Longitudinal associations between early-life fluoride exposures and cardiometabolic outcomes in school-aged children.

Abstract

Highlights

We evaluated longitudinal associations between repeated fluoride measures and cardiometabolic outcomes in children.
Dietary fluoride altered levels of lipids, adipokines, and diabetes-related biomarkers in children during 4–8 years of age.
Dietary fluoride increased zBMI and odds of overweight/obesity status in children at age 8.
Fewer, though consistent, associations were observed with respect to urinary fluoride.
Stronger fluoride-induced associations were observed in boys at age 8 and in girls prior to age 8.

Background/Aim

Fluoride is a natural mineral present in food, water, and dental products, constituting ubiquitous long-term exposure in early childhood and across the lifespan. Experimental evidence shows fluoride-induced lipid disturbances with potential implications for cardiometabolic health. However, epidemiological studies are scarce. For the first time, we evaluated associations between repeated fluoride measures and cardiometabolic outcomes in children.

Methods

We studied – 500 Mexican children from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort with measurements on urinary fluoride at age 4, and dietary fluoride at ages 4, 6, and 8 years approximately. We used covariate-adjusted linear mixed-effects and linear regression models to assess fluoride associations with multiple cardiometabolic outcomes (ages 4–8): lipids (total cholesterol, HDL, LDL, and triglycerides), glucose, HbA1c, adipokines (leptin and adiponectin), body fat, and age- and sex-specific z-scores of body mass index (zBMI), waist circumference, and blood pressure.

Results

Dietary fluoride intake at age 4 was associated with annual increases in triglycerides [B per-fluoride-doubling = 2.02 (95 % CI: 0.37, 3.69)], cholesterol [B = 1.46 (95 % CI: 0.52, 2.39)], HDL [B = 0.39 (95 % CI: 0.02, 0.76)], LDL [B = 0.87 (95 % CI: 0.02, 1.71)], and HbA1c [B = 0.76 (95 % CI: 0.28, 1.24)], and decreased leptin [B = -3.58 (95 % CI: -6.34, -0.75)] between the ages 4 and 8. In cross-sectional analyses at age 8, higher tertiles of fluoride exposure were associated with increases in zBMI, triglycerides, glucose, and leptin (p-tertile trend < 0.05). Stronger associations were observed in boys at year 8 and in girls prior to year 8 (p-sex interaction < 0.05). Fewer but consistent associations were observed for urinary fluoride at age 4, indicating increased annual changes in HDL and HbA1c with higher fluoride levels.

Conclusion

Dietary fluoride exposures in early- and mid-childhood were associated with adverse cardiometabolic outcomes in school-aged children. Further research is needed to elucidate whether these associations persist at later ages.

Full-text article online at https://www.sciencedirect.com/science/article/pii/S0160412023006487?via%3Dihub

EXCERPTS:

We found evidence to suggest a potential dysregulated metabolism induced by fluoride that differed by sex in pre-pubertal children. In Mexico, fluoride exposure primarily originates from fluoridation in salt (Cantoral et al., 2019), followed by naturally occurring drinking-water fluoride exposure (Armienta and Segovia, 2008, Farías et al., 2021). Greater consumption of fluoride-based diets or salty foods in boys at later ages could explain higher fluoride levels in this population and subsequent altered metabolism as evidenced by a higher level of fluoride estimated in boys than girls across all ages and media. Most importantly, we observed that fluoride associations in boys were stronger than in girls during the last follow-up visit where fluoride levels were the highest across time points. However, differences in exposure levels may not fully explain sex interactions, and divergent effects could also be attributed to sex-differences in fluoride absorption, metabolism and/or secretion. During the start of puberty, a wide array of metabolic changes can occur and create susceptibility to endocrine-disrupting chemicals, which can result in delayed or advanced puberty onset (Chen et al., 2011, Grandjean et al., 2012, Harley et al., 2017). In our study, we only found consistent effect modification effects by male sex in cross-sectional analyses around 8 years of age in the last follow-up, though we observed for some biomarkers (triglycerides and adiponectin) interactions by female sex prior to age 8. Previous cross-sectional studies conducted in a Mexican population of adolescents ages 10–18 (Liu et al., 2020) and in a Chinese cohort of children ages 7–13 (Liu et al., 2019) indicated fluoride-induced cardiometabolic effects in girls but not in boys. Even though these studies did not measure dietary fluoride, the latter study in Chinese children measuring urinary fluoride indicated substantially lower average exposure concentrations of about half (0.4 mg/L) the levels in our cohort (0.7 µg/mL). Estimated urinary fluoride levels in our cohort are consistent with previously reported levels in other populations living in areas with water fluoride levels below the recommended safety standard limits (Green et al., 2020, Zohoori et al., 2013, Czarnowski et al., 1996) established in drinking water by the WHO (1.5 mg/L) and the CDC (2.0 mg/L) in the general population (Boehmer et al., 2023, WHO, 2017). The inconsistent results found in Mexican boys around age 8 compared to the results from the aforementioned cross-sectional studies indicating stronger association at later ages in girls may suggest possible susceptible windows for fluoride exposure at different concentrations that could affect cardiometabolic health outcomes distinctly across the life course. This warrants further investigation in other longitudinal cohorts with longer follow-up through adolescence and with variability in fluoride exposures.