Skip to main content
Bioscience Reports logoLink to Bioscience Reports
. 2017 Jul 27;37(4):BSR20170678. doi: 10.1042/BSR20170678

Higher urinary bisphenol A concentration and excessive iodine intake are associated with nodular goiter and papillary thyroid carcinoma

Zhenzhen Zhou 1,*, Jing Zhang 1, Fang Jiang 2, Yan Xie 3, Xiaochen Zhang 4, Ling Jiang 1,
PMCID: PMC5529210  PMID: 28684549

Abstract

In the present study, we investigated whether bisphenol A (BPA) levels and excessive iodine intake were associated with papillary thyroid carcinoma (PTC) and nodular goiter (NG). We determined total BPA concentrations (TBC) in paired serum and urine samples, and urinary iodine concentrations (UIC) in urine samples collected from PTC patients, NG patients, and healthy individuals, then compared BPA concentrations and UIC within and between each patient group. The results showed that there were no gender-specific differences in serum TBC and UIC in each group, and no differences across all patient groups. Urinary BPA concentrations (UBC) were higher in the NG and PTC groups compared with the control group. UBC showed gender-specific differences in the NG and PTC group. Furthermore, UIC were higher in the NG and PTC groups compared with the control group. Higher UBC and excessive iodine intake were risk factors for NG and PTC according to multivariate logistic regression analysis. There was a significant correlation between UBC and UIC in each group. These data suggested that higher UBC and excessive iodine intake are associated with NG and PTC. The metabolic and functional pathways between BPA and iodine are potentially linked to the pathogenesis and progression of NG and PTC.

Keywords: Bisphenol A, endocrine disrupting chemical, iodine excess intake, nodular goiter, papillary thyroid carcinoma

Introduction

In recent years, studies have shown that thyroid-related diseases, such as nodular goiter (NG) and papillary thyroid carcinoma (PTC), are associated with endogenous estrogen activity [15].

Bisphenol A (BPA) is a widely used organic compound and applied in a variety of manufacturing processes [6]. Humans are exposed to BPA in a variety of ways, including dietary ingestion, dermal contact, inhalation, and intravenous administration [68]. BPA has shown to be detectable in human serum, urine, breast milk, cord blood, and mammary tissue [9]. Indeed, it has been detected in 92.6% of volunteers participating in the 2003–2004 National Health and Nutrition Examination in U.S.A. [10], and more than 80% in a sample of 129 Danish children and adolescents [11], and 50% of Chinese people [12]. Exposure to BPA is, therefore, highly prevalent worldwide. BPA is an endocrine disrupting chemical (EDC), acting as a ligand at the estrogen receptor, thereby influencing hormone biosynthesis and metabolism, and interfering with reproduction [1316]. Studies have shown that free BPA can competitively bind to thyroid hormone receptors and inhibit the expression of genes regulated by thyroid hormones [17]. Few studies have examined the possible relationship between BPA and thyroid diseases, such as NG and PTC.

Iodine is an essential element for thyroid function and acquired from the diet. Deficiency or excess of iodine intake has been associated with thyroid disease, including autoimmune thyroiditis, hyperthyroidism, NG, and thyroid cancer [1824]. However, the relationship between BPA exposure and excess iodine intake and their association with PTC and NG remain unclear.

In the present study, we examined serum and urine BPA levels and urine iodine levels in patients with NG and PTC, and investigated the relationship between BPA and iodine exposure and their potential association with NG and PTC.

Materials and methods

Patients and sample collection

Our study was approved by the committee on Human Research at Qilu Hospital of Shandong University, China. Written informed consent was provided by all participants in the study.

All participants were classified into three groups: PTC group, NG group, and healthy control group. Seventy-one patients with NG and 66 patients with PTC pathologically diagnosed were selected from February 2013 to September 2013 in Qilu Hospital of Shandong University, Jinan, Shandong Province, China. Patients were excluded according to the following criteria: (i) abnormal thyroid function, (ii) history of hyperthyroidism or hypothyroidism, (iii) administration of anti-thyroid drugs or thyroid hormone previously, and (iv) abnormal renal function or hepatic function. Finally, 53 PTC patients and 60 NG patients were included in the study. For the healthy control group, 148 healthy volunteers in Jinan were recruited and subjected to examination of the thyroid gland with thyroid ultrasound, and serum tests for thyroid function and hepatic/renal function. Those who had NGs, thyroid cysts, abnormal thyroid function, or abnormal hepatic or renal function were excluded. Finally, 65 volunteers were included into the healthy control group. Blood and spot urine samples were collected in the morning pre-operatively (fasting time >8 h). Serum samples were collected in 5 ml of BPA-free glass tubes from whole blood samples by centrifugation within 2 h, then stored at –80°C for further analysis. Urine samples were collected in 5 ml of BPA-free glass tubes and stored at –20°C. Thyroid hormones (free-T3, free thyroxine, and TSH) were determined with an autoanalyzer (ADVIA centaur Automated Chemiluminescence System, Simens AG, Germany) in Qilu Hospital. The measurement of urinary creatinine was performed with an autoanalyzer (Roche C8000 Chemistry System, Roche, Switzerland).

