The association between Dental Fluorosis and COL1A2 gene polymorphism among a Tunisian Population.

Dental fluorosis (DF) is a prevalent developmental defect of tooth enamel caused by exposure to excessive fluoride, with the severity dependent on various factors. This study aimed to investigate the association between DF and a specific genetic polymorphism (rs412777) in the COL1A2 gene among a Tunisian population. A case-control study was conducted from July to November 2022, involving a total of 95 participants including 51 cases and 44 controls. Dental examinations and genetic analysis were performed to assess the relationship between the COL1A2 gene polymorphism and DF.The results of allelic distribution revealed that A allele carriers were significantly protected against (DF) when compared to those with the C allele (C vs. A, p = 0.001; OR = 0.375 (0.207-0.672)). This suggests a strong correlation between the presence of the C allele and the risk of developing DF. Additionally, significant association between the CC genotype of rs412777 and an increased risk of DF was found under both codominant and dominant genetic models (P = 0.002 and P < 0.001 respectively).The findings suggest that genetic predisposition plays a relevant role in the development of DF. Further research is needed to explore the potential use of genetic markers for DF and their implications for public health. This study provides the first insights into the genetic factors associated with DF in the Tunisian population, contributing to our understanding of this prevalent dental condition.

Association between polymorphism and haplotype of ATP2B1 gene and skeletal fluorosis in Han population.

To evaluate the association between ATP2B1 gene polymorphisms and skeletal fluorosis, a cross-sectional study was conducted. In China, 962 individuals were recruited, including 342 cases of skeletal fluorosis. Four TP2BA1 polymorphisms (rs2070759, rs12817819, rs17249754, and rs7136259) were analysed. The results suggested that rs17249754 and rs7136259 were associated with skeletal fluorosis. After controlling confounders, the protective effect of GG genotype in rs17249754 was apparent in individuals over 45 years old, female, with urine fluoride concentration below 1.6 mg/L, serum calcium above 2.25 mmol/L or serum phosphorus between 1.1 and 1.3. Heterozygote TC in rs7136259 increased the risk of skeletal fluorosis in subjects who are elderly, female, with urinary fluoride more than 1.6 mg/L, serum calcium more than 2.25 mmol/L and blood phosphorus between 1.1 and 1.3 mmol/L. Four loci were found to be tightly related by linkage disequilibrium analysis, and the frequency of distribution of haplotype GCGT was lower in the skeletal fluorosis group.

Integrated 16S rDNA sequencing and metabolomics to explore the intestinal changes in children and rats with dental fluorosis.

Dental fluorosis (DF) is a widely prevalent disease caused by excessive fluoride with limited awareness of its underlying pathogenesis. Here, a pilot population study was conducted to explore the pathogenesis of DF from the perspective of intestinal microbiome changes, and verified it in animal experiments combining intestinal microbiome and metabolomics. A total of 23 children were recruited in 2017 in China and divided into DF (n = 9) and control (n = 14) groups (DFG and CG, respectively). The SD rat model was established by drinking water containing sodium fluoride (NaF). Gut microbiome profiles of children and rats were analyzed by16S rDNA V3-V4 sequencing, and the intestinal metabolomics analysis of rats was performed by LC-MS methods. The 16 S rDNA sequencing revealed that the gut microbiome composition was significantly perturbed in children in DFG compared to that in CG. Acidobacteria and Thermi were specifically observed in DFG and CG, respectively. Besides, 15 fecal microbiotas were significantly altered at the genus level in DFG. Furthermore, only the expression of annotated genes for pentose and glucuronate interconversion pathway was significant lower in DFG than that in CG (P = 0.04). Notably, in NaF-treated rats, we also observed the changes of some key components of pentose and glucuronate interconversion pathway at the level of microorganisms and metabolites. Our findings suggested that the occurrence of DF is closely related to the alteration of intestinal microorganisms and metabolites annotated in the pentose and glucuronate interconversion pathway.

A systematic review on fluoride-induced epigenetic toxicity in mammals.

