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To assess the influence of estrogen deficiency on tooth eruption rate (TER) and gene expression of estrogen receptor alpha and beta (ERα and ERβ) in the odontogenic region of teeth with continuous formation in a rat model.Ovariectomies (OVX; n = 25) and sham surgeries (SHAM; n = 25) were performed in female Wistar rats when animals were 25 days old. The TER of the lower incisors, both in impeded (hyperfunction condition) and unimpeded (trimmed incisal edge-hypofunction condition) conditions, was evaluated using standardized digital photographs acquired every 48-72 h for 3 weeks (35th-53rd day of life), using a camera coupled to a stereomicroscope. Quantitative real-time PCR was performed to evaluate the relative gene expression of ERα and ERβ in the odontogenic region.The OVX group showed a significant reduction in TER when compared to the SHAM group, only in the impeded condition (p = 0.03). There was no statistically significant difference between the groups in ERα gene expression (p = 0.33). ERβ showed a significantly higher gene expression in the OVX group (p ≤ 0.05).Estrogen deficiency decreases TER in teeth under impeded condition. Estrogen deficiency also increases ERβ gene expression in the odontogenic region of teeth with continuous formation.Hormonal disturbances affecting estrogen levels can cause alterations in dental formation and teeth eruption.

The aim of this study was investigate the cranium dimensions of adult female rats, who suffered estrogen deficiency during the prepubertal stage, to assess the impact of estrogen deficiency on craniofacial morphology. Twenty-two female Wistar rats were divided into ovariectomy (OVX) (n = 11) and sham-operated control (n = 11) groups. Bilateral ovariectomy were performed in both groups at 21 days old (prepubertal stage), and rats were euthanized at an age of 63 days (post-pubertal stage). Micro-CT scans were performed with rat skulls, and the cranium morphometric landmark measurements were taken in the dorsal, lateral, and ventral view positions. Differences in measurements between the OVX and sham control groups were assessed using t test with an established alpha error of 5%. The measures of the rats’ skull showed that the inter-zygomatic arch width and anterior cranial base length were significantly larger in OVX group (p = 0.020 and p = 0.050, respectively), whereas the length of parietal bone was significantly higher in the sham group (p = 0.026). For the remaining measurements no significant differences between groups were detected (p > 0.05). This study provides evidence that ovariectomized rats had alterations in cranial bone dimensions, demonstrating that estrogens during puberty are important for skull morphology. To understand the role of estrogen on the postnatal cranium development will impact the clinical diagnose and therapy during childhood and adolescence.

The role of oestrogen in craniofacial growth still remains unclear. Therefore, the present study aimed to assess the effect of oestrogen deficiency on maxilla and mandible dimensions.The study was conducted at the Department of Pediatric Dentistry at the School of Dentistry of Ribeirão Preto, University of São Paulo, and used forty female Wistar rats.Ovariectomy (OVX) and placebo surgery (Sham) were performed when animals were twenty-one days old (prepubertal stage). Dimensions of the maxilla and mandible were assessed by craniometric analysis using radiographs, during and after puberty of the animals (45 and 63 days old, respectively). Quantitative real-time PCR and immunohistochemical analyses were performed to determine the expression and localization, respectively, of oestrogen receptor alpha (ERα) and oestrogen receptor beta (ERβ) in different growth sites of the evaluated structures at puberty. The differences between the groups for each outcome were evaluated using the t test with an established alpha error of 5%.There were significant differences between the OVX and Sham groups for horizontal and vertical linear measurements in the maxilla and the mandible at both pubertal and post-pubertal stages (P .05). The ovariectomized rats showed significantly greater measures for all dimensions assessed. No differences in gene expression of ERα and ERβ were identified at the different growth sites between the OVX and Sham groups (P .05). Immunohistochemical analyses revealed the presence of both oestrogen receptors in osteoblasts and chondrocytes in the midpalatal suture and mandibular condyle, respectively, in the OVX and Sham groups.Our results suggest that oestrogen deficiency from the prepubertal stage might increase the growth of the maxilla and mandible in female rats.