Determination of BPA concentrations

Total (free plus conjugated) urinary and serum BPA concentrations were determined using an HPLC–MS/MS (TSQ vantage, Thermo Electron Corporation, U.S.A.) according to a previously published method [25] after zymohydrolysis by isotope-dilution in solid-phase extraction at the Shandong Province Analysis and Test Center, Shandong Academy of Sciences. In brief, 20 μl (50 ng) of D16-BPA (Dr Ehrenstorfer GmbH, Augsburg, Germany) and 50 μl of β-glucuronidase/sulfatase (Helixpomatia, Sigma–Aldrich, St. Louis, MO, U.S.A.) were dissolved in sodium acetate (pH 5.5), were added to urinary samples (1 ml) or serum samples (0.5 ml), mixed, diluted with 1 ml of water for urine and 2 ml of water for serum, and incubated in a water bath at 37°C for 3 h. Mixtures were then vacuum-pumped to pass through the 4 ml of methanol and 3 ml of water pre-conditioned C18 SPE (solid-phase extractor) cartridges (2.8 μm, 100 A, 2.1×100 mm, Agela Technologies Inc., Delaware, U.S.A.) at 1 ml/min and washed with 2 ml of water and 3 ml of water/methanol (3:20). BPA on the SPE cartridges was eluted with 4 ml of methanol into glass tubes, evaporated/dried in nitrogen, dissolved in 200 ml of methanol, and subjected to HPLC–MS/MS analysis. One to ten nanograms of BPA (Helixpomatia, Aldrich–Sigma, St. Louis, MO, U.S.A.) was spiked to the urine samples, and 5 ng of BPA was spiked to the serum of six healthy individuals as technical controls. The recovery of spiked BPA in the urinary samples ranged from 103 ± 7% to 99 ± 7% and the recovery of BPA was 98 ± 5% for serum samples. The relative standard deviation (RSD) of the analysis was <11%. Systematic error was analyzed using 1 ml of Mill-Q water spiked with 1 ng of BPA. The blank control of BPA in human urine or serum [26] was prepared by mixing samples from six healthy individuals. The linear range was 0.10–100 ng/ml for BPA, and the regression coefficient R2 was >0.995. The RSD were <10.8% and <8.6% for urine or serum samples respectively. SPE analysis was followed according to a previously published report [25]. The limit of quantification (LOQ) of BPA was 0.1 ng/ml for urine and 0.2 ng/ml for serum.

Determination of iodine

UIC were determined according to the Sandell–Kolthoff reaction after ammonium persulfate treatment. The detection limit was 3 μg/l. The linear range of the standard curve was 0–300 μg/l with a standard deviation of 2.8–5.5%. The regression coefficient was R2 >99%. The recovery of iodine was 92.6–107.0%. According to the epidemiological criteria for assessing iodine nutrition based on median UIC announced by WHO and UNICEF, UIC <99 μg/l is considered as iodine deficiency, 100–199 μg/l as adequate iodine nutrition, 200–299 μg/l as above requirements of iodine intake, and >300 μg/l as excess iodine intake. In the present study, the UIC ranged from 142.90 to 1409.90 μg/l, so we classified the subjects into non-excessive iodine intake and excessive iodine intake according to the aforementioned UIC classifications in order to investigate the association between excessive iodine intake and thyroid diseases.

Determination of creatinine and adjustment of BPA and iodine concentrations to creatinine

The concentration of creatinine in urine samples was determined using the basic picric acid method and used to normalize urine BPA and iodine concentrations (herein referred to as adjusted concentration) to eliminate variations resulting from sample processing and handling.

