Does Fluoride Affect Serum Testosterone and Androgen Binding Protein with Age-Specificity? A Population-Based Cross-Sectional Study in Chinese Male Farmers


Many studies have demonstrated that exposure to excess fluoride was associated with a variety of diseases. Little is known about the variation of testosterone (T) levels caused by fluoride exposure. The aim of this study is to explore the association of fluoride exposure and age with serum T and androgen-binding protein (ABP) levels in male farmers. A cross-sectional study was conducted in a county of Henan Province, China, including high fluoride exposure from drinking water villages and control villages. Male farmers aged 18–55 years old who lived in these villages were recruited by cluster sampling and divided into a higher fluoride exposure group (HFG) and a lower fluoride exposure group (LFG) according to the level of urinary fluoride. Levels of T and ABP in serum were measured using chemiluminescence immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA) respectively. Markedly lower T levels were observed in male farmers from the HFG than in those from the LFG (t = 2.496, P < 0.05). Furthermore, younger farmers, 18–29 and 30–39 years old, may be the most likely to have lower T levels when exposed to fluoride (P < 0.05). No significant differences were observed in serum ABP levels in all male farmers between the two groups with different fluoride exposure. These results supported that excess fluoride exposure decreased serum T levels of male farmers with age-specificity.


Fluoride, an ionic compound of fluorine, occurs naturally at varying levels in rocks, water, and soil because of its high reactivity [1]. A low dosage of fluoride has been established to be beneficial for dental health [2] but researchers have demonstrated that exposure to excess fluoride was associated with a variety of diseases including dental fluorosis, skeletal fluorosis, the impairment of thyroid function, and cerebellar development [35]. Recently, an increasing number of studies have focused on the reproductive damage of excess fluoride exposure. Although it is inconclusive that fluoride exposure affects the weight of testis and epididymis of rats [6, 7], most animal experimental research believed that high fluoride exposure could affect the quantity and quality of sperm, damage the structure of testis, epididymis and prostate, subsequently affecting male’s reproductive ability [8, 9]. Testosterone (T), a hormone mainly secreted by the Leydig cells that plays an unparalleled role in the reproductive system, was also believed to be an important biomarker in the study of reproductive damage caused by fluoride. Animal experiments revealed that excess fluoride exposure could damage Leydig cells and Sertoli cells, and reduce the serum T levels in rats [7, 10, 11]. Hao et al. found that serum T level in males from fluoride exposure village was significantly lower than that from the control village [12]. Susheela et al. presented a similar result in skeletal fluorosis patients in India [13]. Han et al. observed that fluoride exposure changed the structures and the expressions of reproductive related genes in the hypothalamus-pituitary-testicular axis of male mice, but they did not find a difference of serum T level in the different fluoride exposure groups [14]. Zhu et al. also did not find a significant difference in serum T level in males from fluoride exposed area compared with in those from the control area [15]. Up to date, it is unclear how fluoride affects sexual hormones like T although previous studies pointed to the adverse effect of fluoride on male reproductive functions. Androgen-binding protein (ABP), mainly secreted by the Sertoli cells, specifically binds to T or dihydrotestosterone, making them less lipophilic and more concentrated in the seminiferous tubules, and aids in the transport of these hormones throughout the body, which continue to play a role in the target organs [16]. However, it is inconclusive if fluoride affects the serum ABP level subsequently implicating the secretion of T.

On the other hand, free T level decreases gradually with age, although there exists an important variability between individual levels [17]. There is good evidence that the age-associated decrease in T levels is at least a co-determinant of the symptoms of aging [17]. In addition, some of the environmental factors that affect reproductive hormones are associated with age. A cross-sectional study conducted by Ananda et al. showed that serum T concentrations were significantly correlated with cellular zinc concentrations and dietary zinc restriction in normal young men, and was associated with a significant decrease in serum T concentrations after weeks of zinc restriction [18]. Zhao et al. observed that serum free T level of males exposed to Bisphenol A decreased especially in those age 30 or older [19]. However, little is known if the variation of serum reproductive hormone caused by fluoride exposure in male is with age specificity. In the present study, we supposed that different serum T and ABP levels may exist in different age groups with long-term fluoride exposure from drinking water. Thus, we conducted a cross-sectional study in endemic fluorosis and control villages to evaluate the impact of fluoride exposure on the levels of T and ABP in serum in male farmers of different ages.

