Fluoride exposure, personal susceptibility and osteoarticular degeneration: Evidence from farmers in the Yellow River Basin of Henan Province.

EXCERPTS:

4. Discussion

This work revealed that increased fluoride exposure, age, hip circumference, and poor night sleep quality contributed positively to OAD risk. The genotype of CG in rs1553005 (CALCA) might be the susceptible genotype to OAD. On the contrary, higher fruit intake (>350 g/d), GNAS methylation status, and TC genotype of rs7121 (GNAS) were negatively related to the OAD risk. It is worth noting that the multiple interactions between fluoride and personal susceptibility might modify the OAD risk.

UF is a good indicator for fluoride exposure evaluation (Li et al., 2009). In this research, an increase of 1.0 mg/L in UF concentrations increased the OAD risk by 48.4 %, indicating that fluoride exposure may accelerate the progression of degeneration. Evidence assumed that fluoride was involved in the degeneration of joints (Czerwinski, 1991). Similarly, elevated fluoride was associated with an increased risk of knee osteoarthritis (Meng et al., 2023). The pathogenesis of fluorosis is complex, the potential mechanism may be linked to the degradation of the extracellular matrix, disruption of chondrocyte differentiation, etc. triggered by fluoride (Li et al., 2020, Wang et al., 2021, Yu et al., 2021). Besides, fluoride exposure was reported to be related to levels of calcitonin and cAMP (Liu et al., 2014, Shashi et al., 2011), and calcitonin and cAMP can regulate osteoarthritis or synovial fibrosis (El Hajjaji et al., 2004, Qadri et al., 2018). Therefore, we speculate that the role of calcitonin and cAMP may also contribute to fluoride-related osteoarticular injury. Collectively, this study provides further epidemiological support for the tight association between fluoride exposure and OAD.

In addition to expression levels, genetic variations also affect disease risk, especially for SNPs. Previously, we have reported significant associations between SNPs in various genes (such as SOD2 and CREB1) and fluoride-related health damage (Du et al., 2022, Xu et al., 2022). Besides, PPARGC1A polymorphisms were suggested to be related to the risk of fluorosis (Song et al., 2024). For CALCA and GNAS, evidence suggested that SNPs in CALCA were associated with procalcitonin concentrations (Schoe et al., 2016), and aseptic loosening was related to the SNPs in GNAS (Bachmann et al., 2008). This study revealed that the genotype of CG in CALCA rs1553005 increased the OAD susceptibility, whereas the TC genotype of GNAS rs7121 was less susceptible to OAD compared to the TT genotype. The TT genotype was associated with the highest mRNA levels of Gas in different T393C (rs7121) genotypes (Frey et al., 2005). Gs expression is conducive to cAMP accumulation. Elevated cAMP levels were observed in patients with fluorosis (Shashi et al., 2011), and inhibition of cAMP-related signal transduction is beneficial to cartilage (Wu et al., 2014). Therefore, we speculated that the TC genotype of rs7121 may lead to relatively lower Gas levels than the TT genotype and further alleviate the effects of cAMP, which may be beneficial for lessening the OAD risk. Our results indicated that OAD risk was associated with SNPs of GNAS and CALCA. Given the significance of GNAS and CALCA on the skeletal system, the specific mechanisms by which their genetic variations regulate the OAD risk deserve to be further explored.

DNA methylation is another widely studied genetic factor that regulates disease susceptibility. In our previous research, RUNX2 methylation mediated the association between excessive fluoride and decreased bone mineral density in women (Gao et al., 2020); other reports also suggested that methylation of various genes such as MMP11, BACH1, BMP1, and METAP2 could interfere with the occurrence of skeletal fluorosis (Daiwile et al., 2019). In another work, we reported that fluoride-related bone mineral density alteration was associated with CALCA methylation in women (Sun et al., 2020). Although no statistical association was observed between CALCA methylation and OAD, another research subject (GNAS methylation) was protective for OAD in this study. GNAS encodes Gas, which can stimulate cAMP. Given the close association of cAMP levels with degeneration and fluoride exposure, we speculated that the increase in GNAS methylation levels may mainly inhibit GNAS expression, thereby reducing the stimulation on Gas and cAMP, finally exerting a protective effect.

Environmental exposure can co-regulate body health with genetic factors. The CALCA methylation was reported to modify the susceptibility of bone mineral density to fluoride exposure in women in our previous study (Sun et al., 2020). In this study, the OAD risk was elevated in adults with higher fluoride levels but lower CALCA methylation status, while it was reduced in those with lower fluoride exposure but higher GNAS methylation levels. Furthermore, a significant interaction between fluoride, SNPs of rs1553005 and rs7121, and GNAS methylation was found and a total of 13 high-risk and 21 low-risk patterns were recognized, of which adults with higher UF levels, lower GNAS methylation status, TT genotype of rs7121, and GG genotype of rs1553005 took the highest OAD risk. Additionally, adults with the rs7121 TC genotype exhibited high risk only in those with higher UF levels and the rs1553005 CG genotype, which further underscores the protective effect of the rs7121 TC genotype on OAD, as well as the adverse effects of higher fluoride exposure and the rs1553005 CG genotype. There is little evidence focused on the combined effects of fluoride and SNPs/methylation on OAD, and these results revealed the high-risk populations of OAD from the perspective of the combined effects of genetics-environment and provided more comprehensive epidemiological evidence for an in-depth understanding of the role of genetic factors in fluorosis.

