damage”, “DNA damage,” “genotoxicity”, “mutagenicity”, “buccal cells”, “oral mucosa cells,” and “micronucleus assay”. The systematic review was designed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Nine studies were retrieved. Some authors demonstrated that OT induces cytogenetic damage in oral mucosal cells. Out of the nine studies included, two were classified as strong, five as moderate, and two as weak, according to the quality assessment components of the Effective Public Health Practice Project (EPHPP). Meta-analysis data revealed no relationship between mutagenicity in oral cells and OT in different months of treatment. At one month, the SMD = 0.65 and p = 0.08; after three months of OT, the SMD = 1.21 and p = 0.07; and after six months of OT, the SMD = 0.56 and p = 0.11. In the analyzed months of OT, I² values were >75%, indicating high heterogeneity. In summary, this review was not able to demonstrate that OT induces genetic damage in oral cells. The study is important for the protection of patients undergoing fixed OT, given that mutagenesis participates in the multi-step process of carcinogenesis.

Mutagenesis; Micronucleus Tests; Mouth Mucosa

Authors	Country	Age of patients (years)	Sex	Treatment	Study design
Angelieri et al.¹¹11. Angelieri F, Carlin V, Martins RA, Ribeiro DA. Biomonitoring of mutagenicity and cytotoxicity in patients undergoing fixed orthodontic therapy. Am J Orthod Dentofacial Orthop. 2011 Apr;139(4 Suppl):e399-404. https://doi.org/10.1016/j.ajodo.2009.06.029 https://doi.org/10.1016/j.ajodo.2009.06....	Brazil	18.5 + 7	10 males; 13 females	Brackets were composed ofiron(71%), nickel(8%), and chromium(19%). The archwires were composed ofnickel(50.8%), titanium(49.2%) during the treatment or stainless steel nickel (8.6%), iron(72.6%), chromium(20%) at the end of orthodontic therapy.	0, 6, and 12 months
Faccioni et al.²⁰20. Faccioni P, De Santis D, Sinigaglia S, Pancera P, Faccioni F, Nocini PF. Short-term “in vivo” study on cellular DNA damage induced by acrylic Andresen activator in oral mucosa cells. Orthod Craniofac Res. 2019 Aug;22(3):208-12. https://doi.org/10.1111/ocr.12312 https://doi.org/10.1111/ocr.12312...	Italy	10.3 + 1.2	14 males; 12 females	Andresen activator (AA): acrylic resin and two Adam’s clasps and a buccalstainless steel arch	0, 7, 15, 30, 60, and 90 days
Flores-Bracho et al.¹⁷17. Flores-Bracho MG, Takahashi CS, Castillo WO, Saraiva MC, Küchler EC, Matsumoto MA, et al. Genotoxic effects in oral mucosal cells caused by the use of orthodontic fixed appliances in patients after short and long periods of treatment. Clin Oral Investig. 2019 Jul;23(7):2913-9. https://doi.org/10.1007/s00784-018-02795-8 https://doi.org/10.1007/s00784-018-02795...	Brazil	nov/35	Not informed	Brackets were bonded with composite Transbond XT and followed the Edgewise standard system: 0.022” × 0.028” slot and are composed of stainless steel (17.0 to 20.0% chromium, 8.0 to 10.5% nickel, molybdenum 0.60% max) with stainless steel wires (0.016”, 0.018”, 0.020”, or 0.019” × 0.025”).	1-12, 13-24, 25-48, and >48 months
Cunha et al.¹²12. Cunha AS, Castillo WO, Takahashi CS, Küchler EC, Segato RA, Silva LA, et al. Genotoxic and cytotoxic effects of Haas appliance in exfoliated buccal mucosa cells during orthodontic treatment. Angle Orthod. 2018 Sep;88(5):590-5. https://doi.org/10.2319/101117-687.1 https://doi.org/10.2319/101117-687.1...	Brazil	06/dez	Not informed	Haas appliances were formed with stainless steel bands. They were madeof silver welded onto 0.9-mm-diameter stainless steel wire. Wires and bands were welded with silver solder, and metallic structures were bondedwith self-curing acrylic resin	0,1, and 3 months