Fluoride, one of the global groundwater contaminants, is ubiquitous in our day-to-day life from various natural and anthropogenic sources. Numerous in vitro, in vivo, and epidemiological studies are conducted to understand the effect of fluoride on biological systems. A low concentration of fluoride is reported to increase oral health, whereas chronic exposure to higher concentrations causes fluoride toxicity (fluorosis). It includes dental fluorosis, skeletal fluorosis, and fluoride toxicity in soft tissues. The mechanism of fluoride toxicity has been reviewed extensively. However, epigenetic regulation in fluoride toxicity has not been reviewed. This systematic review summarizes the current knowledge regarding fluoride-induced epigenetic toxicity in the in vitro, in vivo, and epidemiological studies in mammalian systems. We examined four databases for the association between epigenetics and fluoride exposure. Out of 932 articles (as of 31 March 2022), 39 met our inclusion criteria. Most of the studies focused on different genes, and overall, preliminary evidence for epigenetic regulation of fluoride toxicity was identified. We further highlight the need for epigenome studies rather than candidate genes and provide recommendations for future research. Our results indicate a correlation between fluoride exposure and epigenetic processes. Further studies are warranted to elucidate and confirm the mechanism of epigenetic alterations mediated fluoride toxicity.

Dietary carotenoid intake and dental fluorosis in relation to SOD2 (rs 11968525) polymorphisms in Guizhou, China.

BACKGROUND AND OBJECTIVES: Genetic and dietary factors are important contributors to the development of dental fluorosis (DF). This study investigated the association between DF and dietary carotenoids, and explored whether the association was modified by polymorphisms of the antioxidant enzyme superoxide dismutase 2 (SOD2 rs11968525) in Guizhou, China. METHODS AND STUDY DESIGN: A cross-sectional study with a total of 899 adults aged 18-75 years were enrolled in the study. Face-to-face interviews were conducted to assess dietary habits using a validated 75 item food frequency questionnaire (FFQ). Sociodemographic and lifestyle information, and blood and urine samples were also collected. Genotypes were evaluated using TaqMan single nucleotide polymorphism (SNP) Genotyping Assay. RESULTS: There were significant dose-dependent inverse associations of the prevalence of DF with intake of α-carotene, ß-carotene, lutein/zeaxanthin, lycopene and total carotenoids (p-trend ranged from <0.001-0.004). The odds ratios (ORs) and 95% confidence intervals (CIs) of DF comparing the highest against lowest quartile were 0.56 (0.35, 0.92) for α-carotene, 0.53 (0.35, 0.81) for ß-carotene, 0.44 (0.27, 0.74) for lycopene, 0.35 (0.21, 0.58) for lutein/zeaxanthin in combination and 0.42 (0.25, 0.69) for total carotenoids (all p-trend<0.005). Intake of ß-cryptoxanthin was not found to be related to DF. The inverse association of DF with dietary intake of α-carotene and ß-carotene was more evident in individuals with the AG+AA genotype (p-interaction<0.05). CONCLUSIONS: Higher dietary carotenoids were associated with a lower occurrence of DF, polymorphisms in SOD2 (rs 11968525) modified the associations between dietary intake of carotene and DF. These findings provide evidence for precision prevention of fluorosis.

Possible Association Between Polymorphisms in ESR1, COL1A2, BGLAP, SPARC, VDR, and MMP2 Genes and Dental Fluorosis in a Population from an Endemic Region of West Bengal.

Dental fluorosis (DF) is the most prevalent form of fluorosis in India affecting millions of people all over the country. As estrogen receptor 1 (ESR1), collagen type 1 alpha 2 (COL1A2), bone γ-carboxyglutamic acid protein (BGLAP), secreted protein acidic and cysteine-rich (SPARC), vitamin D receptor (VDR), and matrix metallopeptidase 2 (MMP2) genes play critical roles in bone metabolism, bone formation, mineral metabolism, and mineralization, variants in these genes could influence susceptibility to DF. The present study was aimed at evaluating the association between 15 single-nucleotide polymorphisms (SNPs) in the six candidate genes (namely, ESR1, COL1A2, BGLAP, SPARC, VDR, and MMP2) and DF among 132 individuals (case = 71 and control = 61) living in a fluoride endemic region of West Bengal, India. No statistically significant association with disease risk was found when the genotypes and allele frequencies of each of the 15 SNPs was analyzed individually using odd's ratio with 95% confidence interval. "CC" and "AG" haplotypes of the COL1A2 gene showed a borderline association with DF. The present study is the first in India to use multifactor dimensionality reduction (MDR) analysis for identifying gene-gene and gene-environment interactions in fluorosis. The biomarker of serum fluoride showed a significant association with the disease state among the 17 attributes (15 SNPs and 2 biomarkers of urine fluoride and serum fluoride) (P value = 0.011). The best model of MDR analysis with maximized testing accuracy involved two SNPs from the ESR1 gene (rs9340799 and rs2077647) and one SNP from BGLAP gene (rs1543294) (P value < 0.0001).