In addition to genetic factors, physiological traits inevitably affect the disease. Aging is a risk factor for degeneration. This view was confirmed in this study again, in which an elevated OAD risk was found in participants older than 50 years. Additionally, OAD risk was positively linked to hip circumference in this study, and other relevant evidence also pointed out a causal association between hip circumference and increased osteoarthritis risk (Huang et al., 2024). Higher hip circumference may indicate fat accumulation and increased body load. Load changes are related to the inflammatory state of articular cartilage and the imbalance of biosynthetic metabolism, which can eventually lead to cartilage breakdown (Sun et al., 2021). Lifestyle are associated with disease risk. This work displayed that higher fruit intake (>350 g/d) was significantly associated with decreased OAD risk compared to fruit intake of 200–350 g/d. Additionally, other evidence also suggested a significant relationship between increased fruit intake and decreased osteoarthritis risk (Nguyen et al., 2022). Consuming more fruits can obtain diverse beneficial substances that may reduce the degeneration risk. However, the OAD risk was elevated in those with poor night sleep quality. Poor sleep quality can affect the normal function/metabolism of various organs and tissues, increasing the risk of disease. The latest evidence also revealed a similar result that poor sleep quality might increase the osteoarthritis risk (Zhou et al., 2024). Overall, these findings provide supporting evidence of the association between physiological characteristics and lifestyle with OAD.

Evidence found a significant combined effect between environmental disruption of circadian rhythms and high-fat diet on osteoarthritis promotion (Kc et al., 2015), revealing that environmental factors may interact with the lifestyle to modify disease susceptibility. In addition, the combined effects of physiological factors and environment on health are also worthy of attention. In this work, adults with higher fluoride and older age, both higher fluoride and hip circumference, higher fluoride but lower fruit intake, or higher fluoride but poor night sleep quality got elevated OAD risk. In terms of physiological factors, the combined effect of older age and higher fluoride exposure on the risk of OAD (OR=3.523) was stronger than the combined effect of larger hip circumference and higher fluoride exposure (OR=2.146); besides, in terms of lifestyle, the combined effect of poor night sleep quality and higher fluoride exposure on the risk of OAD (OR=2.904) was stronger than the combined effect of lower fruit intake and higher fluoride exposure (OR=1.762). All these suggested that fluoride exposure may act with aging, larger hip circumference, lower fruit intake, and poor night sleep quality to aggravate OAD progression together. From another point of view, these findings also reminded that controlling hip circumference growth, as well as increasing fruit intake and improving night sleep quality may be beneficial to slow down the progression of OAD in fluoride-exposed population. Additionally, an interaction between fruits and age was discovered, of which the older adults who got insufficient fruit intake (<200 g/d) got highest OAD risk, indicating that physiological factors and dietary habits can also synergistically modify the risk of OAD. In fact, a multidimensional interaction was also presented between UF, age, and fruits, and 7 high-risk and 9 low-risk combinations were recognized. Importantly, the older adults with higher fluoride and lower fruit intake (<200 g/d) got highest OAD risk. It is worth noting that all patterns of higher fruit intake (>350 g/d) showed a low risk. As aging is inevitable, increasing fruit intake for fluoride-exposed residents is of great significance in preventing OAD. Collectively, the above results indicated that the OAD was modified by the joint effects of fluoride and lifestyle/physiological characteristics.

In fact, there may be more complex combined effects among environmental exposure, genetics, and lifestyle/physiological characteristics that jointly regulate disease susceptibility. Based on this, interactions among degeneration contributors, including fluoride, methylation/SNPs, age, hip circumference, fruits, and sleep quality were considered. It was surprising that an interaction was presented between fluoride exposure, SNPs of rs1553005 and rs7121, GNAS methylation, age, hip circumference, and fruits. Especially, the combination of higher UF levels, lower hip circumference, rs7121 TT genotype, r1553005 CG genotype, lower fruit intake, higher age, and high GNAS methylation status took the highest sum score. Although the number of participants with multiple characteristics limited, the results still suggest that fluoride exposure can modify the risk of OAD together with genetic factors, physiological characteristics, and lifestyle. There are limited reports to comprehensively consider the modifying effects of fluoride exposure and personal susceptibility (including genetic factors, physiological traits and lifestyle) on OAD risk currently, our work provided deeper epidemiological evidence for fluoride-related osteoarticular damage.

This study has several advantages. First, this study comprehensively considered the interaction of genetic factors, physiology, and lifestyle based on fluoride-related osteoarticular injury, providing a more complete epidemiological basis for the systematic understanding of OAD risk. In addition, the Dietary Guidelines for Chinese Residents (2016) was regarded as the principle to classify the dietary habits of the adults involved, which was relatively more convincing and of public health significance. Potential limitations have also existed. Firstly, external fluoride exposure was not assessed. Although drinking water is the main pathway for fluoride intake, and the water fluoride in the study area remained stable throughout the year according to surveillance reports of the local Center for Disease Control and Prevention, it is also deserving to consider the influence of different routes of fluoride intake in further studies. Additionally, the lifestyle information of the participants was obtained based on a questionnaire, so there may be unavoidable recall bias. Besides, eating more fruits was beneficial for preventing OAD, but the detailed information on fruit types was not investigated. There are differences in the nutrients contained in different fruits, and more comprehensive information will facilitate a better epidemiological understanding of the protective effects of nutrients on health. More comprehensive research is underway.

5. Conclusion

Higher fluoride exposure, age, hip circumference, and poor night sleep quality were risk factors for OAD. In contrast, more fruit intake was associated with a lower OAD risk. Meanwhile, SNPs of CALCA and GNAS, and methylation of GNAS can regulate the degeneration risk. More importantly, interactions between fluoride exposure and personal susceptibility could modify OAD susceptibility. This study revealed the characteristics of high-risk groups of fluoride-related osteoarticular degeneration from the perspective of genetic factors and lifestyle/physiological traits, which is beneficial to provide a scientific basis for the prevention of fluorosis.

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