Objective: To investigate the association of genetic markers in ESR1 and ESR2 with craniofacial measurements. Design: Cross-sectional study. Setting: School of Dentistry of Ribeirão Preto, University of São Paulo. Participants: A total of 146 biologically unrelated, self-reported Caucasian Brazilians with no syndromic conditions were included. Methods: Sagittal and vertical measurements (ANB, S-N, Ptm’-A’, Co-Gn, Go-Pg, N-Me, ANS-Me, S-Go and Co-Go) from lateral cephalograms were examined for craniofacial evaluation. DNA was extracted from saliva and genetic markers in ESR1 (rs2234693 and rs9340799) and in ESR2 (rs1256049 and rs4986938) were analysed by real-time polymerase chain reaction. Hardy–Weinberg equilibrium was evaluated using the Chi-square test within each marker. The associations between craniofacial dimensions and genotypes were analysed by linear regression and adjusted by sex and age. The established alpha was 5%. Results: Individuals carrying CC in ESR1 rs2234693 had a decrease of –3.146 mm in ANS-Me ( P = 0.044). In addition, rs4986938 in ESR2 was associated with S-N measurement ( P = 0.009/ ß = –3.465). This marker was also associated with Go-Pg measurement, in which the CC genotype had a decrease of –3.925 mm in the length of the mandibular body ( P = 0.043). Conclusion: The present study suggests that in ESR1 and ESR2 are markers for variations in the craniofacial dimensions. However, further research should confirm the results.

Background The aim of this study was investigated if estrogen deficiency during puberty affects the expression of miRNA30a and miRNA503 in maxillary and mandibular growth centers, and also evaluated if ERα and ERβ are correlated with miRNA30a and miRNA503 expressions. Methods Samples from 12 female Wistar rats randomized into experimental group (OVX) and control group (SHAM). At an age of 45 days animals were euthanized for miRNA expression analyses. RT-qPCR was performed to determine miRNA30a and miRNA503 expression in growth sites: midpalatal suture, condyle, mandibular angle, symphysis/parasymphysis and coronoid process. The data was carried out using the parametric tests at 5% of significance level. Results miRNA 30a and miRNA503 presented higher levels in the condylar site in SHAM group when compared with OVX (p = 0.002 and p = 0.020, respectively). In the growth centers, a statistical significant difference was observed only for miRNA30a (p = 0.004), when compared mandibular angle with condyle the in OVX group (p = 0.001). A strong positive correlation between miRNA503 and ERα in the condyle of OVX group was observed (r = 0.90; p = 0.039 and it also between miRNA503 and ERβ in the coronoid process of the OVX group (r = 0.88; p = 0.05). Conclusion The results suggested that estrogen regulates specific miRNAs in maxillary and mandibular growth centers, which may participate in posttranscriptional regulation of estrogen-regulated genes.

Objective: To evaluate if temporomandibular disorders (TMDs) are associated with genetic polymorphisms in ESR1 and ESR2, which are genes encoding oestrogen receptor alpha (ERα) and beta (ERβ). Also...

