Abstract

Highlights:

  • Fluoride exposure could interfere with HPT axis hormones levels in adult males.
  • A nonlinear association between serum GnRH and UF concentrations was observed.
  • Serum calcium improved the interference of fluoride exposure on HPT axis hormones.
Numerous studies have reported the toxicity of fluoride to the male reproductive system, but epidemiological evidence is limited. We conducted a cross-sectional study in Kaifeng City, Henan Province in 2011 to explore the association between fluoride exposure and hypothalamic-pituitary-testicular (HPT) axis hormones in men. Morning urinary fluoride (UF), serum HPT axis hormones and serum calcium (SC) concentrations were detected. Percent changes and 95% confidence intervals in HPT axis hormones associated with UF were estimated using adjusted linear regression models, and performed subgroup analysis based on SC levels. The restricted cubic spline model was used to fit nonlinear relationships. For every 10% increase in UF, the concentrations of serum GnRH, T, SHBG and TSI decreased by 2.13%, 2.39%, 2.19% and 1.96%, while E2 and FEI increased by 1.11% and 3.33%. Subgroup analysis showed that for every 10% increase in UF, the levels of GnRH, T, TSI and FTI decreased by approximately 3.15%, 5.49%, 4.47% and 5.14%, while the E2 level increased by 2.92% in low-serum-calcium group (LCG). The levels of GnRH and T decreased by approximately 2.97% and 1.82% in medium-serum-calcium group (MCG). In high-serum-calcium group (HCG), serum SHBG levels decreased by 4.70%, while FTI and FEI levels increased by 4.93% and 4.20% as UF concentration increased (P<0.05, respectively). The non-linear relationship between serum GnRH and UF concentrations presented an approximately inverted U-shaped curve, with a turning point UF concentration of 1.164mg/L (P<0.001), and their nonlinear relationship in LCG and MCG were similar to that in the overall subjects. In conclusion, excessive exposure to fluoride can interfere with male serum HPT axis hormones, and a moderate increase in SC alleviates the effect of fluoride. Prospective cohort studies are essential to confirm the causality.

Introduction

Fluorine is the element with the highest electronegativity and often exists in the form of fluoride. It is widely distributed in soil, rock, and water1. Fluoride toxicity in humans includes not only skeletal damage such as dental fluorosis and skeletal fluorosis2, 3, but also non-skeletal damage to other organ systems such as the reproductive system4, 5, nervous system6, digestive system7, 8, endocrine system9 and cardiovascular system10. The reproductive toxicity of fluoride has received more attention worldwide.
It is estimated that infertility afflicts 8%?12% of couples globally, with male factors contributing to roughly 50% of infertility in couples11. Numerous health conditions can affect male fertility. Male reproduction, development, and maintenance of male sexual characteristics are principally governed by the hypothalamic-pituitary-testicular (HPT) axis. Genetic, environmental and lifestyle factors can disrupt male reproductive potential by interfering with the delicate balance of the HPT axis, influencing testicular steroidogenesis and metabolic homeostasis12, potentially culminating in testicular failure13. Previous studies have reported the capacity of sodium fluoride to penetrate both the blood-brain barrier14 and testicular barrier15, elicit the detriment upon the hypothalamus, pituitary gland and gonadal, and disrupt the normal process of sperm development16. Furthermore, fluoride evinces the capability to interrupt the enzymatic activities necessary for proper substance and energy metabolism within germ cells, followed by testosterone synthesis disorder17. Experimental studies have shown that fluoride can affect the hormone levels of the HPT axis and interfere with male reproductive endocrine system18. However, population-based epidemiological evidence on the association between fluoride exposure and HPT axis hormones levels is still limited.
Experiments have revealed that an appropriate concentration of extracellular calcium ions might mitigate the deleterious effects of fluoride exposure on osteoblasts19. Calcium supplementation to female rats ameliorates the adverse effects of fluoride on biochemical, hormonal, and histological parameters20. Calcium carbonate can protect against fluoride-induced bone injury by suppressing endoplasmic reticulum stress and mitochondrial dysfunction21. Calcium appears to be essential in terms of reducing fluoride toxicity. Therefore, it is worth exploring whether different serum calcium levels influence the association between fluoride exposure and serum HPT axis hormones.
Although the reproductive toxicity of fluoride has received widespread attention, the population-based epidemiological evidence is still insufficient. We conducted this cross-sectional study to explore the relationship between urinary fluoride (UF) concentration and serum HPT axis hormones levels in males, and whether serum calcium (SC) can modify this association, hoping to provide an epidemiological evidence for the damage of fluoride on the reproductive system.

Section snippets

Study population

Seven villages in Kaifeng City of Henan Province were selected based on the monitoring data of water fluoride content, including four endemic fluorosis villages and three control villages. Detailed information about the study’s design can be found elsewhere22, 23. Except for fluoride level in drinking water, the natural, economic, and living conditions, population composition, crop type, living habits, and dietary structure were similar in these villages, according to the information provided

The distribution of variables in CG and HFG

A total of 339 males aged 18?55 years were included in this study (226 (66.7%) in CG and 113 (33.3%) in HFG), with a median UF concentration of 1.15 mg/L. As shown in Table 1, the differences in age, BMI, current smoker, alcohol consumption, and income between the CG and HFG were not statistically significant (P > 0.05). However, considering their potential confounding effect, we still included them as adjustment variables in the subsequent model. The median concentrations of GnRH and SHBG in

Discussion

Excessive fluoride exposure has been linked to negative impacts on male reproductive function, according to numerous studies30, 31, 32. However, previous studies on the effects of fluoride exposure on reproductive hormones were not entirely consistent, and the role of calcium as an antagonist to fluoride was not considered.
In this cross-sectional study, we found significant negative correlations between UF concentration and serum levels of GnRH, T, SHBG, and TSI, while serum concentrations of E2

Conclusion

Excessive fluoride exposure was associated with changes in serum hypothalamic-pituitary-testicular axis hormones, and moderate increase in serum calcium alleviates the interference of fluoride on hormones levels in males from drinking water fluorosis areas.

Compliance with ethical standards

All procedures were approved by the Institutional Review Board at Zhengzhou University in China and the methods were carried out in accordance with the relevant guidelines and regulations. Informed consent was obtained from all subjects.

Funding

This research was funded by the National Natural Science Foundation of China (81072247).

Declaration of Competing Interest

None