Effects of SNPs in SOD2 and SOD3 interacted with fluoride exposure on the susceptibility of dental fluorosis.

A total of 649 children aged 7-13 years of age were recruited in a cross-sectional study in Tongxu County, China (2017) to assess the effects of interaction between single nucleotide polymorphisms (SNPs) in SOD2 and SOD3 gene and fluoride exposure on dental fluorosis (DF) status. Associations between biomarkers and DF status were evaluated. Logistic regression suggested that the risk of DF in children with rs10370 GG genotype and rs5746136 TT genotype was 1.89-fold and 1.72-fold than that in children with TT/CC genotype, respectively. Increased T-SOD activity was associated with a lower risk of DF (OR = 0.99). The rs2855262*rs10370*UF model was regarded as the optimal interaction model in generalized multifactor dimensionality reduction analyses. Our findings suggested that rs4880 and rs10370 might be useful genetic markers for DF, and there might be interactions among rs10370 in SOD2, rs2855262 in SOD3, and fluoride exposure on DF status.

Moderating Role of TSHR and PTPN22 Gene Polymorphisms in Effects of Excessive Fluoride on Thyroid: a School-Based Cross-Sectional Study.

We aimed to investigate the relationship between the effects excessive of fluoride on thyroid health in children and the moderating role of thyroid stimulating hormone receptor (TSHR) or protein tyrosine phosphatase nonreceptor-22 (PTPN22) gene polymorphisms. Four hundred thirteen children (141 with dental fluorosis and 198 boys) were enrolled from both historical endemic and non-endemic areas of fluorosis in Tianjin, China. The fluoride exposure levels, thyroid health indicators, and TSHR (rs2268458) and PTPN22 (rs3765598) polymorphisms were examined. Multiple logistic models were applied to evaluate the relationship between dental fluorosis and thyroid abnormalities. Children over 9 year old with dental fluorosis have lower FT4 and TGAb levels and thyroid volume and higher TPOAb levels (all P < 0.05). In overall participants, children with dental fluorosis were more likely to have thyroid antibody single positive issues (adjusted P = 0.039) and less likely to have a goiter according to age or body surface area (age or BSA) (adjusted P = 0.003); In the TSHR (rs2268458) SNP = CC/CT or PTPN22 (rs3765598) SNP = CC subgroup, dental fluorosis may cause thyroid antibody single positive (adjusted P = 0.036; adjusted P = 0.002); in the TSHR (rs2268458) SNP = TT or PTPN22 (rs3765598) SNP = CC subgroup, dental fluorosis may protect children from goiter (age or BSA) (adjusted P = 0.018; adjusted P = 0.013). Excessive fluoride may induce thyroid antibody single positive and reduce goiter in children. Heterogeneity exists in the relationship between excessive fluoride and thyroid antibody single positive or goiter issues across children carrying different TSHR (rs2268458) or PTPN22 (rs3765598) genotypes.

Effect of fluoride in drinking water on the level of 5-methylcytosine in human and rat blood.

DNA methylation is an epigenetic modification of genome that is involved in many human diseases. Recent studies revealed DNA methylation may be associated with fluorosis. This study was aimed to evaluate the dose-response effect of fluoride on DNA methylation in human and rat blood. A commercial ELISA kit was employed to evaluate 5-methylcytosine (5-mC) level of genome in human and rat blood. A total of 281 subjects were enrolled in this study and divided into four equal-size groups by the quartile of fluoride in drinking water. The difference of 5-mC among the four groups was significant. The U-shaped relationship was found between fluoride and 5-mC in the population. The U-shaped curve was also observed in the rats with three months of fluoride treatments. Taken together, these results clue the disruption of DNA methylation in mammals may has a certain association with fluoride in natural exposures.