The present cross-sectional, multi-centre, genetic study aimed to determine, whether single nucleotide polymorphisms (SNPs) in tooth agenesis (TA)-associated GLI2 and GLI3 genes contribute to the development of craniofacial skeletal morphology in humans.Orthodontic patients from an ethnically heterogeneous population were selected for the present study (n = 594). The presence or absence of TA was determined by analysis of panoramic radiography and dental records. The subjects were classified according to their skeletal malocclusion and facial growth pattern by means of digital cephalometric analysis. Genomic DNA was extracted from squamous epithelial cells of the buccal mucosa and SNPs in GLI2 (rs3738880, rs2278741) and GLI3 (rs929387, rs846266) were analysed by polymerase chain reaction using TaqMan chemistry and end-point analysis.Class II skeletal malocclusion presented a significantly lower frequency of TA (P 0.05). Subjects without TA showed significantly higher ANB angles (P 0.05). Genotype and/or allele distributions of the SNPs in GLI2 (rs3738880, rs2278741) and GLI3 (rs846266) were associated with the presence of TA (P 0.05). The SNPs rs3738880, rs2278741 and rs929387 were also associated with some type of skeletal malocclusion (P 0.05), but not with the facial growth pattern (P 0.05). The G allele for TA-related GLI2 rs3738880 was strongly linked to the presence of Class III skeletal malocclusion (OR = 2.03; 95% CI = 1.37-3.03; P3125 × 10The present study suggests that SNPs in TA-associated GLI2 and GLI3 genes may also play a role in the development of skeletal malocclusions. rs3738880 and rs2278741 in GLI2 seems to contribute to the genetic background for skeletal Class III and TA, respectively. TA could be an additional predictor of craniofacial morphology in some cases. Further research replicating the reported associations should be performed.

Consumption of toxic substances such as alcohol is widespread in the general population and thus also in patients receiving orthodontic treatment. Since human periodontal ligament (hPDL) fibroblasts play a key role in orthodontic tooth movement (OTM) by expressing cytokines and chemokines, we wanted to clarify whether ethanol modulates the physiological activity and expression pattern of hPDL fibroblasts during static compressive force application. We pre-incubated hPDL fibroblasts for 24 h with different ethanol concentrations, corresponding to casual (0.041% blood alcohol concentration [BAC], % by volume) and excessive (0.179%) alcohol consumption. At each ethanol concentration, we incubated the cells for another 48 h with and without an additional physiological compressive force of 2 g/cm2 occurring during orthodontic tooth movement in compression areas of the periodontal ligament. Thereafter, we analyzed expression and secretion of genes and proteins involved in OTM regulation by RT-qPCR and ELISA. We also performed co-culture experiments to observe hPDL-fibroblast-mediated osteoclastogenesis. We observed no effects of ethanol on cytotoxicity or cell viability of hPDL fibroblasts in the applied concentrations. Ethanol showed an enhancing effect on angiogenesis and activity of alkaline phosphatase. Simultaneously, ethanol reduced the induction of IL-6 and increased prostaglandin E2 synthesis as well as hPDL-fibroblast-mediated osteoclastogenesis without affecting the RANK-L/OPG-system. hPDL fibroblasts thus seem to be a cell type quite resistant to ethanol, as no cytotoxic effects or influence on cell viability were detected. High ethanol concentrations, however, seem to promote bone formation and angiogenesis. Ethanol at 0.179% also enhanced hPDL-induced osteoclastogenesis, indicating increased bone resorption and thus tooth movement velocity to be expected during orthodontic therapy.

This study aimed to evaluate the association of genetic variants inACTN3 and MYO1H with craniofacial skeletal patterns in Brazilians.This cross-sectional study enrolled orthodontic and orthognathic patients selected from 4 regions of Brazil. Lateral cephalograms were used and digital cephalometric tracings and analyzes were performed for craniofacial phenotype determination. Participants were classified according to the skeletal malocclusion in Class I, II or III; and according to the facial type in Mesofacial, Dolichofacial or Brachyfacial. Genomic DNA was extracted from saliva samples containing exfoliated buccal epithelial cells and analyzed for genetic variants inACTN3 (rs678397 and rs1815739) and MYO1H (rs10850110) by real-time PCR. Chi-square or Fisher's exact tests were used for statistical analysis (α = 5%).A total of 646 patients were included in the present study. There was statistically significant association of the genotypes and/or alleles distributions with the skeletal malocclusion (sagittal skeletal pattern) and facial type (vertical pattern) for the variants assessed inACTN3 (P 0.05). For the genetic variant evaluated in MYO1H, there was statistically significant difference between the genotypes frequencies for skeletal Class I and Class II (P 0.05). The reported associations were different depending on the region evaluated.ACTN3 and MYO1H are associated with sagittal and vertical craniofacial skeletal patterns in Brazilian populations.

