A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Protein kinase D1 overexpression potentiates epidermal growth factor signaling pathway in MCF-7 cells.

BACKGROUND: Protein kinase D1, PKD1, is a serine-threonine kinase implicated in cell proliferation, migration, invasion, and/or apoptosis and its activation by several growth factors sets this enzyme as a key regulator of tumorigenesis and tumor progression. Despite many studies, its role in the regulation of intracellular signaling pathways remains widely disparate and needs to be clarified. METHODS AND RESULTS: By using human breast cancer cells MCF-7, overexpressing or not PKD1, we demonstrated that PKD1 expression level modulated the tumor growth-promoting epidermal growth factor (EGF) signaling pathway. We also showed that EGF acutely stimulated PKD1 phosphorylation with similar time courses both in control and PKD1-overexpressing cells. However, PKD1 overexpression specifically and markedly increased EGF-induced phosphorylation of Akt (onto T308 and S473 residues) and extracellular-regulated protein kinase (ERK1/2). Finally, pharmacological inhibition of PKD1 activity or lowering its expression level using specific siRNAs drastically reduced EGF-stimulated Akt and ERK phosphorylation in PKD1overexpressing cells, but not in control cells. CONCLUSIONS: Overall, these results identified the level of PKD1 expression as a key determinant in the regulation of the EGF signaling pathway highlighting its crucial role in a tumorigenic setting.

Regulatory and academic studies to derive reference values for human health: The case of bisphenol S.

The close structural analogy of bisphenol (BP) S with BPA, a recognized endocrine-disrupting chemical and a substance of very high concern in the European Union, highlights the need to assess the extent of similarities between the two compounds and carefully scrutinize BPS potential toxicity for human health. This analysis aimed to investigate human health toxicity data regarding BPS, to find a point of departure for the derivation of human guidance values. A systematic and transparent methodology was applied to determine whether European or international reference values have been established for BPS. In the absence of such values, the scientific literature on human health effects was evaluated by focusing on human epidemiological and animal experimental studies. The results were analyzed by target organ/system: male and female reproduction, mammary gland, neurobehavior, and metabolism/obesity. Academic experimental studies were analyzed and compared to regulatory data including subchronic studies and an extended one-generation and reproduction study. In contrast to the regulatory studies, which were performed at dose levels in the mg/kg bw/day range, the academic dataset on specific target organs or systems showed adverse effects for BPS at much lower doses (0.5-10 µg/kg bw/day). A large disparity between the lowest-observed-adverse-effect levels (LOAELs) derived from regulatory and academic studies was observed for BPS, as for BPA. Toxicokinetic data on BPS from animal and human studies were also analyzed and showed a 100-fold higher oral bioavailability compared to BPA in a pig model. The similarities and differences between the two bisphenols, in particular the higher bioavailability of BPS in its active (non-conjugated) form and its potential impact on human health, are discussed. Based on the available experimental data, and for a better human protection, we propose to derive human reference values for exposure to BPS from the N(L)OAELs determined in academic studies.

Origins of Alterations to Rankl Null Mutant Mouse Dental Root Development.

The purpose of the present study was to assess the early stages of development of mouse first molar roots in the osteopetrotic context of RANKL invalidation in order to demonstrate that the radicular phenotype observed resulted not only from defective osteoclasts, but also from loss of cell-to-cell communication among dental, periodontium and alveolar bone cells involving RANKL signaling. Two experimental models were used in this study: Rankl mutants with permanent RANKL invalidation, and C57BL/6J mice injected during the first postnatal week with a RANKL neutralizing antibody corresponding to a transient RANKL invalidation. The dento-alveolar complex was systematically analyzed using micro-CT, and histological and immunohistochemical approaches. These experiments showed that the root elongation alterations observed in the Rankl-/- mice were associated with reduced proliferation of the RANK-expressing HERS cells with a significant decrease in proliferating cell nuclear antigen (PCNA) expression and a significant increase in P21 expression. The phenotypic comparison of the adult first molar root at 35 days between permanent and transitory invalidations of RANKL made it possible to demonstrate that alterations in dental root development have at least two origins, one intrinsic and linked to proliferation/differentiation perturbations in dental-root-forming cells, the other extrinsic and corresponding to disturbances of bone cell differentiation/function.

Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations.

BACKGROUND: Amelogenesis imperfecta (AI) is a group of genetic diseases characterised by tooth enamel defects. AI was recently described in patients with familial hypercalciuria and hypomagnesaemia with nephrocalcinosis (FHHNC) caused by CLDN16 mutations. In the kidney, claudin-16 interacts with claudin-19 to control the paracellular passage of calcium and magnesium. FHHNC can be linked to mutations in both genes. Claudin-16 was shown to be expressed during amelogenesis; however, no data are available on claudin-19. Moreover, the enamel phenotype of patients with CLDN19 mutations has never been described. In this study, we describe the clinical and genetic features of nine patients with FHHNC carrying CLDN19 mutations and the claudin-19 expression profile in rat ameloblasts. METHODS: Six FHHNC Brazilian patients were subjected to mutational analysis. Three additional French patients were recruited for orodental characterisation. The expression profile of claudin-19 was evaluated by RT-qPCR and immunofluorescence using enamel epithelium from rat incisors. RESULTS: All patients presented AI at different degrees of severity. Two new likely pathogenic variations in CLDN19 were found: p.Arg200Gln and p.Leu90Arg. RT-qPCR revealed low Cldn19 expression in ameloblasts. Confocal analysis indicated that claudin-19 was immunolocalised at the distal poles of secretory and maturing ameloblasts. CONCLUSIONS: For the first time, it was demonstrated that AI is associated with FHHNC in patients carrying CLDN19 mutations. The data suggest claudin-19 as an additional determinant in enamel formation. Indeed, the coexistence of hypoplastic and hypomineralised AI in the patients was consistent with claudin-19 expression in both secretory and maturation stages. Additional indirect systemic effects cannot be excluded.

Distorted Patterns of Dentinogenesis and Eruption in Msx2 Null Mutants: Involvement of Sost/Sclerostin.

The muscle segment homeogenes Msx1 and Msx2 play a major role in tooth and bone formation. Periodontal osteoclast impairment also occurs in Msx2 null mutant mice, which is restored by overexpression of the receptor activator of NF-κB targeted in osteoclast lineage. Here, we investigated the role of Msx2 in dentinogenesis. Experiments were performed on Msx2(-/-) mice and the MDPC-23 odontoblastic cell line. After Msx2 gene silencing, real-time quantitative RT-PCR data showed significant overexpression of Runx2, Bglap, Dspp, and Alpl. Of three inhibitors of Wnt/ß-catenin signaling (Dkk1, SostDc1, and Sost/Sclerostin), only Sost was expressed in postnatal teeth and overexpressed in Msx2(-/-) tooth samples. Initial crown dentin formation-primary dentinogenesis-occurred fairly normally in Msx2(-/-) teeth, albeit with distorted cusp patterns. Later stages of tooth development were characterized by a deviation from secondary toward tertiary dentinogenesis with osteodentin formation and impaired dentin deposition leading to limited root elongation. In Msx2(-/-)/receptor activator of NF-κB-transgenic double mutants, the dentin phenotype, notably in the roots, was rescued and sclerostin levels were normalized. These data suggest that Msx2 may act indirectly on dentinogenesis by controlling osteoclast activity and the signaling network related to eruption, supporting and further extending the concept that Msx2 controls formation of mineralized tissues by inhibition of the Wnt/ß-catenin pathway; Sost in dentin and Dkk1 in bone, as previously demonstrated.

[Enamel: a unique self-assembling in mineral world]. / L'émail - Un autoassemblage unique dans le monde du minéral.