Materials and Methods

Location and Population

Detailed information regarding the study design is described elsewhere [20]. Briefly, seven villages in Tongxu County in Henan Province were selected and divided according to fluoride concentration in drinking water (Chinese Sanitary Standards for Drinking Water), which included four endemic fluorosis villages and three control villages. Male farmers aged 18–55 years old who were born in the investigated villages or lived there for at least 5 years were recruited via cluster sampling. A total of 348 eligible subjects were recruited, with a 96.94 % participate rate, and then divided into two groups according to urinary fluoride (UF) concentration, with 1.6 mg/L as the cutoff value for high fluoride burden [21]. The higher fluoride exposure group (HFG) was defined as subjects with urinary fluoride levels greater than or equal to 1.6 mg/L and the lower fluoride exposure group (LFG) was defined as subjects with UF levels less than 1.6 mg/L. Interviews were conducted on those who agreed to be interviewed by trained study interviewers at the clinic of the investigated villages. After obtaining written consent, a standardized, structured questionnaire was used to collect information on occupational history and other suspected impact factors for fluoride exposure and serum reproductive hormone levels such as living habits, medical conditions, marriage status, medication uses including supplemental vitamins, smoking and alcohol consumptions, the main source of heating and cooking fuel and dietary intakes and so on. Fasting blood and instant urine samples were collected during the interview, and the fasting blood samples were then centrifuged and stored at −80 °C for further study. All procedures were performed in accordance to protocols approved by the Human Investigation Committees at Zhengzhou University.

Detection of the Levels of Fluoride Exposure and Serum Reproductive Hormones

We assessed participants’ recent exposure to fluoride from air, drinking water, vegetables, and grains such as wheat and corn, as well as measured fluoride levels in the urine samples using fluoride ion selective electrode (Shanghai Exactitude Instrument Company, China). Detailed information of fluoride exposure detection was described in our previous publication [22]. All the serum samples were stored in a −80 °C freezer and had no thaws prior to assay for T and ABP levels. T and ABP levels were measured in fasting blood plasma samples using chemiluminescence immunoassay (CLIA) and enzyme-linked immunosorbent assay (ELISA), respectively. The CLIA test kit and chemiluminescence apparatus were provided by Autobio Company (LUmo Luminometer, Autobio Labtec Instruments Co. Ltd., Zhengzhou, China), the ELISA test kit was provided by R&D Company (USA), and the Microlab FAME was provided by Biotek Company. Each sample ran in duplicate, and 15 % of total samples were retested randomly for quality control.

Data Analysis

The database was established using Epidata 3.0 software (Epidata 3.0 for windows, Epidata Association Odense, Denmark), and all the data was double entered into the database by different people. The Student’s t test was employed to compare age and serum T levels among groups with different fluoride exposures. In addition, current smokers were defined as having smoked at least one cigarette a day for more than a month, tea drinkers were defined as who drink tea at least three times a week and alcohol consumption as drinking at least 50 ml liquor a week for more than a month. A chi-square test was performed to test for the differences in distributions of age, marital status, smoking, alcohol consumption, tea-drinking, educational attainment, average monthly income, and frequency of sexual activity per week between farmers in the HFG and the LFG. Median and inter-quartile of ABP levels (serum ABP levels were skewed distribution) were calculated separately among males living in the LFG and the HFG, and differences between the two groups were tested for statistical significance using the Mann–Whitney U test. Furthermore, Person correlation analysis was used to evaluate the correlation of age and T in each group, and the interaction between age and fluoride exposure on T and ABP levels was evaluated by the general linear model (GLM) of factorial design. Lastly, subjects in each group were divided into four different age groups (18–29, 30–39, 40–49, and 50–55 years) using approximate inter-quartile range (IQR), and then Student’s t test was performed to analyze the differences of T levels among groups with different UF exposure. A P value of <0.05 was considered statistically significant. All analyses were performed using the SPSS software, version 21.0 (IBM SPSS In., Chicago, USA).


