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Methylphenidate effects on mice odontogenesis and connections with human odontogenesis

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Abstract

The purpose of this study is to evaluate the effects of Methylphenidate exposure on mice odontogenesis and connect them by bioinformatics with human odontogenesis. Thirty-two pregnant Swiss mice were divided into treated group and control group, which received, respectively, 5 mg/kg of Methylphenidate and saline solution from the 5th to the 17th day of pregnancy. The mouse embryos tooth germs were analyzed through optical microscopy, and the data collected were analyzed statistically by Fisher’s exact test. The presence and similarity of Methylphenidate-associated genes (Pharmgkb database) in both organisms and their interaction with dental development genes (AmiGO2 database) were verified on STRING database. Rates of tooth germ malformations were higher in treated than in control group (Control: 18; Treated: 27; p = 0.035). Mouse embryo malformations were connected with 238 interactions between 69 dental development genes with 35 Methylphenidate genes. Fourteen interactions for four Methylphenidate genes with four dental development genes, with human experimental data, were connected with mouse phenotype data. By homology, the interactions and conservation of proteins/genes may indicate similar outcomes for both organisms. The exposure to Methylphenidate during pregnancy affected odontogenesis in mouse embryos and may affect human odontogenesis. The study of malformations in mice, with a bioinformatics approach, could contribute to understanding of the Methylphenidate effect on embryo development. These results may provide novel hypotheses for further testing and reinforce the FDA protocol: as Methylphenidate is included in category C, its use during pregnancy should be considered if the benefits outweigh the risks.

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References

  1. Thapar A, Cooper M. Attention deficit hyperactivity disorder. Lancet. 2015;6736:1240–50.

    Google Scholar 

  2. Agnew-Blais JC, Polanczyk GV, Danese A, Wertz J, Moffitt TE, Arseneault L. Evaluation of the persistence, remission, and emergence of attention-deficit/hyperactivity disorder in young adulthood. JAMA Psychiat. 2016;73:713–20.

    Article  Google Scholar 

  3. Pottegård A, Bjerregaard BK. The use of medication against attention deficit hyperactivity disorder in Denmark: a drug use study from a national perspective. Eur J Clin Pharmacol. 2012;68:1443–500.

    Article  Google Scholar 

  4. Huybrechts KF, Bröms G, Christensen LB, Einarsdóttir K, Engeland A, Furu K, Gissler M, Hernandez-Diaz S, Karlsson P, Karlstad O, Kieler H, Lahesmaa-Korpinen AM, Mogun H, Nørgaard M, Reutfors J, Sørensen HT, Zoega H, Bateman BT. Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the international pregnancy safety study consortium. JAMA Psychiat. 2017;75:167–75.

    Article  Google Scholar 

  5. Peters HT, Strange LG, Brown SD, Pond BB. The pharmacokinetic profile of methylphenidate use in pregnancy: a study in mice. Neurotoxicol Teratol. 2016;54:1–4.

    Article  Google Scholar 

  6. Olley R, Xavier GM, Seppala M, Volponi AA, Geoghegan F, Sharpe PT, Cobourne MT. Expression analysis of candidate genes regulating successional tooth formation in the human embryo. Front Physiol. 2014;5:1–8.

    Article  Google Scholar 

  7. Thesleff I. Current understanding of the process of tooth formation: transfer from the laboratory to the clinic. Aust Dent J. 2014;59:48–544.

    Article  Google Scholar 

  8. Billings RJ, Berkowitz RJ, Watson G. Teeth. Pediatrics. 2004;113:1120–7.

    PubMed  Google Scholar 

  9. Kawakami T, Nakamura Y, Karibe H. Cyclophosphamide inhibits root development of molar teeth in growing mice. Odontology. 2015;103:143–51.

    Article  Google Scholar 

  10. Ornoy A. Pharmacological treatment of attention deficit hyperactivity disorder during pregnancy and lactation. Pharm Res. 2018;35:1–11.

    Article  Google Scholar 

  11. Dideriksen D, Potteg A, Hallas J, Aagaard L, Damkier P. First trimester in utero exposure to methylphenidate. Basic Clin Pharmacol Toxicol. 2013;112:73–6.

    Article  Google Scholar 

  12. Humphreys C, Garcia-Bournissen F, Ito S, Koren G. Motherisk update exposure to attention deficit hyperactivity disorder medications during pregnancy. Can Fam Physician. 2007;53:1153–5.