Enamel is a unique tissue in vertebrates, acellular, formed on a labile scaffolding matrix and hypermineralized. The ameloblasts are epithelial cells in charge of amelogenesis. They secrete a number of matrix proteins degraded by enzymes during enamel mineralization. This ordered cellular and extracellular events imply that any genetic or environmental perturbation will produce indelible and recognizable defects. The specificity of defects will indicate the affected cellular process. Thus, depending on the specificity of alterations, the teratogenic event can be retrospectively established. Advances in the field allow to use enamel defects as diagnostic tools for molecular disorders. The multifunctionality of enamel peptides is presently identified from their chemical roles in mineralization to cell signaling, constituting a source of concrete innovations in regenerative medicine.

Enamel defects reflect perinatal exposure to bisphenol A.

Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), are environmental ubiquitous pollutants and associated with a growing health concern. Anecdotally, molar incisor hypomineralization (MIH) is increasing concurrently with EDC-related conditions, which has led us to investigate the effect of BPA on amelogenesis. Rats were exposed daily to BPA from conception until day 30 or 100. At day 30, BPA-affected enamel exhibited hypomineralization similar to human MIH. Scanning electron microscopy and elemental analysis revealed an abnormal accumulation of organic material in erupted enamel. BPA-affected enamel had an abnormal accumulation of exogenous albumin in the maturation stage. Quantitative real-time PCR, Western blotting, and luciferase reporter assays revealed increased expression of enamelin but decreased expression of kallikrein 4 (protease essential for removing enamel proteins) via transcriptional regulation. Data suggest that BPA exerts its effects on amelogenesis by disrupting normal protein removal from the enamel matrix. Interestingly, in 100-day-old rats, erupting incisor enamel was normal, suggesting amelogenesis is only sensitive to MIH-causing agents during a specific time window during development (as reported for human MIH). The present work documents the first experimental model that replicates MIH and presents BPA as a potential causative agent of MIH. Because human enamel defects are irreversible, MIH may provide an easily accessible marker for reporting early EDC exposure in humans.

Enamel hypomineralization due to endocrine disruptors.

There has been increasing concerns over last 20 years about the potential adverse effects of endocrine disruptors (EDs). Bisphenol A (BPA), genistein (G) and vinclozolin (V) are three widely used EDs having similar effects. Tooth enamel has recently been found to be an additional target of BPA that may be a causal agent of molar incisor hypomineralization (MIH). However, populations are exposed to many diverse EDs simultaneously. The purpose of this study was therefore to assess the effects of the combination of G, V and BPA on tooth enamel. Rats were exposed daily in utero and after birth to low doses of EDs mimicking human exposure during the critical fetal and suckling periods when amelogenesis takes place. The proportion of rats presenting opaque areas of enamel hypomineralization was higher when rats were treated with BPA alone than with a combination of EDs. The levels of mRNAs encoding the main enamel proteins varied with BPA treatment alone and did not differ significantly between controls and combined treatment groups. In vitro, rat ameloblastic HAT-7 cells were treated with the three EDs. BPA induced enamelin and reduced klk4 expression, G had no such effects and V reduced enamelin expression. These findings suggest that combinations of EDs may affect enamel less severely than BPA alone, and indicate that enamel hypomineralization may differ according to the characteristics of the ED exposure.

Analysis of Resin-Based Dental Materials' Composition Depending on Their Clinical Applications.

The objective of this study was to detail the monomer composition of resin-based dental materials sold in the market in 2023 and to evaluate the proportion of bisphenol A (BPA)-derivatives in relation to their applications. A search on manufacturers' websites was performed to reference resin-based dental materials currently on the European market (including the European Union (EU) and United Kingdom (UK). Their monomer composition was determined using material-safety data sheets and was completed by a search on the PubMed database. Among the 543 material compositions exploitable, 382 (70.3%) contained BPA derivatives. Among them, 56.2% contained BisGMA and 28% BisEMA, the most frequently reported. A total of 59 monomers, of which six were BPA derivatives, were found. In total, 309 materials (56.9%) contained UDMA and 292 (53.8%) TEGDMA. Less than one third of materials identified contained no BPA derivatives. These proportions vary a lot depending on their applications, with materials dedicated to the dental care of young populations containing the highest proportions of BPA-derivative monomers. The long-term effects on human health of the different monomers identified including BPA-derivative monomers is a source of concern. For children and pregnant or lactating women arises the question of whether to take a precautionary principle and avoid the use of resin-based dental materials likely to release BPA by opting for alternative materials.