Gonçalves et al.¹⁸18. Gonçalves TS, Menezes LM, Trindade C, Thomas P, Fenechc M, Henriques JA. In vivo evaluation of the genotoxic effects of Hyrax auxiliary orthodontic appliances containing silver-soldered joints. Mutat Res Genet Toxicol Environ Mutagen. 2015 Sep;791:25-9. https://doi.org/10.1016/j.mrgentox.2015.07.007 https://doi.org/10.1016/j.mrgentox.2015....	Brazil	jul/14	Not informed	Metallic extensions of the Hyrax expansion screw were silver-soldered (eight silver-soldered joints in each appliance). The bands, according to the manufacturer’s information, were composed of: Cr, 17–20%; Ni, 8–10%; Mo, max. 0.60%, and Fe; the silver-soldered alloy wascomposed of Ag, 55–57%; Cu, 21–23%; Zn, 15–19%; and Sn, 4–6%	-7,0, and 28 days, 6 and 12 months
Heravi et al.²²22. Heravi F, Abbaszadegan MR, Merati M, Hasanzadeh N, Dadkhah E, Ahrari F. DNA damage in oral mucosa cells of patients with fixed orthodontic appliances. J Dent (Tehran). 2013 Nov;10(6):494-500.	Iran	dez/20	10 males; 15 females;	Brackets (standard edge-wise, 0.018-in slot). The bands and brackets were made of stainless steel.The archwires used over the course of this study included 0.014-in nickel-titanium (NiTi;), 0.016-in stainless steel and 0.016×0.022-in stainless steel	0 and 9 months
Toy et al.²¹21. Toy E, Yuksel S, Ozturk F, Karatas OH, Yalcin M. Evaluation of the genotoxicity and cytotoxicity in the buccal epithelial cells of patients undergoing orthodontic treatment with three light-cured bonding composites by using micronucleus testing. Korean J Orthod. 2014 May;44(3):128-35. https://doi.org/10.4041/kjod.2014.44.3.128 https://doi.org/10.4041/kjod.2014.44.3.1...	Turkey	14 + 1.79	12 males; 18 females	Transbond XT, Kurasper F	0, 1, 3, and 6 months
Natarajan et al.¹⁰10. Natarajan M, Padmanabhan S, Chitharanjan A, Narasimhan M. Evaluation of the genotoxic effects of fixed appliances on oral mucosal cells and the relationship to nickel and chromium concentrations: an in-vivo study. Am J Orthod Dentofacial Orthop. 2011 Sep;140(3):383-8. https://doi.org/10.1016/j.ajodo.2010.07.027 https://doi.org/10.1016/j.ajodo.2010.07....	India	14-24	Not informed	Orthodontic appliances were composed of0.07% carbon,0.70% manganese, 1% silicon, 1%-17.5% chromium,3.0%-5.0% nickel, 3.0%-5.0% copper, 0.04% phosphorus, 0.04% sulfur, and 0.15%-0.45% tantalum and niobium	0 and 18 months
Westphalen et al.¹⁹19. Westphalen GH, Menezes LM, Prá D, Garcia GG, Schmitt VM, Henriques JA, et al. In vivo determination of genotoxicity induced by metals from orthodontic appliances using micronucleus and comet assays. Genet Mol Res. 2008;7(4):1259-66. https://doi.org/10.4238/vol7-4gmr508 https://doi.org/10.4238/vol7-4gmr508...	Brazil	16 + 2.54	6 males; 14 females	Orthodontic appliances were made of stainless steel (0.07% carbon, 1.0% manganese, 1.0% silicon, 15.5-17.5% chromium, 3-5% nickel, 3-5% copper, 0.15-0.45% niobium + tantalum)	0 and 30 days

Authors	Exclusion criteria	Control group	Stain	Number of cells evaluated participant	Analysis of cytotoxicity	Number of patients	Blindedreview	Proper statistical description
