Exposure of pregnant rats to stress and/or sertraline: Side effects on maternal health and neurobehavioral development of male offspring.

AIMS: Sertraline (SE) is one of the most prescribed medications for treating gestational depression, anxiety and stress. However, little is known about its effects on nervous-system development in offspring. Therefore, this study investigated the somatic, reflex and neurobehavioral development of rats exposed to SE during pregnancy, associated or not with stress. MAIN METHODS: Pregnant Wistar rats were assigned to the following groups (n = 10-8 rats/group): CO - control animals administered filtered water by gavage; SE - animals administered 20 mg/kg SE by gavage; ST - animals subjected to restraining stress and administered filtered water; ST/SE - animals subjected to restraining stress and administered 20 mg/kg SE. The treatment was administered between gestational days (GD) 13 to 20. Somatic and reflex developments were investigated in the male offspring from postnatal day (PND) 1 to 21. The elevated plus maze was performed on PND 25 and 80. The open field and light/dark box test were performed on PND 90 and 100, respectively. KEY FINDINGS: Body weight reduction and vaginal bleeding were observed in pregnant rats exposed to SE. The male offspring of the SE group showed delay in incisor eruption, fur development and negative geotaxis. In addition, the SE group was less exploratory (anxious personality) compared to the CO and ST groups. SIGNIFICANCE: The results obtained in the present study demonstrate that sertraline not only impairs maternal health, but also, associated or not with stress, can compromise the somatic, reflex and neurobehavioral development of male rats.

Dexamethasone inhibits BMP7-induced osteogenic differentiation in rat dental follicle cells via the PI3K/AKT/GSK-3ß/ß-catenin pathway.

Impacted third molars are commonly seen in teenagers and young adults and can cause considerable suffering. Preventing eruption of the third molars can reduce pain at the source. Our previous study has shown that dexamethasone (DEX) at a certain concentration can prevent the eruption of third molars without damaging alveolar bone in Sprague-Dawley (SD) rats, but the relevant molecular mechanisms need to be explored. This study aimed to explore the effects of high concentrations of DEX on osteogenic signaling pathways, including BMP/Smad and Wnt/ß-catenin pathways, in rat dental follicle cells (rDFCs) and to elucidate the possible mechanisms. The results showed that BMP7 induced osteogenic differentiation by increasing the activity of ALP and the protein levels of OPN in rDFCs. DEX decreased endogenous BMP7 and phosphorylated Smad1/5/8 expression as well as BMP7-induced osteogenic differentiation. DEX also reduced the mRNA and protein levels of ß-catenin by enhancing the expression of GSK-3ß. In addition, regardless of DEX intervention, overexpression of BMP7 promoted the expression of ß-catenin, while knockdown of BMP7 attenuated it. Further investigation revealed that overexpression of BMP7 attenuated the DEX-mediated inhibition of AKT and GSK-3ß phosphorylation, but knockdown of BMP7 exerted the opposite effects. This study suggests that high concentrations of DEX may inhibit the expression of ß-catenin via the PI3K/AKT/GSK-3ß pathway in a manner mediated by BMP7. The findings further illustrate the possible molecular mechanisms by which DEX prevents tooth development.

IL-1α Regulates Osteogenesis and Osteoclastic Activity of Dental Follicle Cells Through JNK and p38 MAPK Pathways.

Inflammatory cytokines such as interleukin-1α (IL-1α) are increased in teeth with periapical lesions. Primary teeth with periapical lesions have a propensity for accelerated eruption of the successors. In this study, we asked whether increased levels of IL-1α in the dental follicle (DF) occurring as the result of periapical lesions promote tooth eruption, possibly due to enhanced osteoclastic remodeling of DF cells (DFCs). To this end, we studied the effect and possible mechanism of IL-1α on osteogenic differentiation, osteoclastogenic activity, and matrix remodeling of DFCs. Results demonstrated that DFCs cultured with IL-1α exhibited reduced osteogenic capacity, higher osteoclastogenic activity, and stronger invasive ability. Phosphorylation of JNK and p38 was upregulated, and pretreatment with SB203580 and SP600125 reversed the effect of IL-1α on DFCs. Neonatal rats subjected to subcutaneous injection of an IL-1 receptor antagonist exhibited a reduced number in activated osteoclasts, increased expression of alkaline phosphatase and osteopontin, and delayed tooth eruption. These data support our hypothesis that increased IL-1α cytokine levels as they occur during periodontal and periapical inflammation cause osteoclastic remodeling of the alveolar socket as a requirement for tooth eruption and thus may indirectly promote the vertical eruption of teeth toward the occlusal plane.