MIH and Dental Caries in Children: A Systematic Review and Meta-Analysis.

(1) Background: Molar-incisor hypomineralization (MIH) is a clinical condition affecting permanent teeth in children, with a documented rising trend in the last two decades. The aim of the present study was to analyze and synthesize the available evidence on caries experience (dmft/DMFT) and MIH in children. (2) Methods: A systematic review and meta-analysis were conducted according to the PRISMA statement. (3) Results: 59 papers published between 2007 and 2022 were included in the qualitative synthesis and 18 in the meta-analysis. The total sample of subjects was 17,717 (mean: 896), of which 2378 (13.4%) had MIH (mean: 119), with a girl/boy ratio of 1:1. The mean age of the enrolled participants was 8.6 (age range 7-10 years). Meta-analysis showed that MIH has a positive correlation with both dmft (effect size of 0.67, 95% CI [0.15, 1.19]) and DMFT (effect size of 0.56, 95% CI [0.41, 0.72]); (4) Conclusions: Children with MIH should be diagnosed correctly and on time. Treatment and management options for moderate and severe forms of MIH should consider prognosis based on known risk factors, and secondary and tertiary prevention policies should also consider the multifactorial nature of caries etiology.

Multi-scale characterization of Developmental Defects of Enamel and their clinical significance for diagnosis and treatment.

Developmental Defects of Enamel (DDE) such as Dental Fluorosis (DF) and Molar Incisor Hypomineralization (MIH) are a major public health problem. Their clinical aspects are extremely variable, challenging their early and specific diagnosis and hindering progresses in restorative treatments. Here, a combination of macro-, micro- and nano-scale structural and chemical methods, including, among others, Atom Probe Tomography recently applied on tooth enamel, were used to study and compare MIH, DF and healthy teeth from 89 patients. Globally, we show that DF is characterized by an homogenous loss of mineral content and crystallinity mainly disrupting outside layer of enamel, whereas MIH is associated with localized defects in the depth of enamel where crystalline mineral particles are embedded in an organic phase. Only minor differences in elemental composition of the mineral phase could be detected at the nanoscale such as increased F and Fe content in both severe DDE. We demonstrate that an improved digital color measurement of clinical relevance can discriminate between DF and MIH lesions, both in mild and severe forms. Such discriminating ability was discussed in the light of enamel composition and structure, especially its microstructure, organics presence and metal content (Fe, Zn). Our results offer additional insights on DDE characterization and pathogenesis, highlight the potentiality of colorimetric measurements in their clinical diagnosis and provide leads to improve the performance of minimally invasive restorative strategies. STATEMENT OF SIGNIFICANCE: Developmental Defects of Enamel (DDE) are associated to caries and tooth loose affecting billions of people worldwide. Their precise characterization for adapted minimally invasive care with optimized materials is highly expected. Here In this study, first we propose the use of color parameters measured by a spectrophotometer as a means of differential clinical diagnosis. Second, we have used state-of-the-art techniques to systematically characterize the structure, chemical composition and mechanical optical properties of dental enamel teeth affected by two major DDE, Dental Fluorosis (DF) or Molar Incisor Hypomineralization (MIH). We evidence specific enamel structural and optical features for DF and MIH while chemical modifications of the mineral nanocrystals were mostly correlated with lesion severity. Our results pave the way of the concept of personalized dentistry. In the light of our results, we propose a new means of clinical diagnosis for an adapted and improved restoration protocol for these patients.