Evaluating the Association Between Dental Fluorosis and Polymorphisms in Bone Development and Mineralization Genes Among Population from a Fluoride Endemic Region of Eastern India.

Close to 12 million people in India are affected by more than the desirable level of fluoride in drinking water that could lead to dental, skeletal, and non-skeletal fluorosis. Dental fluorosis is a developmental defect that results in hypo-mineralization and pronounced porosity of enamel in the affected individuals. As estrogen receptor 1 (ESR1), collagen type 1 alpha 2 (COL1A2), bone γ-carboxyglutamic acid protein (BGLAP), and secreted protein acidic and cysteine rich (SPARC) genes are involved in bone development and mineralization, polymorphisms in these genes could be determining factors in influencing the risk to fluorosis among the exposed individuals in fluoride endemic areas. A case-control study was carried out among a total of 87 individuals (case = 36, control = 51) to examine the association between selected polymorphisms in the ESR1, COL1A2, BGLAP, and SPARC genes and risk of dental fluorosis from a fluoride endemic region of Eastern India. Altogether, 10 single nucleotide polymorphisms (SNPs) in ESR1 (rs2234693, rs2228480, rs3798577, rs2077647, and rs9340799), COL1A2 (rs42524, rs412777), BGLAP (rs1800247), and SPARC (rs6579885, rs4958278) genes were genotyped through PCR-RFLP in these subjects. The association of the SNPs for disease risk estimation was measured by odds ratio with 95% confidence interval. The risk genotypes of none of the 10 SNPs showed statistically significant association with risk of dental fluorosis. Frequencies of the haplotypes in the intragenic SNPs of the ESR1, COL1A2, and SPARC genes did not reveal any statistically significant difference between the case and control groups. The present study is the first of its kind from India that has attempted to investigate possible involvement of genetic factors in influencing the risk to fluorosis among the population from a fluoride endemic region.

Single nucleotide polymorphism rs4284505 in microRNA17 and risk of dental fluorosis.

OBJECTIVES: The aim of this study is to evaluate the association between the single nucleotide polymorphism (SNP) rs4284505 within the gene that codifies microRNA17 (miRNA17) and dental fluorosis (DF) in a group of children. METHODS: Children living in a city with fluoridation of public water supplies were included. DF was assessed in erupted permanent teeth by Dean's modified index. The miR-SNP rs4284505 was selected in miRNA17 and genotyping was carried out by real-time PCR. Genotype and allelic distributions between DF and control, and between DF phenotypes (mild, moderate and severe) and control were analysed. RESULTS: Among a total of 527 children enrolled for the study, 383 were DF free and 144 presented DF. In the dominant model analysis (AA + AG vs. GG) the miR-SNP rs4284505 was associated with moderate DF, with carriers of the GG genotype having an increased risk of more than two times for DF (p = 0.031; Odds Ratio = 2.26, Confidence Interval 95%= 1.04-4.73). Allelic distribution showed borderline statistical significance for moderate DF with the carriers of G allele having an increased risk for DF (p = .050; Odds Ratio = 1.75, Confidence Interval 95%= 1.00-3.12). CONCLUSION: The miR-SNP rs4284505 in miRNA17 was associated with an increased risk of DF.

ENAM Gene Variation in Students Exposed to Different Fluoride Concentrations.