Distributions of Selected Variables in HFG and LFG

As shown in Table 1, subjects from the HFG were more likely to be smokers compared to subjects from the LFG. Distributions of age, marital status, alcohol consumption, educational attainment, sexual activity per week in farmers, and family average monthly income between farmers in the HFG and the LFG were similar. We also investigated the habit of tea-drinking in all subjects, but no significant differences were observed in tea-drinking habit in all male farmers between the two groups.

Table 1 Distributions of selected variables in two groups

The Concentrations of UF, ABP, and T in Farmers from HFG, LFG

Table 2 presents the levels of UF, ABP, and T across various groups of fluoride exposure in the study population. Mean serum UF level was 0.94 ± 0.31 mg/L in male farmers from the LFG, significantly lower compared to in those from the HFG (2.64 ± 1.03 mg/L). It could be found that the serum T level of farmers in the LFG was higher than that of those in the HFG. In contrast, no significant difference was found in serum ABP levels in farmers between the LFG or the HFG.

Table 2 Statistical significance of UF (mg/L), serum ABP and T levels (nmol/L) between LFG and HFG

The Interaction between Age and UF on Serum T Levels

The interaction between age and fluoride exposure on serum T levels was shown in Table 3. The result showed that UF level was the independent factor which influences serum T level. We also observed a positive interactive effect between age and fluoride on serum T levels (P < 0.001) (Table 3).

Table 3 The interaction between age and fluoride on T levels

The Effect of Fluoride Exposure on Serum ABP and T Levels in Farmers from Different Age Groups

We analyzed the correlation between age and serum T and ABP level in each group. The results suggested that age and serum ABP concentrations in male farmers from the two groups were not correlated (r = 0.049, P = 0.466 for LFG, and r = 0.118, P = 0.208 for HFG). However, a weak negative correlation between serum T levels and age was observed in male farmers from the LFG (r = −0.207, P = 0.002). On the contrary, a weak positive correlation was observed between age and serum T levels in male farmers from the HFG (r = 0.185, P = 0.047). Thus, we further analyzed serum ABP and T levels in the HFG and the LFG according to different age groups (Table 4). In 18–29 years group and 30–39 years group, serum T level was lower in farmers from the HFG compared to in those from the LFG (P < 0.05). No significant differences were observed in the 40–49 and 50–55 years groups between the HFG and the LFG (P > 0.05). Furthermore, no significant differences of ABP levels were found in farmers between the HFG and the LFG in every age group.

Table 4 Statistical significance of serum ABP and T (nmol/L) levels in men between LFG and HFG with different age groups


Endemic fluorosis is a major public concern in China due to the excessive consumption of fluoride in drinking water. To date, studies of fluoride’s adverse effects mainly focus on bone and dental damage. Few epidemiological studies paid attention to the effect of fluoride exposure on human reproductive hormones with a larger sample size, although some of the studies observed the reproductive damage in animal experiments [23, 24]. T is an important reproductive hormone for mammals and could affect the bone micro architecture of males, the development of sperm cells, and the spermatic morphology [2527]. In the current study, we observed that serum T level of male farmers in HFG was lower than that in LFG, which was consistent with several previous epidemiological and experimental studies [12, 28, 29]. In view of the influence of age on serum T level in males, we further analyzed the interaction of age and UF on serum T levels. The result indicated that fluoride is the independent factor that influences serum T level. Interaction of age and fluoride on serum T level was also observed. However, we did not find a positive result between age and serum T levels in the whole of the investigated participants. Accordingly, we analyzed the correlation between age and serum T level in each group. Surprisingly, we observed the opposite result in different fluoride exposure group, a weak negative correlation in LFG, and a weak positive correlation in HFG. It may explain the negative result of age on serum T levels in the whole participants that the strong effect of fluoride offsetting the effect of age on serum T level. Previous studies on the effect of fluoride or age on serum T levels may support our result. For example, Hao and Chen reported that the serum T level was downregulated in males exposed to excess fluoride [12, 30]. On the other hand, Kelsey et al. believed that the total T decreased with age but stopped declining after age 40 [31]. Sartorius et al. also observed that serum T did not decrease with age among healthy men over age 40 [32]. The results mentioned above suggest that 40 may be a key age when adult male’s serum T is stabilized.