Fluoride Intake Through Dental Care Products: A Systematic Review.

Fluoride (F) is added to many dental care products as well as in drinking water to prevent dental decay. However, recent data associating exposure to F with some developmental defects with consequences in many organs raise concerns about its daily use for dental care. This systematic review aimed to evaluate the contribution of dental care products with regard to overall F intake through drinking water and diet with measurements of F excretion in urine used as a suitable biomarker. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using keywords related to chronic exposure to F in the human population with measurements of F levels in body fluids, 1,273 papers published between 1995 and 2021 were screened, and 28 papers were finally included for data extraction concerning daily F intake. The contribution of dental care products, essentially by toothbrushing with kinds of toothpaste containing F, was 38% in the mean regardless of the F concentrations in drinking water. There was no correlation between F intake through toothpaste and age, nor with F levels in water ranging from 0.3 to 1.5 mg/L. There was no correlation between F intake and urinary F excretion levels despite an increase in its content in urine within hours following exposure to dental care products (toothpastes, varnishes, or other dental care products). The consequences of exposure to F on health are discussed in the recent context of its suspected toxicity reported in the literature. The conclusions of the review aim to provide objective messages to patients and dental professionals worried about the use of F-containing materials or products to prevent initial caries or hypomineralized enamel lesions, especially for young children.

Use of Dental Defects Associated with Low-Dose di(2-Ethylhexyl)Phthalate as an Early Marker of Exposure to Environmental Toxicants.

BACKGROUND: Markers of exposure to environmental toxicants are urgently needed. Tooth enamel, with its unique properties, is able to record certain environmental conditions during its formation. Enamel formation and quality are dependent on hormonal regulation and environmental conditions, including exposure to endocrine disrupting chemicals (EDCs). Among EDCs, phthalates such as di-(2-ethylhexyl) phthalate (DEHP) raise concerns about their contribution to various pathologies, including those of mineralized tissues. OBJECTIVES: The effects of exposure to low-doses of DEHP on the continually growing incisors were analyzed in mouse males and females. METHODS: Adult male and female C57BL/6J mice were exposed daily to 0.5, 5, and 50µg/kg per day DEHP for 12 wk and their incisors clinically examined. Incisors of males were further analyzed by scanning electron microscopy (SEM), micro X-ray computed tomography (micro-computed tomography; µCT), and nanoindentation for the enamel, histology and real-time quantitative polymerase chain reaction (RT-qPCR) for the dental epithelium. RESULTS: Clinical macroscopic observations of incisors showed various dose-dependent dental lesions such as opacities, scratches, and enamel breakdown in 30.5% of males (10 of 34 total incisors across three independent experiments), and 15.6% of females (7 of 46 incisors) at the highest dose, among which 18.1% (6 of 34 total incisors across three independent experiments) and 8.9% (4 of 46 incisors), respectively, had broken incisors. SEM showed an altered enamel surface and ultrastructure in DEHP-exposed male mice. Further characterization of the enamel defects in males by µCT showed a lower mineral density than controls, and nanoindentation showed a lower enamel hardness during all stages of enamel mineralization, with more pronounced alterations in the external part of the enamel. A delay in enamel mineralization was shown by several approaches (µCT, histology, and RT-qPCR). DISCUSSION: We conclude that DEHP disrupted enamel development in mice by directly acting on dental cells with higher prevalence and severity in males than in females. The time window of DEHP effects on mouse tooth development led to typical alterations of structural, biochemical, and mechanical properties of enamel comparable to other EDCs, such as bisphenol A. The future characterization of dental defects in humans and animals due to environmental toxicants might be helpful in proposing them as early markers of exposure to such molecules. https://doi.org/10.1289/EHP10208.

Transcriptional regulation of MSX1 natural antisense transcript.