The ENAM gene is important in the formation of tooth enamel; an alteration can affect the lengthening of the crystals, and the thickness in enamel. The objective was to determine the presence of the single nucleotide variant (SNV) rs12640848 of the ENAM gene in students exposed to different concentrations of fluoride. METHODS: A cross-sectional study was conducted on students exposed to high concentrations of fluoride in the city of Durango which were divided according to the severity of fluorosis and dental caries. Genotype determination was performed by DNA sequencing. The relationship between the severity of dental fluorosis and the allele distribution was determined by the Fisher's exact and Kruskal-Wallis tests. RESULTS: Seventy-one students were included for the sequencing. In the different allelic variations, for the normal genotype AA/TT, the control group presented 75%, for the AG/TC variation, 70.8% in the TF ≤ 4 group, 65% in TF ≥ 5, and 16.7% in TF = 0; with respect to GG/CC variation, 12.5% in TF ≤ 4, 22% in TF ≥ 5, and 8.3% in TF = 0 group (p = 0.000). CONCLUSION: The ENAM gene showed an association in the population exposed to different concentrations of fluoride.

Fluoride exposure alters Ca2+ signaling and mitochondrial function in enamel cells.

Fluoride ions are highly reactive, and their incorporation in forming dental enamel at low concentrations promotes mineralization. In contrast, excessive fluoride intake causes dental fluorosis, visually recognizable enamel defects that can increase the risk of caries. To investigate the molecular bases of dental fluorosis, we analyzed the effects of fluoride exposure in enamel cells to assess its impact on Ca2+ signaling. Primary enamel cells and an enamel cell line (LS8) exposed to fluoride showed decreased internal Ca2+ stores and store-operated Ca2+ entry (SOCE). RNA-sequencing analysis revealed changes in gene expression suggestive of endoplasmic reticulum (ER) stress in fluoride-treated LS8 cells. Fluoride exposure did not alter Ca2+ homeostasis or increase the expression of ER stress-associated genes in HEK-293 cells. In enamel cells, fluoride exposure affected the functioning of the ER-localized Ca2+ channel IP3R and the activity of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) pump during Ca2+ refilling of the ER. Fluoride negatively affected mitochondrial respiration, elicited mitochondrial membrane depolarization, and disrupted mitochondrial morphology. Together, these data provide a potential mechanism underlying dental fluorosis.

DNA sequencing reveals AMELX, ODAM and MMP20 variations in dental fluorosis.

OBJECTIVE: Dental fluorosis (DF) is a dental development disorder caused by chronic fluoride overconsumption. There are differences in the susceptibility to and severity of DF in studied populations. The objective of the present study was to determine if single-nucleotide variations (SNVs) in the genes Amelogenin (AMELX), Odontogenic Ameloblast Associated (ODAM) and Matrix Metalloproteinase 20 (MMP20) are associated with DF by evaluating the relationship between variations in these genes and the degree of DF severity. SUBJECTS AND METHODS: Schoolchildren from two regions of Durango State and Mexico City, Mexico, were studied. The DF phenotype was determined using the Thylstrup and Fejerskov (TF) index. DNA was obtained from the buccal mucosa of each participant, and the presence of the variations rs946252 in AMELX, rs1514392 in ODAM and rs1784418 in MMP20 was determined by bidirectional DNA sequencing. RESULTS: A total of 180 DNA samples from 30 schoolchildren from 2 areas of Durango State were sequenced and analyzed. Differences in the severity of DF were found between the study areas (p = 0.006). SNVs in theMMP20 gene were present in 76.9 % of the participants in the high fluoride concentration and lower DF severity area. CONCLUSION: AMELX and ODAM variations was not different between the two populations with respect to DF severity; however, the presence of rs1784418 differed between phenotypes with regard to susceptibility to DF. Therefore, MMP20 might be related to the various phenotypes of DF and may serve as a protective marker.

Oestrogen receptor Rsa I gene polymorphism in osteoporosis periodontitis patients with or without dental fluorosis.