Subsequently, we stratified and analyzed the study population by age for the serum T and ABP levels in male farmers from different fluoride exposure groups to explore whether the fluoride affects serum reproductive hormone with age specificity or not. We noted that the serum T levels of farmers aged 18–29 and 30–39 years from the HFG were lower than in those from the LFG, but no significant differences were observed in male farmers aged 40–49 and 50–55 years between the two groups. It is noteworthy that farmers aged 18–29 years have the lowest average levels of serum T in HFG compared with those in all other age groups. This result suggested that young males may be more susceptible to fluoride exposure. We mentioned in the introduction that Zhao et al. observed that serum free T level of workers exposed to Bisphenol A decreased, especially in those aged 30 or older [19]. Combined with our result, we supposed that serum T may be susceptible to some chemicals with age specificity. Certainly, the secretion and production of T are very complicated processes and many factors, such as diet, unhealthy habits like alcohol consumption and tobacco use, as well as some chronic metabolic diseases, affect the secretion and metabolism of T. It was found that alcohol intake affects the activity of the HPG axis [33] and exerts its harmful effect directly on the testes by reducing the testicular biosynthesis of T [34]. Recent research showed that osteocalcin acts male reproductive functions by promoting testosterone biosynthesis via a pancreas-bone-testis axis that regulates, independently of and in parallel to the hypothalamus-pituitary-testis axis [35]. Preclinical studies also suggested that osteoblasts were able to induce T production by the testis, a process mediated by osteocalcin [36]. The change in serum T level as the result of fluoride on skeleton cannot be concluded. Nevertheless, the current results gave us a hint that we should pay more attention to young males of reproductive age in the study of reproductive damage caused by fluoride exposure. Further studies on the exact mechanism involved in the fluoride on reproductive hormones need to be considered in the greater population.

Differences of ABP level among the male farmers from the LFG and the HFG were not observed in the present study. ABP could bind and transport androgen, especially T, to protect them from degradation [37, 38] and control their bioavailability in the testis, which facilitates the development and maturation of spermatogenic cells [39]. Thus, high levels of ABP are essential for maintaining the microenvironment as well as enabling spermatogenesis in the seminiferous tubules and sperm maturation in the epididymis. Few studies explored the influence of fluoride on serum ABP although some studies found that Sertoli cells, a very important cell for ABP secretion, could be damaged by fluoride exposure in animal experiments such as apoptosis in the Sertoli cells of rats and so on [10, 11]. Whether the change of serum ABP level is the consequence of Sertoli cell damage caused by fluoride exposure is unclear. The current study showed that in different age groups of 18–29, 30–39, 40–49, and 50–55 years old, there were no significant differences in serum ABP levels in male farmers between the HFG and the LFG. It suggested that serum ABP level in males may not be associated with either fluoride exposure or age in our study population.


In conclusion, this study shows that the serum T level, not ABP level, is associated with fluoride exposure in male farmers. Young farmers (aged 18–29 years old) may be more susceptible to fluoride exposure, with serum T levels decreasing. This result may provide the basis for making health policies to prevent reproductive barriers that result from excess fluoride exposure. Further research should conduct longitudinal approaches to confirm these results and experimental research is also necessary to explore the mechanism as to why serum T in young males is more susceptible to fluoride exposure.


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We express our sincere thanks to all individuals who volunteered to participate in this study and the numerous doctors and nurses of the Tongxu Center for Disease Prevention and Control. The study was supported by the grant 81072247 from the National Natural Science Foundation of China and grant 13 A330653 from the Education Department of Henan Province, China.

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Correspondence to Yue Ba.

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All procedures were performed in accordance to protocols approved by the Human Investigation Committees at Zhengzhou University.

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Duan, L., Zhu, J., Wang, K. et al. Does Fluoride Affect Serum Testosterone and Androgen Binding Protein with Age-Specificity? A Population-Based Cross-Sectional Study in Chinese Male Farmers. Biol Trace Elem Res 174, 294–299 (2016).

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  • Fluorine
  • Male
  • Androgen binding protein
  • Testosterone
  • Age