Msx homeogenes play an important role in the epithelial-mesenchymal interactions leading development. Msx1 is relevant for dental and craniofacial morphogenesis, as suggested by phenotypes of Msx1 mutations in human and Msx1 KO mice. Our group showed that Msx1 gene expression can be regulated by a bidirectional transcription generating long noncoding antisense (AS) RNA the expression which is linked to the Msx1 sense (S) RNA level. Thus, the aim of the present study was to analyze the synthesis of Msx1 (AS) RNA. In vivo Msx1 AS expression analysis showed that (i) the putative promoter sequence but not the transcribed sequence was important and necessary for its expression, (ii) 2 different areas of alveolar bone can be distinguished depending on Msx1 S and AS expression, and (iii) Msx1 presence was necessary for Msx1 AS RNA full expression. In silico analysis of the Msx1 AS putative promoter region showed the presence of 4 Msx response elements possibly involved in Msx1 regulation. Msx1 constitutes an example of a bidirectionally transcribed gene giving rise to an S/AS RNA pair included in the big and growing family of AS noncoding RNAs. Our results contribute to defining a link between Msx1 S and AS RNAs resulting in a fine-tuned regulatory loop of Msx1 expression. The significance of this finding is that disturbance of the balance between Msx1 S and AS RNA status may be associated with tooth agenesis and bone loss.

The Role of GH/IGF Axis in Dento-Alveolar Complex from Development to Aging and Therapeutics: A Narrative Review.

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones.

[Oral cavity as a target and a marker of environmental exposures: developmental dental defects]. / La sphère orale, cible et marqueur de l'exposition environnementale - I. Défauts du développement dentaire.

The oral cavity is one of the main route for environmental contaminations associated to many chronic diseases (cancers, fertility and behavior disorders for example) via alimentation, medications and respiration. These environmental factors including, among others, endocrine disruptors and excessive fluoride can disrupt dental development and thus generate irreversible enamel defects. These defects are then treated with materials that may release molecules capable of generating these defects, leading to a vicious circle, particularly in pregnant women and young children. The present paper aims to review the state of knowledge, questions and controversies on common environmental factors in contact with the oral cavity. It also reviews their mechanisms of action and the mediators involved in enamel pathologies associated with environmental conditions. Dental tissues can not only be targeted by environmental factors but can also serve as early and easily accessible markers of exposure to these agents. Understanding and characterizing the environmental impact in the oral cavity will help to prevent multiple diseases, oral and distant, whose link with oral homeostasis is just being explored.

TITLE: La sphère orale, cible et marqueur de l'exposition environnementale - I. Défauts du développement dentaire. ABSTRACT: La cavité buccale est l'une des voies majeures des contaminations environnementales connues pour être impliquées dans de nombreuses pathologies chroniques (cancers, troubles de la fertilité et du comportement) via l'alimentation, les médications ou même la respiration. Ces facteurs environnementaux incluant, entre autres, des perturbateurs endocriniens et le fluor en excès, peuvent perturber le développement dentaire et ainsi générer des défauts irréversibles de l'émail. Ces défauts sont alors traités avec des matériaux dont certains libèrent des molécules capables à leur tour de générer ces défauts, conduisant à un cercle vicieux, notamment chez la femme enceinte et le jeune enfant. Cette synthèse fait le point sur l'état des connaissances, les questions et controverses sur les facteurs environnementaux courants susceptibles d'entrer en contact avec la sphère orale, leurs mécanismes d'actions et les médiateurs impliqués dans les pathologies de l'émail associées aux conditions environnementales.

[Oral cavity as a target and a marker of environmental exposures: diseases diagnosed during adulthood]. / La sphère orale, cible et marqueur de l'exposition environnementale - II. Maladies diagnostiquées chez l'adulte.

The oral cavity is one of the main route for environmental contaminations associated to many chronic diseases via alimentation, medications and respiration. Other factors may also impact the oral environment, some of them are endogenous, like microbiota, hormones and saliva, and others are exogenous, like dental materials and pathogens.