Antiretroviral treatment and its impact on oral health outcomes in 5 to 7 year old Ugandan children: A 6 year follow-up visit from the ANRS 12174 randomized trial.

BACKGROUND: Antiretroviral therapy for HIV in sub-Saharan Africa has transformed the highly infectious virus to a stable chronic condition, with the advent of Highly active antiretroviral therapy (HAART). The longterm effects of HAART on the oral health of children are understudied. OBJECTIVE: To compare the effect of lopinavir-ritonavir and lamivudine on oral health indicators (dental caries, gingivitis, tooth eruption, and oral health related quality of life) in 5 to 7 year old HIV-1 exposed uninfected children from the ANRS 12174 trial. METHODS: This study used data collected in 2017 among children aged 5 to 7 years from the Ugandan site of the ANRS 12174 randomized trial (ClinicalTrials.gov no: NCT00640263) implemented between 2009 and 2012 in Mbale district, Eastern Uganda. The intervention was lopinavir-ritonavir or lamuvudine treatment to prevent vertical HIV-1 transmission. One hundred thirty-seven and 139 children were randomized to receive lopinavir-ritonavir or lamivudine treatment at day 7 postpartum to compare efficacy of prevention of vertical HIV-1 transmission. At follow up, the children underwent oral examination using the World Health Organization methods for field conditions. The oral health related quality of life was assessed using the early childhood oral health impact scale. Negative binomial and logistic regression were used for the analysis of data. MAIN OUTCOME MEASURES: Dental caries, gingivitis, tooth eruption, and oral health related quality of life) in 5 to 7 year old HIV-1 exposed uninfected children. RESULTS: The prevalence of dental caries was 48% in the study sample: 49% in the lopinavir-ritonavir arm and 48% in the lamivudine treatment group. The corresponding mean decayed missing filled teeth and standard deviation was 1.7 (2.4) and 2.3 (3.7) The mean number (standard deviation) of erupted permanent teeth was 3.8 (3.7) and 4.6 (3.9) teeth in the lopinavir- and lamivudine group, respectively. The prevalence of reported impacts on oral health was 7% in the lopinavir-ritonavir and 18% in the lamivudine group. Gingivitis had a prevalence of 7% in the lopinavir-ritonavir and 14% lamivudine treatment group. The regression analysis revealed 70% less reported impacts on oral health in lopinavir-ritonavir group than the lamivudine treatment group with an incidence rate ratio of 0.3 (95% confidence interval: 0.1-0.9). CONCLUSIONS: HIV exposed uninfected infants in the lopinavir-ritonavir group reported less impacts on oral health than the lamivudine treatment group. Dental caries, gingivitis, and tooth eruption were not significantly affected by the treatment lopinavir-ritonavir or lamivudine. TRIAL REGISTRATION CLINICALTRIALS. GOV IDENTIFIER: NCT00640263.

Bisphosphonate Therapy and Tooth Development in Children and Adolescents with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a heterogeneous connective tissue disorder characterized by repeated fractures and skeletal disorders. At present, bisphosphonate (BP) therapy is the gold standard for OI treatment. The present retrospective study evaluated the effect of BP therapy on tooth development and eruption of permanent teeth in a cohort of children receiving pamidronate. Three groups were studied: patients with OI who were treated with BPs (n = 45), patients with OI who were not treated with BPs (n = 117), and age- and gender-matched healthy controls (n = 121). Dental age, dental maturity, and tooth eruption were assessed on panoramic radiographs using the methods of Demirjian et al. (Hum Biol 45(2):211-227, 1973) and Haavikko (Suom Hammaslaak Toim 66(3):103-170, 1970) and were evaluated using the t-test, Chi-square test, and the Mann-Whitney U test. Dental age in the study group was significantly (p < 0.05) lower than chronological age compared with both control groups. Dental maturity and the eruption of permanent teeth were also significantly (p < 0.05) delayed in the study group in relation to the two control groups. The dental age was significantly lower (p < 0.001) in patients with OI type III treated with BPs compared with healthy controls and the dental maturation was significantly delayed in patients with OI type IV treated with BPs compared with those not treated. In conclusion, BP therapy in OI patients seems to lower the dental age, delay the dental maturity, and tooth eruption. BP administration before 2 years of age might be a contributing factor.