Statistical analysis

Statistical analysis was performed using SPSS 19.0 software (SPSS Inc., Chicago, IL, U.S.A.). A value of 0.05 ng/ml was assigned as the standardized BPA level, which was below LOQ according to a previously published study [12,13]. Normal distribution of data, including creatinine-adjusted and unadjusted UIC, urinary BPA, and serum BPA concentrations, were tested using one-way analysis of variance. Other data were analyzed using Mann–Whitney U test. Analysis of Spearman’s rank correlation coefficient was performed to examine the relationship among paired serum and urinary BPA concentrations (UBC), creatinine-unadjusted/adjusted UBC and UIC. The Chi-square test was used to analyze the differences in the rates of excessive iodine intake and detection rates of UBC among the NG, PTC, and control groups. There was no standard range and classification of UBC. In order to analyze conveniently, we used receiver operating characteristic curve to cut off the UBC (>2.84 ng/ml, AUC = 0.70) and creatinine-adjusted UBC (>5.90 μg/g, AUC = 0.72). We carried out logistic regression analyses to evaluate the odds ratios (ORs) of the higher UBC (>2.84 ng/ml), creatinine-adjusted UBC (>5.90 μg/g), and excess iodine intake for thyroid disease.

Results

Urine but not serum BPA concentrations are associated with NG and PTC

We first examined BPA concentrations in all paired urine and serum samples. The results showed that all serum samples contained detectable BPA (free BPA and conjugated BPA) that ranged from 4.03 to 13.82 ng/ml (Table 1). There were no differences in serum TBC among the NG, PTC, and the healthy control groups (Table 1). UBC were detected in all samples of three groups (Table 1). UBC, either unadjusted or adjusted according to creatinine concentrations, in the NG group and the PTC group were significantly higher than those of the healthy control group (P=0.00 and P<0.04 respectively) (Table 1). However, there was no difference in the creatinine-unadjusted/adjusted UBC between the NG group and the PTC group (Table 1). These results suggested that high UBC but not serum TBC were associated with NG and PTC.

Table 1. Serum and UBC in the study groups.

Characteristic Overall PTC group NTG group Healthy control group
Participants 178 53 60 65
Sex
  Male 50 14 14 22
  Female 128 39 46 43
Serum BPA (ng/ml)
  Detection rate (N / percent) 178/100 53/100 60/100 65/100
  Range 4.03–13.82 4.33–13.82 4.26–11.51 4.03–13.81
  GM 7.42 7.61 7.07 7.62
  Median 7.50 7.45 7.07 8.06
  P25 6.61 6.87 6.28 4.70
  P75 8.77 8.37 8.41 10.38
Higher urinary BPA (>2.84 ng/ml) (N / percent) 121/68 41/77 50/83 30/46
Urinary BPA (ng/ml)
  Detection rate (N / percent) 148/83 51/96 52/87 45/69
  Range 0.05–34.46 0.05–34.46 0.05–30.67 0.05–11.52
  GM 2.26 4.06* 3.35* 0.98
  Median 4.18 4.66 5.03 2.56
  P25 1.74 2.90 3.63 0.05
  P75 7.01 7.68 8.43 5.40
Urinary BPA/creatinine (μg/g)
  Range 0.016–50.78 0.032–29.30 0.022–50.78 0.015–27.88
  GM 2.82 4.68* 5.22* 1.06
  Median 5.46 6.25 7.57 3.00
  P25 2.18 3.01 3.71 0.05
  P75 9.52 8.88 16.45 5.89

*P<0.05, there is statistical difference compared with the healthy control group; GM, geometric mean.

Association of UIC with NG and PTC

We next examined UIC, which ranged from 142.90 to 1409.90 μg/l (Table 2). The results showed that the creatinine-unadjusted/adjusted UIC in the NG group and the PTC group were significantly higher than those of the control group (P=0.00 and P<0.04, respectively) (Table 2). However, there was no difference in UIC between the NG group and PTC group (Table 2). These results suggested that high UIC were associated with both NG and PTC.

Table 2. Iodine concentrations in all groups.

Characteristic Overall PTC group NTG group Healthy control group
Excessive iodine intake (N / percent) 51/29 23/43* 22/37* 6/9
Non-excessive iodine intake (N / percent) 127/71 30/57 38/63 59/91
Urinary iodine (ng/ml)
  Range 142.90–1409.90 169.52–1409.90 144.10–1007.60 142.90–433.70
  GM 268.25 319.66* 273.34* 228.51
  Median 252.45 289.60 271.30 230.20
  P25 215.33 240.20 198.30 184.20
  P75 325.52 399.10 357.83 266.60
Creatinine (g/l)
  Range 0.10–3.24 0.20–2.66 0.11–2.24 0.10–2.24
  GM 0.80 0.87 0.64 0.64
  Median 0.85 0.94 0.70 0.70
  P25 0.53 0.58 0.43 0.56
  P75 1.35 1.31 1.07 1.59
Urinary iodine/creatinine (μg/g)
  Range 71.25–2995.74 94.85–2149.31 77.86–2995.74 71.25–2130.37
  GM 335.05 368.71* 426.02* 248.26
  Median 316.69 355.72 386.25 230.94
  P25 193.57 194.63 260.34 148.57
  P75 551.65 632.14 658.60 396.84

*P<0.05, there is statistical difference compared with the healthy control group.