Angelieri et al.¹¹11. Angelieri F, Carlin V, Martins RA, Ribeiro DA. Biomonitoring of mutagenicity and cytotoxicity in patients undergoing fixed orthodontic therapy. Am J Orthod Dentofacial Orthop. 2011 Apr;139(4 Suppl):e399-404. https://doi.org/10.1016/j.ajodo.2009.06.029 https://doi.org/10.1016/j.ajodo.2009.06....	No	Yes	Feulgen	2	Yes	23	No	Yes
Faccioni et al.²⁰20. Faccioni P, De Santis D, Sinigaglia S, Pancera P, Faccioni F, Nocini PF. Short-term “in vivo” study on cellular DNA damage induced by acrylic Andresen activator in oral mucosa cells. Orthod Craniofac Res. 2019 Aug;22(3):208-12. https://doi.org/10.1111/ocr.12312 https://doi.org/10.1111/ocr.12312...	Yes	Yes	DAPI	1	No	25	No	Yes
Flores-Bracho et al.¹⁷17. Flores-Bracho MG, Takahashi CS, Castillo WO, Saraiva MC, Küchler EC, Matsumoto MA, et al. Genotoxic effects in oral mucosal cells caused by the use of orthodontic fixed appliances in patients after short and long periods of treatment. Clin Oral Investig. 2019 Jul;23(7):2913-9. https://doi.org/10.1007/s00784-018-02795-8 https://doi.org/10.1007/s00784-018-02795...	Yes	Yes	Feulgen	2	Yes	95	Yes	Yes
Cunha et al.¹²12. Cunha AS, Castillo WO, Takahashi CS, Küchler EC, Segato RA, Silva LA, et al. Genotoxic and cytotoxic effects of Haas appliance in exfoliated buccal mucosa cells during orthodontic treatment. Angle Orthod. 2018 Sep;88(5):590-5. https://doi.org/10.2319/101117-687.1 https://doi.org/10.2319/101117-687.1...	Yes	Yes	Feulgen	1	Yes	28	Yes	No
Gonçalves et al.¹⁸18. Gonçalves TS, Menezes LM, Trindade C, Thomas P, Fenechc M, Henriques JA. In vivo evaluation of the genotoxic effects of Hyrax auxiliary orthodontic appliances containing silver-soldered joints. Mutat Res Genet Toxicol Environ Mutagen. 2015 Sep;791:25-9. https://doi.org/10.1016/j.mrgentox.2015.07.007 https://doi.org/10.1016/j.mrgentox.2015....	Yes	Yes	Feulgen	2	Yes	20	Yes	Yes
Heravi et al.²²22. Heravi F, Abbaszadegan MR, Merati M, Hasanzadeh N, Dadkhah E, Ahrari F. DNA damage in oral mucosa cells of patients with fixed orthodontic appliances. J Dent (Tehran). 2013 Nov;10(6):494-500.	Yes	Yes	Giemsa	1	No	25	No	Yes
Toy et al.²¹21. Toy E, Yuksel S, Ozturk F, Karatas OH, Yalcin M. Evaluation of the genotoxicity and cytotoxicity in the buccal epithelial cells of patients undergoing orthodontic treatment with three light-cured bonding composites by using micronucleus testing. Korean J Orthod. 2014 May;44(3):128-35. https://doi.org/10.4041/kjod.2014.44.3.128 https://doi.org/10.4041/kjod.2014.44.3.1...	Yes	Yes	Acridine Orange	2	Yes	30	Yes	Yes
Natarajan et al.¹⁰10. Natarajan M, Padmanabhan S, Chitharanjan A, Narasimhan M. Evaluation of the genotoxic effects of fixed appliances on oral mucosal cells and the relationship to nickel and chromium concentrations: an in-vivo study. Am J Orthod Dentofacial Orthop. 2011 Sep;140(3):383-8. https://doi.org/10.1016/j.ajodo.2010.07.027 https://doi.org/10.1016/j.ajodo.2010.07....	Yes	Yes	Papanicolaou	Not informed	No	40	No	Yes
Westphalen et al.¹⁹19. Westphalen GH, Menezes LM, Prá D, Garcia GG, Schmitt VM, Henriques JA, et al. In vivo determination of genotoxicity induced by metals from orthodontic appliances using micronucleus and comet assays. Genet Mol Res. 2008;7(4):1259-66. https://doi.org/10.4238/vol7-4gmr508 https://doi.org/10.4238/vol7-4gmr508...	Yes	Yes	Giemsa	Not informed	No	20	Yes	Yes

Authors	Main findings

	Cytotoxicity	Mutagenicity