Isorhamnetin 3-O-neohesperidoside promotes the resorption of crown-covered bone during tooth eruption by osteoclastogenesis.

Delayed resorption of crown-covered bone is a critical cause of delayed tooth eruption. Traditional herbal medicines may be good auxiliary treatments to promote the resorption of crown-covered bone. This study was carried out to analyse the effect of isorhamnetin 3-O-neohesperidoside on receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis in vitro and resorption of the crown-covered bone of the lower first molars in mice in vivo. Isorhamnetin 3-O-neohesperidoside promoted osteoclastogenesis and the bone resorption of mouse bone marrow macrophages (BMMs) and upregulated mRNA expression of the osteoclast-specific genes cathepsin K (CTSK), vacuolar-type H + -ATPase d2(V-ATPase d2), tartrate resistant acid phosphatase (TRAP) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). NFATc1, p38 and AKT signalling was obviously activated by isorhamnetin 3-O-neohesperidoside in osteoclastogenesis. Isorhamnetin 3-O-neohesperidoside aggravated resorption of crown-covered bone in vivo. In brief, isorhamnetin 3-O-neohesperidoside might be a candidate adjuvant therapy for delayed intraosseous eruption.

Effects of bleomycin on tooth eruption: a novel potential application.

There are many kinds of potentially undesirable teeth. At present, surgical extraction is the most efficient way to eliminate these teeth, but it's very complex and invasive. In this study, we investigated the effects of bleomycin (BLM) on dental follicle and tooth eruption as a potential conservative therapy for undesirable teeth. Our data showed that local injection of 0.2 U/kg BLM had no significant effects on tooth eruption compared to the control group in Wistar rats. With higher dose of BLM (0.5 or 2 U/kg), the eruption of treated teeth was interrupted and their root formation failed until 4 weeks postnatal without significant systemic toxicity. Additionally, those effects were not depending on the toxicity of overdose evidenced by TUNEL assay. In summary, injecting BLM into dental follicle at an early stage could interrupt tooth development and eruption, and may prevent the potentially clinical problems resulting from undesirable teeth instead of surgical removal.

Biological Effects of Anti-RANKL Antibody and Zoledronic Acid on Growth and Tooth Eruption in Growing Mice.

The anti-bone resorptive drugs denosumab, an anti-human-RANKL antibody, and zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, have recently been applied for treatment of pediatric patients with bone diseases, though details regarding their effects in growing children have yet to be fully elucidated. In the present study, we administered these anti-resorptive drugs to mice from the age of 1 week and continued once-weekly injections for a total of 7 times. Mice that received the anti-RANKL antibody displayed normal growth and tooth eruption, though osteopetrotic bone volume gain in long and alveolar bones was noted, while there were nearly no osteoclasts and a normal of number osteoblasts observed. In contrast, ZOL significantly delayed body growth, tooth root formation, and tooth eruption, with increased osteoclast and decreased osteoblast numbers. These findings suggest regulation of tooth eruption via osteoblast differentiation by some types of anti-resorptive drugs.

[Effects of post-natal inhibition of RANKL on molar eruption and root formation in C57BL/6 mice]. / Effets de l'inhibition post-natale de RANKL sur l'éruption et la formation radiculaire des molaires de souris C57BL/6.