    PubMed  PubMed Central  Google Scholar 

  13. Costa GA, Galvão TC, Bacchi AD, Moreira EG, Salles MJS. Investigation of possible teratogenic effects in the offspring of mice exposed to methylphenidate during pregnancy. Reprod Biomed. 2016;32:170–7.

    Article  Google Scholar 

  14. Koren G, Barer Y, Ornoy A. Fetal safety of Methylphenidate—a scoping review and meta analysis. Reprod Toxicol. 2020;93:230–4.

    Article  Google Scholar 

  15. Batterson KD, Southard KA, Dawson DV, Staley RN, Qian F, Slayton RL. The effect of chronic Methylphenidate administration on tooth maturation in a sample of Caucasian children. Pediatr Dent. 2005;27:292–8.

    PubMed  Google Scholar 

  16. Dutta S, Sengupta P. Men and mice: relating their ages. Life Sci. 2016;152:244–8.

    Article  Google Scholar 

  17. Montagnini BG, Bortolan S, Santos BD, Moreno AP, Camin NA, Gerardin DCC, Moreira EG. Evaluation of escitalopram, sertraline, and methylphenidate in the immature rat uterotrophic assay. Int J Toxicol. 2013;32:426–30.

    Article  Google Scholar 

  18. McFadyen-Leussis MP, Lewis SP, Bond TLY, Carrey N, Brown RE. Prenatal exposure to Methylphenidate hydrochloride decreases anxiety and increases exploration in mice. Pharmacol Biochem Behav. 2004;77:491–500.

    Article  Google Scholar 

  19. Institute For Laboratory Animal Research. Guide for the care and use of laboratory animals. 8th ed. Washington: The National Academies Press; 2011.

    Google Scholar 

  20. AmiGO2 database. https://amigo.geneontology.org/amigo. Accessed 15 July 2020.

  21. Pharmgkb database. https://www.pharmgkb.org/. Accessed 15 July 2020.

  22. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2013;92:414–7.

    Article  Google Scholar 

  23. UNIPROT database. https://www.uniprot.org/. Accessed 15 July 2020.

  24. LALIGN. https://www.ebi.ac.uk/Tools/psa/lalign. Accessed 15 July 2020.

  25. McWilliam H, Li W, Uludag M, Squizzato S, Park YM, Buso N, Cowley AP, Lopez R. Analysis tool web services from the EMBL-EBI. Nucleic Acids Res. 2013;41:W597–600.

    Article  Google Scholar 

  26. STRING database. https://string-db.org/. Accessed 15 July 2020.

  27. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, von Mering C. STRING v11: protein—protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res Oxford University Press. 2019;47:D607–D613613.

    Article  Google Scholar 

  28. Takara K, Maruo N, Oka K, Kaji C, Hatakeyama Y, Sawa N, Kato Y, Yamashita J, Kojima H, Sawa Y. Morphological study of tooth development in podoplanin-deficient mice. PLoS ONE. 2017;12:1–23.

    Article  Google Scholar 

  29. Baker AS, Freeman MP. Management of attention deficit hyperactivity disorder during pregnancy. Obstet Gynecol Clin NA. 2018;45:495–509.

    Article  Google Scholar 

  30. Zheng Y, Jia L, Liu P, Yang D, Hu W, Wei S. Insight into the maintenance of odontogenic potential in mouse dental mesenchymal cells based on transcriptomic analysis. PeerJ. 2016;4(e1684):1–18.

    Google Scholar 

  31. Kim BN, Kim JW, Cummins TDR, Bellgrove MA, Hawi Z, Hong SB, Yang YH, Kim HJ, Shin MS, Cho SC, Kim JH, Son JW, Shin YM, Chung US, Han DH. Norepinephrine genes predict response time variability and Methylphenidate-induced changes in neuropsychological function in attention deficit hyperactivity disorder. J Clin Psychopharmacol. 2013;33:356–62.

    Article  Google Scholar 

  32. Nobles M, Benians A, Tinker A. Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proc Natl Acad Sci. 2005;102:18706–11.

    Article  Google Scholar 

  33. de Oliveira PG, Ramos MR, Amaro AJ, Dias RA, Vieira SI. Gi/o-Protein coupled receptors in the aging brain. Front Aging Neurosci. 2019;11:1–44.

    Article  Google Scholar 

  34. Yang J, Cai W, Lu X, Liu S, Zhao S. RNA-sequencing analyses demonstrate the involvement of canonical transient receptor potential channels in rat tooth germ development. Front Physiol. 2017;8:1–10.