BackgroundEstrogen is a well-known and important hormone involved in skeletal homeostasis, which regulates genes involved in bone biology. Some studies support that estrogen is important for craniofacial growth and development. Therefore this in vivo animal study aimed to investigate, whether and in which way low estrogen levels in the prepubertal period affect craniofacial development in the postpubertal stage and to quantify the gene expression of RANK, RANKL and OPG in cranial growth sites in ovariectomized estrogen-deficient rats during puberty.MethodsControl (sham-operated,n = 18) and ovariectomy (OVX, n = 18) surgeries were performed on 21-days-old female Wistar rats. Animals euthanized at an age of 45 days (pubertal stage) were used for gene expression analyses (n = 6 per group) and immunohistochemistry of RANK, RANKL and OPG. Animals euthanized at 63 days of age (post-pubertal stage) were used for craniofacial two-dimensional and three-dimensional craniofacial measurements using μCT imaging (n = 12 per group).ResultsIn the μCT analysis of the mandible and maxilla many statistically significant differences between sham-operated and OVX groups were observed, such as increased maxillary and mandibular bone length in OVX animals (p p = 0.036) and the RANKL:OPG ratio levels were higher in the OVX group (p = 0.015).ConclusionsOur results suggest that estrogen deficiency during the prepubertal period is associated with alterations in the maxillary and mandibular bone length and condylar growth.

The aim of this study was investigate the cranium dimensions of adult female rats, who suffered estrogen deficiency during the prepubertal stage, to assess the impact of estrogen deficiency on craniofacial morphology.Twenty-two female Wistar rats were divided into ovariectomy (OVX) (n = 11) and sham-operated control (n = 11) groups. Bilateral ovariectomy were performed in both groups at 21 days old (prepubertal stage), and rats were euthanized at an age of 63 days (post-pubertal stage). Micro-CT scans were performed with rat skulls, and the cranium morphometric landmark measurements were taken in the dorsal, lateral, and ventral view positions. Differences in measurements between the OVX and sham control groups were assessed using t test with an established alpha error of 5%.The measures of the rats' skull showed that the inter-zygomatic arch width and anterior cranial base length were significantly larger in OVX group (p = 0.020 and p = 0.050, respectively), whereas the length of parietal bone was significantly higher in the sham group (p = 0.026). For the remaining measurements no significant differences between groups were detected (p0.05).This study provides evidence that ovariectomized rats had alterations in cranial bone dimensions, demonstrating that estrogens during puberty are important for skull morphology.To understand the role of estrogen on the postnatal cranium development will impact the clinical diagnose and therapy during childhood and adolescence.

To investigate the association of genetic markers inCross-sectional study.School of Dentistry of Ribeirão Preto, University of São Paulo.A total of 146 biologically unrelated, self-reported Caucasian Brazilians with no syndromic conditions were included.Sagittal and vertical measurements (ANB, S-N, Ptm'-A', Co-Gn, Go-Pg, N-Me, ANS-Me, S-Go and Co-Go) from lateral cephalograms were examined for craniofacial evaluation. DNA was extracted from saliva and genetic markers inIndividuals carrying CC inThe present study suggests that in

BackgroundThe aim of the present study was to assess if genetic polymorphisms in tooth agenesis (TA)-related genes are associated with craniofacial morphological patterns.MethodsThis cross-sectional, multi-center, genetic study evaluated 594 orthodontic Brazilians patients. The presence or absence of TA was determined by analysis of panoramic radiography. The patients were classified according to their skeletal malocclusion and facial growth pattern by means of digital cephalometric analysis. Genomic DNA was extracted from squamous epithelial cells of buccal mucosa and genetic polymorphisms inMSX1(rs1042484),PAX9(rs8004560),TGF-α(rs2902345),FGF3(rs1893047),FGF10(rs900379), andFGF13(rs12838463, rs5931572, and rs5974804) were genotyped by polymerase chain reaction using TaqMan chemistry and end-point analysis.ResultsGenotypes (p= 0.038) and allele (p= 0.037) distributions for theFGF3rs1893047 were significantly different according to the skeletal malocclusion. Carrying at least one G allele increased in more than two times the chance of presenting skeletal class III malocclusion (OR = 2.21, CI 95% = 1.14–4.32;p= 0.017). There was no association between another skeletal craniofacial pattern and some polymorphism assessed in the present study.ConclusionOur results suggest that the genetic polymorphism rs1893047 inFGF3might contribute to variations in the craniofacial sagittal pattern.