INTRODUCTION: Recent observations performed in the orthodontic department of La Pitié-Salpêtrière hospital in Paris reported an increase of non-familial eruption defects of permanent molars. Our recent data have evidenced the involvement of osteoclasts (OC) in both the eruption and the dental retention processes through the RANKL/RANK/OPG signaling pathway. These facts are at the origin of the hypothesis of the existence of an environmental etiology for those eruption defects that would correspond to the perturbation of cellular autocrine/paracrine signaling pathways as the RANKL/ RANK/OPG. MATERIALS AND METHODS: C57BL/6 mice were submitted to repeated injections with anti-RANKL neutralizing antibody during the nine days following birth. A phenotypic comparison with transgenic mice overexpressing RANK was performed for the functional characterization of the RANKL/RANK/OPG pathway. The dento-alveolar complex was analyzed using micro-CT for bone density and Masson's trichrome staining for histological examination. RESULTS: The RANKL transient invalidation of RANKL stopped the molar root development and tooth eruption contrary to transgenic mice overexpressing RANK. The recruitment and the OC activity were strongly impacted. DISCUSSION: This research is of direct clinical interest in understanding the pathology of eruption as indirect in establishing orthodontic treatment protocols for particular cases.

The toxicological analysis of Cu, Mn and Zn as elemental impurities in pharmaceutical herbal products for teething available in pharmacies in Poland.

The monitoring of elemental impurities (EIs) in pharmaceutical materials is often not adequately treated, although it is a very important topic because the directive ICH Q3D requires a wide range of elements, often at low concentrations, to be monitored. This article describes the quantitative toxicological analysis of copper, manganese and zinc as EIs in the pharmaceutical gels for teething containing herbs available in Poland. The levels of EIs were measured to evaluate whether the intake of these metals through the gels was within recommended levels. The flame absorption spectrometry (FAAS) following microwave induced digestion (concentrated nitric acid) was applied to determine the levels of Cu, Mn and Zn in the products. This article was motivated especially by the facts that: (i) herbs can be a potential source of EIs; (ii) Cu, Mn and Zn are essential trace elements in the infancy period; (iii) there is a general lack of data around the risk assessment associated with exposure to these EIs in this kind of pharmaceutical. Our safety assessment is based on triple approach including: (1) profile of EIs in gels; (2) the actual amount of EIs in the appropriate amount of gel applied with a single administration (one drop) and (3) the daily exposure of EIs in analysed teething pharmaceuticals due to the maximum daily dose. Our results show that all EI levels meet the standards of directive ICH Q3D. It can be concluded that all of the teething gels investigated, based on herbs, available in Polish pharmacies do not represents a health hazard to babies.

Toxicological analysis of Pb and Cd by ET AAS in local anaesthetics for teething (teething gels) based on herbs available in Polish pharmacies.

Studies related to the toxicological analyses of metallic impurities in pharmaceuticals (drugs) is an important issue but there is a lack of refereed literature around the safety of teething remedies from herbal origin related to toxic metals impurities. In this article, the levels of Pb and Cd were measured in samples of local anaesthetics for teething (gels) based on herbs. This article was motivated by the fact that Pb and Cd are relevant toxic metals that may cause an adverse effect in babies even at low levels. Additional justifications were (1) the insufficient control of metal impurities in teething gels, (2) the lack of sufficient validation steps and (3) the inadequate sensitivity of applied analytical techniques. The aim of this article was a qualitative and quantitative analysis of Pb and Cd in the most popular and available local anaesthetic for teething (teething gels) based on herbs (n = 5) available in Poland. Metals were determined by ET AAS (electrothermal atomization atomic absorption spectrometry), after digestion in a microwave unit using concentrated nitric acid. It was observed that all samples contained Pb and Cd. The levels of Pb and Cd as impurities (independently of the producer and declared composition) are similar. The concentrations of Pb and Cd, at ng/day levels, to which the user is exposed at daily doses meet the standards of the directive ICH Q3D.

What are pharmacists recommending for infant teething treatment?