Background & objectives: : There is a paucity of information on association between dental fluorosis, osteoporosis and periodontitis. The aim of this pilot study was to evaluate oestrogen receptor (ER). Rsa 1: gene polymorphism in osteoporosis periodontitis patients with and without dental fluorosis. Methods: : Twenty one primary osteoporotic patients suffering from periodontitis with dental fluorosis and 20 primary osteoporotic patients suffering from periodontitis without dental fluorosis participated in this study. Periodontitis was diagnosed based on age, gender T-scores using clinical parameters such as plaque scores, gingival bleeding scores and probing pocket depth, clinical attachment level (CAL) and severity of dental fluorosis. DNA was genotyped at the RsaI RFLP (in exon 5) inside the ER gene to study ER Rsa I gene polymorphism in osteoporosis periodontitis patients with and without dental fluorosis. Results: : Patients with dental fluorosis had higher degree of osteoporosis than those without fluorosis. CAL was significantly higher (P <0.05) in those with dental fluorosis compared with those without. Rr heterozygote (21.95%) was observed in patients without fluorosis whereas RR mutant homozygote was absent in both the groups. Rr wild homozygote type was seen more in the patients with fluorosis (51.21%). Significant differences were found in distribution of these genotypes between patients with and without dental fluorosis. Interpretation & conclusions: : This preliminary study showed the presence of ER I gene polymorphism in osteoporosis periodontitis patients without dental fluorosis. Further studies with large sample size are needed to confirm the association shown in this preliminary study.

Low-to-moderate fluoride exposure, relative mitochondrial DNA levels, and dental fluorosis in Chinese children.

BACKGROUND: The alteration of mitochondrial DNA (mtDNA) content contributes to many diseases, however, little is known about its effect on the prevalence of dental fluorosis (DF). OBJECTIVES: We conducted a cross-sectional study to investigate the association of low-to-moderate fluoride exposure with relative mtDNA levels in relation to DF in children. METHODS: We recruited 616 resident children, aged 7-13 years, randomly from low-to-moderate fluoride areas in Tianjin, China. We measured the fluoride concentrations in drinking water and urine using the national standardized ion selective electrode method, and determined the relative levels of mtDNA using a quantitative real-time polymerase chain reaction assay. The association among fluoride exposure, relative mtDNA levels, and the prevalence of DF were examined using multivariable linear and logistic regression models. We also performed stratified and mediation analyses. RESULTS: The relative mtDNA levels of participants in the DF group were significantly lower than in the non-DF group (0.95 ±â€¯0.44 vs. 1.12 ±â€¯0.45, P < 0.001). In the adjusted models, we found that a 1 mg/L increment in water fluoride concentration was associated with a 0.10-unit decrease in circulating relative mtDNA levels (95% CI: -0.14, -0.06) and a 2.85-fold increase (95% CI: 2.01, 3.92) in moderate DF prevalence. A 1 mg/L increment in urinary fluoride level was associated with a 0.12-unit decrease in circulating relative mtDNA levels (95% CI: -0.14, -0.09) and a 1.85-fold increase (95% CI: 1.39, 2.39) in moderate DF prevalence. Stratified analysis indicated a weaker positive association of DF prevalence with fluoride exposure, while a stronger inverse relationship with relative mtDNA levels in boys than in girls. Assuming causality, we estimated that circulating mtDNA levels mediated 13.0% (95% CI: 5.2, 28.7%) and 9.6% (95% CI: 4.7, 18.5%) of the estimated effect of a 1 mg/L increment in water fluoride and urinary fluoride on prevalence of moderate DF, respectively. CONCLUSIONS: Gender potentially modifies the associations of DF prevalence with relative mtDNA levels and low-to-moderate fluoride exposure. The reduced circulating mtDNA levels may partly mediate the elevated prevalence of moderate DF in children under such exposure.

The pathogenesis of endemic fluorosis: Research progress in the last 5 years.

Fluorine is one of the trace elements necessary for health. It has many physiological functions, and participates in normal metabolism. However, fluorine has paradoxical effects on the body. Many studies have shown that tissues and organs of humans and animals appear to suffer different degrees of damage after long-term direct or indirect exposure to more fluoride than required to meet the physiological demand. Although the aetiology of endemic fluorosis is clear, its specific pathogenesis is inconclusive. In the past 5 years, many researchers have conducted in-depth studies into the pathogenesis of endemic fluorosis. Research in the areas of fluoride-induced stress pathways, signalling pathways and apoptosis has provided further extensive knowledge at the molecular and genetic level. In this article, we summarize the main results.

Evaluation of genetic polymorphisms in MMP2, MMP9 and MMP20 in Brazilian children with dental fluorosis.