Angelieri et al.¹¹11. Angelieri F, Carlin V, Martins RA, Ribeiro DA. Biomonitoring of mutagenicity and cytotoxicity in patients undergoing fixed orthodontic therapy. Am J Orthod Dentofacial Orthop. 2011 Apr;139(4 Suppl):e399-404. https://doi.org/10.1016/j.ajodo.2009.06.029 https://doi.org/10.1016/j.ajodo.2009.06....	No significant changes	No significant changes
Faccioni et al.²⁰20. Faccioni P, De Santis D, Sinigaglia S, Pancera P, Faccioni F, Nocini PF. Short-term “in vivo” study on cellular DNA damage induced by acrylic Andresen activator in oral mucosa cells. Orthod Craniofac Res. 2019 Aug;22(3):208-12. https://doi.org/10.1111/ocr.12312 https://doi.org/10.1111/ocr.12312...	-	↑ MN, BN, and bud cells
Flores-Bracho et al.¹⁷17. Flores-Bracho MG, Takahashi CS, Castillo WO, Saraiva MC, Küchler EC, Matsumoto MA, et al. Genotoxic effects in oral mucosal cells caused by the use of orthodontic fixed appliances in patients after short and long periods of treatment. Clin Oral Investig. 2019 Jul;23(7):2913-9. https://doi.org/10.1007/s00784-018-02795-8 https://doi.org/10.1007/s00784-018-02795...	↑ Karyolysis	No significant changes
Cunha et al.¹²12. Cunha AS, Castillo WO, Takahashi CS, Küchler EC, Segato RA, Silva LA, et al. Genotoxic and cytotoxic effects of Haas appliance in exfoliated buccal mucosa cells during orthodontic treatment. Angle Orthod. 2018 Sep;88(5):590-5. https://doi.org/10.2319/101117-687.1 https://doi.org/10.2319/101117-687.1...	↑Pyknosis and karyolysis	↑ BN and bud cells
Gonçalves et al.¹⁸18. Gonçalves TS, Menezes LM, Trindade C, Thomas P, Fenechc M, Henriques JA. In vivo evaluation of the genotoxic effects of Hyrax auxiliary orthodontic appliances containing silver-soldered joints. Mutat Res Genet Toxicol Environ Mutagen. 2015 Sep;791:25-9. https://doi.org/10.1016/j.mrgentox.2015.07.007 https://doi.org/10.1016/j.mrgentox.2015....	No significant differences	No significant differences
Heravi et al.²²22. Heravi F, Abbaszadegan MR, Merati M, Hasanzadeh N, Dadkhah E, Ahrari F. DNA damage in oral mucosa cells of patients with fixed orthodontic appliances. J Dent (Tehran). 2013 Nov;10(6):494-500.	-	No significant differences
Toy et al.²¹21. Toy E, Yuksel S, Ozturk F, Karatas OH, Yalcin M. Evaluation of the genotoxicity and cytotoxicity in the buccal epithelial cells of patients undergoing orthodontic treatment with three light-cured bonding composites by using micronucleus testing. Korean J Orthod. 2014 May;44(3):128-35. https://doi.org/10.4041/kjod.2014.44.3.128 https://doi.org/10.4041/kjod.2014.44.3.1...	↑ Karyolysis	↑ BN
Natarajan et al.¹⁰10. Natarajan M, Padmanabhan S, Chitharanjan A, Narasimhan M. Evaluation of the genotoxic effects of fixed appliances on oral mucosal cells and the relationship to nickel and chromium concentrations: an in-vivo study. Am J Orthod Dentofacial Orthop. 2011 Sep;140(3):383-8. https://doi.org/10.1016/j.ajodo.2010.07.027 https://doi.org/10.1016/j.ajodo.2010.07....	-	↑ MN
Westphalen et al.¹⁹19. Westphalen GH, Menezes LM, Prá D, Garcia GG, Schmitt VM, Henriques JA, et al. In vivo determination of genotoxicity induced by metals from orthodontic appliances using micronucleus and comet assays. Genet Mol Res. 2008;7(4):1259-66. https://doi.org/10.4238/vol7-4gmr508 https://doi.org/10.4238/vol7-4gmr508...	-	↑ MN

Author	Study design	Blinding	Data analysis	Confounders	Final rating
