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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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RESUMO

Introdução: O metilfenidato (MFD) é um derivado anfetamínico estimulante do sistema nervoso central, que vem sendo cada vez mais consumido pela população mundial, incluindo as mulheres em idade fértil. Ainda não foram estabelecidos os efeitos deste medicamento nas glândulas salivares, durante a gestação. Objetivo: Identificar alterações histomorfológicas em glândulas salivares maternas expostas ao metilfenidato. Material e método: Para análise histológica, foram utilizadas 32 fêmeas de camundongos Swiss prenhes, distribuídas em um grupo controle e um grupo tratado. A administração foi realizada do quinto ao 17º dia de gestação, via injeção subcutânea; o grupo tratado recebeu 5 mg/kg de metilfenidato, enquanto o grupo controle recebeu o mesmo volume de solução salina estéril. As fêmeas foram eutanasiadas e tiveram suas glândulas salivares removidas e incluídas em parafina para análise em microscopia óptica. Para avaliar a associação entre as variáveis dos grupos, o teste de Kolmogorov-Smirnov e o teste T foram utilizados. Resultado: As glândulas parótidas do grupo tratado apresentaram alterações no raio dos ductos e na quantidade de ácinos, quando comparadas às glândulas parótidas do grupo controle. A glândula submandibular do grupo tratado foi a mais afetada: mostrou diferença estatisticamente significativa na espessura da parede dos ductos secretores, no raio dos ductos e no raio dos ácinos, quando comparada à glândula submandibular do grupo controle. A glândula sublingual não apresentou alterações significativas. Conclusão: Neste delineamento experimental, o metilfenidato apresentou-se como agente indutor de alterações morfológicas das glândulas salivares, promovendo alterações significativas nos raios de ductos e ácinos das mesmas, sendo a glândula submandibular a mais susceptível a este fármaco.

Introduction: Methylphenidate (MFD) is a stimulant amphetamine derivative of the central nervous system, which is being increasingly consumed by the world population, including women of childbearing age. It has not yet established the effects of this medicine in the salivary glands during pregnancy. Objective: Evaluate the exposure effects to the MPD in the maternal salivary glands. Material and method: For prenatal study, 32 pregnant female Swiss mice were used, divided into a control and a treated group. The treated group received 5 mg/kg of MPD via subcutaneous injection from the 5th to the 17th day and the control received sterile saline in the same volume and pregnancy period. Females were euthanized and had their salivary glands removed and embedded in paraffin for analysis in optical microscopy. To evaluate the association between the variables of the groups, the Kolmogorov-Smirnov test and and T test were used. Result: The parotid glands of the treated group showed statistically significant change within the ducts and the amount of acini when compared to the control group. The submandibular gland was the most affected, it showed a difference statistically significant in wall thickness of the secretory ducts, within the ducts and within the acini when compared to the control group. The sublingual gland showed no significant changes. Conclusion: In this experiment methylphenidate is presented as inducing agent morphological changes of the salivary glands, promoting significant changes in ducts radii and acini, submandibular gland being more susceptible to this drug.

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