Objective The aim of this study was to evaluate the association between genetic polymorphisms in RANK, RANKL and OPG with maxillary and mandibular dimensions in humans. Design DNA extracted from saliva and the rs3826620, rs9594738 and rs2073618 polymorphisms in RANK, RANKL and OPG, respectively, were analysed by real-time PCR. Four linear measurements (Co-Gn, GoPg, Co-Go and PTM-A) from lateral cephalograms were examined for the evaluation of craniofacial measurements. ANOVA testing and a multivariate linear regression analysis, adjusted for age and gender, were used for statistical analysis, with an alpha of 5%. Hardy-Weinberg equilibrium was also evaluated using the chi-square test within each polymorphism. Setting School of Dentistry of Ribeirao Preto, University of Sao Paulo. Participants A total of 100 unrelated non-syndromic Brazilian Caucasian subjects were included in this study. Results The polymorphism in RANK was associated with a higher Go-Pg measurement (p = .039). In the multivariate analysis, adjusted for age and gender, the polymorphism in RANK was associated with Go-Pg (p = .017) and Co-Gn (p = .043). Conclusion The polymorphism rs3826620 in RANK is associated with the mandibular size.

Sex hormones have an effect on bone metabolism. However, it remains unclear how estrogen hormone affects mandible and maxilla growth and development. The aim of this study was to perform a systematic review to evaluate if estrogen is associated with developmental alterations in the maxilla/mandible phenotype. Material and methods: A computer search of the literature was performed using: Pubmed Medline (1966 – August 2018), Google Scholar and manual searching. A combination of the terms ‘estrogens', ‘mandible’, ‘dental arch’, ‘maxilla’, ‘craniofacial’, ‘growth’ and ‘development’ was used. Studies that used animal models to evaluate the role of estrogen during growth and development on the dimensions of the maxilla and/or mandible were included. Results: 5 studies were selected to compose this systematic review. One study used zebrafish as a model. Two studies used female mice and 2 studies used female rats as a model. Two studies treated the animals with estrogen. Four studies demonstrated that estrogen has an effect on mandible dimension and 2 studies demonstrated that estrogen has an effect on maxilla. One study did find an association between estrogen deficiency and mandible/maxilla dimensions Conclusion: The current evidence suggested that both, increased and decreased levels of estrogen, have an effect on the maxilla and mandible dimensions.