OBJECTIVES: In 2011, the Food and Drug Administration issued a warning to avoid the use of any benzocaine-containing products for infant teething treatment owing to a risk of methemoglobinemia. Several benzocaine-containing products targeted for infant teething are currently available over the counter. Pharmacists are commonly asked for medical advice in the community, and there is no current literature evaluating what pharmacists are recommending for infant teething. The objectives of this study were to evaluate what pharmacists are currently recommending for infant teething treatment and assess what percentage would inappropriately recommend a benzocaine-containing product. METHODS: From March to June 2016, a 16-item in-person paper-and-pen questionnaire was administered to 200 pharmacists in the San Francisco Bay area at 115 outpatient over-the-counter pharmacies. Questions included demographic information, work and educational background, infant teething recommendations, and preferred educational resources. RESULTS: The overall response rate was 94.3%. One-half (50.5%) of the pharmacists' approaches to infant teething treatment was to recommend a nondrug option first and then, if needed, an over-the-counter medication. A majority (63.0%) of the pharmacists surveyed would inappropriately select a benzocaine-containing product. CONCLUSION: Despite warnings, the majority of pharmacists would still inappropriately recommend a benzocaine-containing product for treatment of infant teething. Further education is warranted to ensure that all pharmacists, health care providers, and consumers are aware of the potential harm of benzocaine use in infants.

Fluoride, Thyroid Hormone Derangements and its Correlation with Tooth Eruption Pattern Among the Pediatric Population from Endemic and Non-endemic Fluorosis Areas.

AIM: To comparatively evaluate the status of fluoride in the body with thyroid activity in the pediatric population of endemic fluorosis areas. The present study also attempted to elucidate whether any correlation exists between fluoride and thyroid hormone derangement with delayed tooth eruption. MATERIALS AND METHODS: A total of 400 pediatric subjects were included in the present study. All the patients were divided into two broad groups; groups A and B. Group A included 200 subjects who belonged to the endemic fluorosis area while Group B included remaining 200 subjects, who belonged to the fluorosis non-endemic area. Group B subjects were taken as control. Group A subjects were further divided into two study groups as follows: Group A1: 100 Pediatric subjects with dental fluorosis, and Group A 2: A total of one hundred pediatric subjects without dental fluorosis. Dean's index of fluorosis was calculated in all the patients. Blood samples were collected and were sent to a laboratory for assessment of thyroid hormone levels. All the results were subjected to statistical analysis by Statistical Package for the Social Sciences (SPSS) software. RESULTS: Mean thyroid stimulating hormone (TSH), water fluoride levels, urine fluoride levels and serum fluoride levels of subjects in group 1 were found to be significantly higher than that of subjects of group 2. Delayed tooth eruption was absent in subjects of group B while it was present in 100 subjects of group A. Thyroid hormone level derangement was seen in 54 percent subjects of group B, while it was seen in 67.5% subjects of group A. CONCLUSION: Positive correlation exists between fluorosis and thyroid functional activity. However; the tooth eruption pattern is independent up on the thyroid hormone derangement. CLINICAL SIGNIFICANCE: Delayed tooth eruption and alteration in thyroid hormone levels can occur in subjects of the endemic fluoride areas. Therefore, adequate measures should be taken for controlling such adverse effects.

Doxycycline reduces the expression and activity of matrix metalloproteinase-2 in the periodontal ligament of the rat incisor without altering the eruption process.

BACKGROUND AND OBJECTIVE: Doxycycline is an antibiotic agent that inhibits the activity of matrix metalloproteinases (MMPs) present in the extracellular matrix. In this study, the rat incisor was submitted to a hypofunctional condition, and the effects of doxycycline (80 mg/kg/d) on the expression and activity of MMP-2, as well as on eruption rate, were determined in the odontogenic region and in the periodontal ligament for 14 d. MATERIAL AND METHODS: Rats were distributed into four groups: normofunctional (NF); doxycyline normofunctional (DNF); hypofunctional (HP); and doxycyline hypofunctional (DHP). The left lower incisors of 10 rats were shortened every 2 d, using a high-rotation drill, to produce the HP and DHP groups, after starting doxycycline treatment (80 mg/kg) by gavage. Eruption was measured using a millimeter ocular, from the gingival margin to the top of the tooth in the HP and DHP groups, and also by a mark made in the tooth previously, in the NF and DNF groups. The hemimandibles were removed and the teeth were extracted to collect the periodontal and odontogenic tissues for immunohistochemical analyses and zymography. RESULTS: The eruption rates were higher in the HP and the DHP groups than in the NF and DNF groups, respectively (p < 0.05). In the odontogenic region, neither of the treatments changed the expression and activity of MMP-2. In the HP group, the shortening treatment decreased the expression, but not the activity, of MMP-2, while doxycycline was able to inhibit the increase of expression and activity of MMP-2. CONCLUSION: We conclude that the inhibition of MMP-2 by doxycycline, during incisor shortening, was not enough to alter the eruption rate, which suggests that MMP-2 may have an important role in the turnover of extracellular matrix of the periodontal ligament during the tooth-eruption process.