TITLE: La sphère orale, cible et marqueur de l'exposition environnementale - II. Maladies diagnostiquées chez l'adulte. ABSTRACT: La cavité buccale est l'une des voies majeures des contaminations environnementales connues pour être impliquées dans de nombreuses maladies chroniques via l'alimentation, les médications ou même la respiration. D'autres facteurs peuvent également influer sur l'environnement oral, certains endogènes, comme le microbiote, les variations hormonales, la salive, d'autres exogènes, comme les biomatériaux dentaires et les agents pathogènes. Cette synthèse fait le point sur l'état des connaissances, les questions et controverses sur les facteurs environnementaux courants au contact de la sphère orale impliqués dans les maladies de la cavité orale diagnostiquées chez l'adulte telles que les cancers des voies aéro-digestives supérieures, les ostéonécroses des mâchoires, et les parodontites, ces dernières pouvant d'ailleurs être directement liées à des pathologies systémiques comme les accidents vasculaires cérébraux, la maladie d'Alzheimer ou la maladie de Crohn notamment. La caractérisation des impacts environnementaux sur le microbiote oral, la salive, l'émail dentaire peut servir de marqueur pronostic précoce des maladies diagnostiquées ultérieurement, en lien avec ces expositions.

Primary Retention of Molars and RANKL Signaling Alteration during Craniofacial Growth.

The primary retention of molars observed in clinic corresponds to a still-unexplained absence of molar eruption despite the presence of an eruption pathway, resembling the experimental transient inhibition of RANKL signaling in mice. The aim of the present study was to confront the hypothesis according to which the primary retention of molars is associated with transitory perturbations to RANKL signaling during growth as part of a wider craniofacial skeleton pattern. The experimental strategy was based on combining a clinical study and an animal study corresponding to the characterization of the craniofacial phenotypes of patients with primary retention of molars and analyses in mice of the consequences of transient inhibition of RANKL signaling on molar eruption and craniofacial growth. The clinical study validated the existence of a particular craniofacial phenotype in patients with primary retention of molars: a retromandibular skeletal class II typology with reduced mandibular dimensions which manifests itself at the dental level by a class II/2 with palatoversion of the upper incisors and anterior overbite. The animal study demonstrated that transient invalidation of RANKL signaling had an impact on the molar eruption process, the severity of which was dependent on the period of inhibition and was associated with a reduction in two craniofacial morphometric parameters: total skull length and craniofacial vault length. In conclusion, primary retention of molars may be proposed as part of the craniofacial skeleton phenotype associated with a transitory alteration in RANKL signaling during growth.

Autoregulatory loop of Msx1 expression involving its antisense transcripts.

The Msx1 homeogene plays an important role in epithelial-mesenchymal interactions leading organogenesis. Msx1 gene is submitted to bidirectional transcription generating a long non-coding antisense (AS) RNA potentially involved in Msx1 expression regulation. RT-Q-PCR and RNA-FISH studies indicated that transient overexpression of the Msx1 AS transcript in 705IC5 mouse odontoblasts decreased the abundance of endogenous Msx1 S mRNA at the post-transcriptional level. Conversely, Msx1 overexpression increased the AS RNA level probably by activating AS transcription. In vivo mapping by RT-PCR evidenced both Msx1 RNAs in all adult mouse tissues tested raising the issue of Msx1 function during adulthood. The expression patterns of the two RNAs were similar, confirming the tight S/AS relationship. In particular, both Msx1 mRNAs and Msx1 protein were similarly distributed in eyes, and were found in regions with a common ectodermic origin and in cells potentially involved in regeneration. In conclusion, we report that Msx1 S RNA is negatively controlled by its AS RNA at a post-transcriptional level, and that the AS RNA is retrocontrolled positively by Msx1. The tight link between Msx1 S and AS RNAs constitutes a regulatory loop resulting in a fine-tuned expression of Msx1 which appears to be significant for adult homeostasis.