    Google Scholar 

  35. Sancho-Bru P, Bataller R, Colmenero J, Gasull X, Moreno M, Arroyo V, Brenner DA, Gines P. Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2006;291:G877–G884884.

    Article  Google Scholar 

  36. Sung U, Binda F, Savchenko V, Owens WA, Daws LC. Ca2+ dependent surface trafficking of norepinephrine transporters depends on threonine 30 and Ca2+ calmodulin kinases. J Chem Neuroanat. 2016;1:19–35.

    Google Scholar 

  37. Nanci A, Tencate A. Ten Cate’s oral histology: development, structure, and function. 8th ed. Saint Louis: Elsevier; 2013.

    Google Scholar 

  38. Huang X, XuJr XPB, Hung YP, Chai Y. Smad4-Shh-Nfic signaling cascade—mediated regulating tooth root development. J Bone Miner Res. 2010;25:1167–78.

    PubMed  Google Scholar 

  39. Sousa-Romero L, Moreno-Fernández AM. Growth and transcription factors in tooth development. Int J Craniofacial Sci. 2016;2:15–29.

    Article  Google Scholar 

  40. Katchburian E, Arana-Chavez V. Histologia e embriologia oral: texto-atlas-correlações clínicas. 3rd ed. Rio de Janeiro: Guanabara-Koogan; 2012.

    Google Scholar 

  41. Lee HK, Lee DS, Park SJ, Cho KH, Bae HS, Park JC. Nuclear Factor I-C (NFIC) regulates dentin sialophosphoprotein (DSPP) and E-cadherin via control of Krüppel-like factor 4 (KLF4) during dentinogenesis. J Biol Chem. 2014;289:28225–36.

    Article  Google Scholar 

  42. Kim TH, Bae CH, Yang S, Park JC, Cho ES. Nfic regulates tooth root patterning and growth. Anat Cell Biol. 2015;48:188–94.

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Miss Lorena Frítola, who provided all the help needed with the text translation.

Funding

This study was all supported by the authors’ resources and did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of General Biology, State University of Londrina (UEL), Km 380, Celso Garcia Cid Road, Londrina, 86057-970, Brazil

    Karol Sartori Lima, Antônio Eduardo Sparça Salles, Gabriel de Araújo Costa, Márjori Frítola Yokoyama & Maria José Sparça Salles

  2. Department of Histology, State University of Londrina (UEL), Km 380, Celso Garcia Cid Road, Londrina, 86057-970, Brazil

    Solange de Paula Ramos

  3. PPGBioEvo, Institute of Biology, Federal University of Bahia (UFBA), 668, Barão de Jeremoabo Street, Salvador, 40170-115, Brazil

    Vanessa Rodrigues Paixão-Côrtes & Renata Lúcia Leite Ferreira de Lima

Authors
  1. Karol Sartori Lima
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  3. Gabriel de Araújo Costa
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Contributions

KSL: investigation, methodology, project administration, resources, and writing—review and editing. GAC: investigation, methodology, project administration, resources, and writing—review and editing. AES: data curation, writing—review and editing. SPR: data curation, writing—original draft, and writing—review and editing. MFY: software, validation, visualization, writing—original draft, and writing—review and editing. VRP-C: software, validation, visualization, and writing—review and editing. RLLFL: software, validation, visualization, and writing—review and editing. MJSS: conceptualization, data curation, project administration, formal analysis, funding acquisition, investigation, supervision, validation, visualization, and writing.

Corresponding author

Correspondence to Márjori Frítola Yokoyama.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures described herein comply with ARRIVE guidelines and are following the National Institutes of Health (NIH) guidelines regarding the care and use of animals for experimental procedures (National Research Council, 2011). They were also approved by the Ethics Committee for Animal Experimentation of the State University of Londrina (9397.2014.90) and carried out with the consent of each author.

Research involving human participants and/or animals: statement of animal welfare

To guarantee the welfare of the animals from the sample of this study, the research team considered some practices during the experimental phase: the maintenance of controlled conditions of light and temperature in the bioterium; unlimited access to water and feed; the allocation of animals in the proportion of two female mice for each male mice, in cages, measuring 30 × 20 cm × 13 cm, made of polypropylene with a zinc-plated wire cover and lined with wood shavings; the realization of daily treatments by only two people out of the research team, most quickly and comfortably; euthanasia most quickly and comfortably.

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Lima, K.S., Salles, A.E.S., de Araújo Costa, G. et al. Methylphenidate effects on mice odontogenesis and connections with human odontogenesis. Odontology 109, 336–348 (2021). https://doi.org/10.1007/s10266-020-00548-2

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