Use of new targeted cancer therapies in children: effects on dental development and risk of jaw osteonecrosis: a review.

New targeted cancer therapies such as bisphosphonates, denosumab, and bevacizumab are routinely used in adult for the past decades. Their introduction into pediatric medicine is more recent that means there is a paucity of data on long-term effects on dental development and on the risk of osteonecrosis of jaw. This study aimed to outline adverse effects of new targeted cancer therapies on oral cavity including dental abnormalities observed in pediatric population treated with these molecules and the risk of osteonecrosis of the jaw (ONJ). The impact of bisphosphonates and denosumab on bone remodeling (inhibition of osteoclasts) could interfere with teeth exfoliation and eruption processes, causing a tooth eruption delay. This hypothesis was confirmed, bisphosphonate-treated rats presented tooth eruption delay, and bisphosphonate therapy was associated with a mean delay of 1.67 years in tooth eruption in children with osteogenesis imperfecta. Another study showed that the inhibition of RANK/RANKL by denosumab was associated with a lack of tooth eruption in animals. Several animal studies reported that bisphosphonate could also induce dental abnormalities including defective amelogenesis and dentinogenesis in rats, but there is no evidence of such effects in children; only one case of enamel hypoplasia in a child treated for idiopathic arterial calcification with bisphosphate was reported. To date, there has been no reported case of ONJ in children treated with bisphosphonates, denosumab, or bevacizumab.

Implantation of octacalcium phosphate collagen composites (OCP/Col) after extraction of canine deciduous teeth achieved undisturbed permanent tooth eruption.

OBJECTIVE: Composite of synthetic octacalcium phosphate and collagen (OCP/Col) enhances bone regeneration if implanted into human, canine, or rodent bone defects. This study was designed to investigate the influence on eruption of the permanent successor tooth and alveolar height of OCP/Col implantation into extraction cavities of deciduous teeth. DESIGN: Disks of OCP/Col prepared from synthetic granules of octacalcium phosphate (OCP) and porcine atelocollagen, and commercially available sintered porous ß-tricalcium phosphate (ß-TCP) was implanted into the prepared defect of eleven male beagle dogs by extraction of two deciduous premolars. Untreated group had nothing implanted into the prepared defect, and physiological group (Physiol group) was observed without any treatment. Periodical macroscopic and radiographic examinations were performed until the period equivalent to the physiological eruption of permanent successor teeth (P3 and P4). RESULTS: Although no unerupted permanent successor teeth were observed among the OCP/Col, Untreated, and Physiol groups, two permanent successor teeth were unerupted in the ß-TCP group. No significant difference of the alveolar heights or the eruptive position in P3 and P4 was observed between OCP/Col and Physiol groups. CONCLUSION: OCP/Col implantation in the alveolar region that included the unerupted permanent successor teeth would cause no disturbance of permanent tooth eruption and preserve the alveolar ridge.

Parathyroid hormone intermittent administration promotes delay on rat incisor eruption.

OBJECTIVE: This study evaluated the influence of parathyroid hormone (PTH) (1-34) intermittent administration on rat eruption rates of lower incisors under normo, hyper and hypofunctional conditions, Sharpey fibers insertion, and alveolar bone formation. MATERIALS AND METHODS: Wistar male rats received PTH (1-34) three times a week during the entire experimental period, 31days. Control animals received the same concentration of the vehicle solution during the same period. Three injections of alizarin were also performed. The experiment evaluated the eruptive rate, the alveolar bone formation and also the morphology, and the area density of Sharpey fibers. After the sacrifice, the mandibles were dissected and samples were prepared for fluorescence and scanning electron microscopy observations. RESULTS: PTH-treated animals showed significantly reduced eruption rates in all different functional conditions. Analysis evidenced that PTH-treated rats present an increase in bone formation and area density of the Sharpey fibers. CONCLUSION: We concluded that the PTH (1-34) intermittent administration reduced the eruptive process rates, through bone formation enhancement and increase in the area density of Sharpey fibers.