Recent studies suggested that genetics contribute to differences in dental fluorosis (DF) susceptibility among individuals having the same environmental exposure. This study evaluated if MMP2, MMP9 and MMP20 are expressed during enamel development and assessed the association between polymorphisms in these genes with DF. Mice susceptible and resistant to DF were used to evaluate if MMPs were candidate genes for DF. The animals received fluoride and their enamels were used for immunohistochemistry. Additionally, 481 subjects from a city with fluoridation of public water supplies were recruited. Genotyping was performed using real time PCR. Allele/genotype frequencies were compared between groups. MMP2, MMP9 and MMP20 immunostaining was detected in both animal groups. DF was observed in 22.4% of the subjects. A borderline association was observed in MMP2 (rs243865), MMP9 (rs17576) and in MMP20 (rs1784418) (p = 0.06, p = 0.08 and p = 0.06 respectively). Briefly, MMPs were expressed during enamel maturation and genetic polymorphisms were not associated with DF.

Estrogen receptor gene is associated with dental fluorosis in Brazilian children.

OBJECTIVES: The aim of this study was investigate the association between genetic polymorphisms in ESR1, ESR2, and ESRRB and dental fluorosis (DF) in a well-characterized sample of children from Curitiba, Brazil. MATERIAL AND METHODS: From a representative sample of 538 children, 12-year-old were evaluated. DF was assessed in erupted permanent teeth by the Dean's index modified. Fourteen polymorphisms were selected in intronic and intergenic regions of ESR1, ESR2, and ESRRB and genotyped in genomic DNA source from saliva using TaqMan chemistry and end-point analysis. Allele and genotype distributions between DF and DF free groups were analyzed using the Epi Info 7.2. Chi-square or Fisher's exact tests at a level of significance of 5% and odds ratios calculations with 95% confidence intervals were used to determine the statistical associations. RESULTS: Among 538 children, 147 were DF and 391 were DF free. Genotype distribution for the polymorphism rs12154178 in ESR1 was different between the two groups (p = 0.037; OR = 0.91; CI = 0.67-1.22). The dominant model analysis (AA+AC vs. CC) demonstrated that CC is a protective factor for DF (p = 0.038; OR = 0.51, 0.27-0.97 95% CI). We did not find differences in frequency distributions in the other evaluated polymorphisms. CONCLUSION: This study provides evidence that ESR1 is associated with DF. CLINICAL RELEVANCE: Dental fluorosis is an important condition that affects the mineralized tissues of the teeth. In severe cases, the treatment takes time and is extremely costly. This research provides evidences that there are genetic factors involved in dental fluorosis and will help professionals to plan more precise strategies to reduce dental fluorosis occurrence.

Analysis of Polymorphisms in Genes Differentially Expressed in the Enamel of Mice with Different Genetic Susceptibilities to Dental Fluorosis.

Genes expressed during amelogenesis are candidates to increase the risk of dental fluorosis (DF). Thus, this study aimed to evaluate the association between polymorphisms in enamel development genes and susceptibility to DF in mice. Mice of both sexes, representing strains 129P3/J (n = 20; resistant to DF) and A/J (n = 20; susceptible to DF), were divided into 2 groups. Each strain received a diet with a low concentration of fluoride (F) and drinking water containing 0 or 50 mg/L of F for 6 weeks. Clinical evaluation and analysis of Vickers enamel microhardness of the incisors were performed. Livers were collected for genomic DNA extraction. Seventeen genetic polymorphisms in Amelx, Ambn, Ambn, Col14a1, Col1a1, Col5a2, Enam, Fam20a, Fam83h, Foxo1, Klk4, Mmp20, Serpinf1, Serpinh1, Smad3, Tuft1, and Wdr72 were genotyped by real-time PCR using Taqman chemistry. Overrepresentation of alleles and genotypes in DF was evaluated using the χ2 test with an alpha of 5%. The clinical aspects of the enamel and the surface enamel microhardness confirmed the DF condition. In the polymorphisms rs29569969, rs13482592, and rs13480057 in Ambn, Col14a1, and Mmp20, respectively, genotype and allele distributions were statistically significantly different between A/J and 129P3/J strains (p < 0.05). In conclusion, polymorphisms in Ambn, Col14a1, and Mmp20 are associated with the susceptibility to DF.