Angelieri et al.¹¹11. Angelieri F, Carlin V, Martins RA, Ribeiro DA. Biomonitoring of mutagenicity and cytotoxicity in patients undergoing fixed orthodontic therapy. Am J Orthod Dentofacial Orthop. 2011 Apr;139(4 Suppl):e399-404. https://doi.org/10.1016/j.ajodo.2009.06.029 https://doi.org/10.1016/j.ajodo.2009.06....	Moderate	Weak	Strong	Strong	Moderate
Faccioni et al.²⁰20. Faccioni P, De Santis D, Sinigaglia S, Pancera P, Faccioni F, Nocini PF. Short-term “in vivo” study on cellular DNA damage induced by acrylic Andresen activator in oral mucosa cells. Orthod Craniofac Res. 2019 Aug;22(3):208-12. https://doi.org/10.1111/ocr.12312 https://doi.org/10.1111/ocr.12312...	Strong	Strong	Strong	Weak	Moderate
Flores-Bracho et al.¹⁷17. Flores-Bracho MG, Takahashi CS, Castillo WO, Saraiva MC, Küchler EC, Matsumoto MA, et al. Genotoxic effects in oral mucosal cells caused by the use of orthodontic fixed appliances in patients after short and long periods of treatment. Clin Oral Investig. 2019 Jul;23(7):2913-9. https://doi.org/10.1007/s00784-018-02795-8 https://doi.org/10.1007/s00784-018-02795...	Moderate	Strong	Strong	Strong	Strong
Cunha et al.¹²12. Cunha AS, Castillo WO, Takahashi CS, Küchler EC, Segato RA, Silva LA, et al. Genotoxic and cytotoxic effects of Haas appliance in exfoliated buccal mucosa cells during orthodontic treatment. Angle Orthod. 2018 Sep;88(5):590-5. https://doi.org/10.2319/101117-687.1 https://doi.org/10.2319/101117-687.1...	Moderate	Strong	Weak	Moderate	Moderate
Gonçalves et al.¹⁸18. Gonçalves TS, Menezes LM, Trindade C, Thomas P, Fenechc M, Henriques JA. In vivo evaluation of the genotoxic effects of Hyrax auxiliary orthodontic appliances containing silver-soldered joints. Mutat Res Genet Toxicol Environ Mutagen. 2015 Sep;791:25-9. https://doi.org/10.1016/j.mrgentox.2015.07.007 https://doi.org/10.1016/j.mrgentox.2015....	Weak	Strong	Strong	Strong	Moderate
Heravi et al.²²22. Heravi F, Abbaszadegan MR, Merati M, Hasanzadeh N, Dadkhah E, Ahrari F. DNA damage in oral mucosa cells of patients with fixed orthodontic appliances. J Dent (Tehran). 2013 Nov;10(6):494-500.	Strong	Weak	Strong	Weak	Weak
Toy et al.²¹21. Toy E, Yuksel S, Ozturk F, Karatas OH, Yalcin M. Evaluation of the genotoxicity and cytotoxicity in the buccal epithelial cells of patients undergoing orthodontic treatment with three light-cured bonding composites by using micronucleus testing. Korean J Orthod. 2014 May;44(3):128-35. https://doi.org/10.4041/kjod.2014.44.3.128 https://doi.org/10.4041/kjod.2014.44.3.1...	Strong	Strong	Strong	Strong	Strong
Natarajan et al.¹⁰10. Natarajan M, Padmanabhan S, Chitharanjan A, Narasimhan M. Evaluation of the genotoxic effects of fixed appliances on oral mucosal cells and the relationship to nickel and chromium concentrations: an in-vivo study. Am J Orthod Dentofacial Orthop. 2011 Sep;140(3):383-8. https://doi.org/10.1016/j.ajodo.2010.07.027 https://doi.org/10.1016/j.ajodo.2010.07....	Strong	Weak	Strong	Weak	Weak
Westphalen et al.¹⁹19. Westphalen GH, Menezes LM, Prá D, Garcia GG, Schmitt VM, Henriques JA, et al. In vivo determination of genotoxicity induced by metals from orthodontic appliances using micronucleus and comet assays. Genet Mol Res. 2008;7(4):1259-66. https://doi.org/10.4238/vol7-4gmr508 https://doi.org/10.4238/vol7-4gmr508...	Strong	Strong	Strong	Weak	Moderate

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[1] Corresponding Author: Daniel Araki Ribeiro E-mail: daribeiro@unifesp.br