PTH intermittent administration may be a useful therapeutic agent to avoid premature eruption of the tooth.

Parathyroid hormone (PTH) acts as a controller of bone remodeling and has influence on periodontal tissues. In addition to the well-established catabolic effects (activation of bone resorption) of PTH, it is recognized that the PTH intermittent administration has anabolic effects (promotion of bone formation). However, there is no information regarding the effects of the PTH intermittent administration on the eruption tooth rate. Studies have shown that tooth eruption depends on the presence of osteoclasts to create an eruption pathway through the alveolar bone. It may also be controlled by osteoblast, precursor of osteoclast, and cells of periodontal ligament. Our hypothesis is based on previous studies showing that the PTH intermittent administration can promote bone formation, particularly in the areas around which the tooth erupts. Furthermore, the PTH intermittent administration influenced periodontal ligament fiber, what may be seen as greater organization, and isomerization, as well as higher birefringence of the periodontal ligament fiber, which then offers increased resistance to the process, delaying tooth eruption. Thus, this article opens new perspectives for the treatment and maintenance of teeth that can erupt early.

Developmental and Post-Eruptive Defects in Molar Enamel of Free-Ranging Eastern Grey Kangaroos (Macropus giganteus) Exposed to High Environmental Levels of Fluoride.

Dental fluorosis has recently been diagnosed in wild marsupials inhabiting a high-fluoride area in Victoria, Australia. Information on the histopathology of fluorotic marsupial enamel has thus far not been available. This study analyzed the developmental and post-eruptive defects in fluorotic molar enamel of eastern grey kangaroos (Macropus giganteus) from the same high-fluoride area using light microscopy and backscattered electron imaging in the scanning electron microscope. The fluorotic enamel exhibited a brownish to blackish discolouration due to post-eruptive infiltration of stains from the oral cavity and was less resistant to wear than normally mineralized enamel of kangaroos from low-fluoride areas. Developmental defects of enamel included enamel hypoplasia and a pronounced hypomineralization of the outer (sub-surface) enamel underneath a thin rim of well-mineralized surface enamel. While the hypoplastic defects denote a disturbance of ameloblast function during the secretory stage of amelogenesis, the hypomineralization is attributed to an impairment of enamel maturation. In addition to hypoplastic defects, the fluorotic molars also exhibited numerous post-eruptive enamel defects due to the flaking-off of portions of the outer, hypomineralized enamel layer during mastication. The macroscopic and histopathological lesions in fluorotic enamel of M. giganteus match those previously described for placental mammals. It is therefore concluded that there exist no principal differences in the pathogenic mechanisms of dental fluorosis between marsupial and placental mammals. The regular occurrence of hypomineralized, opaque outer enamel in the teeth of M. giganteus and other macropodids must be considered in the differential diagnosis of dental fluorosis in these species.

ClC-7 Deficiency Impairs Tooth Development and Eruption.

CLCN7 gene encodes the voltage gated chloride channel 7 (ClC-7) in humans. The mutations in CLCN7 have been associated with osteopetrosis in connection to the abnormal osteoclasts functions. Previously, we found that some osteopetrosis patients with CLCN7 mutations suffered from impacted teeth and root dysplasia. Here we set up two in vivo models under a normal or an osteoclast-poor environment to investigate how ClC-7 affects tooth development and tooth eruption. Firstly, chitosan-Clcn7-siRNA nanoparticles were injected around the first maxillary molar germ of newborn mice and caused the delay of tooth eruption and deformed tooth with root dysplasia. Secondly, E13.5 molar germs infected with Clcn7 shRNA lentivirus were transplanted under the kidney capsule and presented the abnormal changes in dentin structure, periodontal tissue and cementum. All these teeth changes have been reported in the patients with CLCN7 mutation. In vitro studies of ameloblasts, odontoblasts and dental follicle cells (DFCs) were conducted to explore the involved mechanism. We found that Clcn7 deficiency affect the differentiation of these cells, as well as the interaction between DFCs and osteoclasts through RANKL/OPG pathway. We conclude that ClC-7 may affect tooth development by directly targeting tooth cells, and regulate tooth eruption through DFC mediated osteoclast pathway.