Introduction: Tooth agenesis (TA) is the congenital absence of teeth. Several studies have proposed a strong genetic background for this condition. Aim: The present cross-sectional study aimed to evaluate whether genetic polymorphisms in the genes that code for estrogen receptors (ESR1 and ESR2) are associated with the presence of isolated TA in a Brazilian sample. Methods: Panoramic radiographs of 142 orthodontic patients were assessed to determine TA of permanent teeth (excluding third molars). DNA of patients was extracted from buccal cells from saliva to evaluate genetic polymorphisms in ESR1 (rs2234693 and rs9340799) and ESR2 (rs1256049 and rs4986938) by genotyping using the real-time PCR technique. For statistical analyses, associations between the distributions of the alleles and genotypes, and the ocurrence of TA were assessed for each genetic polymorphism, with an established alpha of 5%. Results: Thirteen patients had at least 1 congenital missing tooth. The number of congenitally missing teeth ranged from 1 to 11. The genetic polymorphisms rs2234693 and rs9340799 in ESR1 and rs1256049 in ESR2 were not associated with TA (p > 0.05). For the genetic polymorphism rs4986938 in ESR2, the genotype and allele distributions were significantly different between the patients with and without TA (p < 0.05). The CC genotype and the C allele were overrepresented in the TA patients. Conclusion: The genetic polymorphism rs4986938 in ESR2 was associated with the ocurrence of TA. Introdução: A agenesia dentária (AD) é a ausência congênita de um ou mais dentes. Vários estudos vêm sugerindo o forte componente genético para essa condição. Objetivo: O presente estudo teve como objetivo avaliar se os polimorfismos genéticos nos genes que codificam os receptores de estrógeno (ESR1 e ESR2) estão associados à ocorrrência de AD isolada em uma amostra brasileira. Métodos: Radiografias panorâmicas de 142 pacientes ortodônticos foram avaliadas para determinar AD de dentes permanentes (excluindo terceiros molares). O DNA dos pacientes foi extraído das células da mucosa bucal contidas na saliva para avaliar polimorfismos genéticos em ESR1 (rs2234693 e rs9340799) e ESR2 (rs1256049 e rs4986938) por genotipagem usando a técnica de PCR em tempo real. Para análises estatísticas, associações entre as distribuições dos alelos e genótipos e a ocorrrência de AD foram avaliadas para cada polimorfismo genético, com um alfa estabelecido de 5%. Resultados: Treze pacientes tiveram pelo menos 1 dente congenitamente ausente. O número de dentes congenitamente ausentes variou de 1 a 11. Os polimorfismos genéticos rs2234693 e rs9340799 no ESR1 e rs1256049 no ESR2 não foram associados à AD (p > 0,05). Para o polimorfismo genético rs4986938 no ESR2, as distribuições dos genótipos e dos alelos foram estatisticamente diferentes entre os pacientes com e sem AD (p < 0,05). O genótipo CC e o alelo C estavam super-representados nos pacientes com AD. Conclusão: Houve associação entre o polimorfismo genético rs4986938 no ESR2 e a ocorrrência de AD.

Background: Tooth enamel mineralization is assumed to be a target of endogenous estrogen imbalances. Objective: To evaluate the effect of estrogen deficiency during amelogenesis on the mineral composition of dental enamel. Methods: Ten female Wistar Hannover rats were randomly divided into two groups according to the intervention received: ovariectomy surgery (OVX, experimental) and fictitious surgery (SHAM, control). After 21 days, the rats of both groups were euthanized, and the upper incisors were extracted for analysis of the mineral composition by energy-dispersive X-ray fluorescence. The sensitivity of the enamel organ to estrogen was evaluated in both groups by immunohistochemical analysis of the odontogenic region of the lower incisors for the presence of estrogen receptors alpha and beta (ERα and ERβ, respectively) in ameloblasts in the maturation stage. Differences in the mineral composition between groups were compared using Student’s t-test (P < 0.05). Results: No statistically significant difference was detected in the mineral composition between the OVX and SHAM groups (P > 0.05). ERα was immunostained in the ameloblasts of both groups. Conclusion: Although ameloblasts express ERα, estrogen deficiency during amelogenesis did not appear to affect the dental enamel composition in this murine model.

The aim of this study was to evaluate whether genetic polymorphisms in AMELX, AMBN, ENAM, TFIP11, and TUFT1 genes are associated with dental fluorosis (DF). A total of 1,017 children from 2 Brazilian cohorts were evaluated. These populations lived in cities with fluoridation of public water supplies. DF was assessed in erupted permanent teeth using the modified Dean index. The polymorphisms rs946252, rs12640848, rs4694075, rs5997096, and rs4970957 were analyzed by real-time PCR from genomic DNA. Associations between DF, genotype, and allele distribution were evaluated using the χ2 test, with an alpha of 5%. The polymorphisms rs4694075, rs5997096, and rs4970957 in AMBN, TFIP11, and TUFT1 were associated with DF (p < 0.05). In conclusion, enamel matrix genes are associated with DF.