We next examined the prevalence of excessive iodine intake (UIC >300 μg/l) and non-excessive iodine intake (UIC <300 μg/l) in the PTC group, NG group, and the healthy control group. The results showed that 43% of patients in the PTC group and 37% of patients in the NG group had excessive iodine intake, significantly higher than the control group, at only 9% (Table 2). This supported the notion that high UIC were associated with both NG and PTC. There was no significant difference in the prevalence of excessive iodine intake between the PTC group and the NG group, according to Chi-squared test (Table 2).

Comparison of gender-specific BPA concentrations among the PTC, NG, and healthy control groups

We examined and compared gender-specific BPA concentrations among the PTC, NG, and healthy control groups. The results showed that there was no significant difference in serum TBC between males and females in each group, and indeed, across all groups (Table 3). Only unadjusted UBC in PTC group and adjusted UBC in NG group showed gender-specific differences. The unadjusted UBC in the male PTC group were significantly higher than the female PTC group (P =0.02). The adjusted UBC in the male NG group were significantly lower than the female NG group (P=0.01) (Table 3).

Table 3. Comparison of gender-specific BPA and iodine concentrations among the PTC, NG, and healthy control groups.

Variables GM Median P25 P75 Range
PTC group
Serum BPA (ng/ml)
  Male 8.21 7.52 6.96 9.39 6.80–13.82
  Female 7.40 7.40 6.64 8.13 4.33–12.67
Unadjusted urinary BPA (ng/ml)
  Male 7.27,* 6.35 4.43 12.62 1.99–34.46
  Female 3.29,* 3.91 2.64 5.94 0.05–23.90
Adjusted urinary BPA (μg/g)
  Male 5.87* 6.75 2.98 9.09 2.11–27.38
  Female 4.32*, 6.25 2.86 8.90 0.03–29.30
Unadjusted urinary iodine (ng/ml)
  Male 346.68* 288.30 251.50 417.83 217.20–1409.90
  Female 310.48* 289.60 235.90 401.70 169.52–1058.61
Adjusted urinary iodine (μg/g)
  Male 279.97 280.72 131.02 508.20 94.85–1120.23
  Female 407.01* 414.92 196.03 637.08 111.11–2149.31
NG group
Serum BPA (μg/l)
  Male 7.13 7.29 6.05 8.54 4.39–11.26
  Female 7.05 7.07 6.30 8.35 4.26–11.51
Unadjusted urinary BPA (ng/ml)
  Male 3.24 4.56 3.75 5.70 0.05–7.97
  Female 3.38* 5.32 3.60 9.25 0.05–30.67
Adjusted urinary BPA (μg/g)
  Male 3.45 3.99 3.12 7.54 0.10–11.34
  Female 5.92,*, 10.50 4.72 19.66 0.02–50.78
Unadjusted urinary iodine (ng/ml)
  Male 319.30* 288.30 252.14 402.00 153.10–1007.60
  Female 260.71 246.83 190.10 341.20 144.10–813.25
Adjusted urinary iodine (μg/g)
  Male 339.20* 336.18 232.79 514.34 166.23–709.38
  Female 456.62* 397.05 266.42 714.61 77.86–2995.74
Healthy control group
Serum BPA (ng/ml)
  Male 8.18 8.37 7.33 9.62 4.53–13.52
  Female 7.35 7.82 4.49 10.90 4.03–13.81
Unadjusted urinary BPA (ng/ml)
  Male 1.02 2.70 0.05 6.51 0.05–11.40
  Female 0.96 2.39 0.05 4.57 0.05–11.52
Adjusted urinary BPA (μg/g)
  Male 0.96 2.64 0.03 7.06 0.02–18.08
  Female 1.12 3.45 0.06 5.65 0.02–27.88
Unadjusted urinary iodine (ng/ml)
  Male 222.44 229.00 181.34 254.53 176.21–313.70
  Female 231.68 230.50 185.30 268.27 142.90–433.70
Adjusted urinary iodine (μg/g)
  Male 209.88 162.17 134.40 391.02 82.38–658.62
  Female 270.53 246.96 162.67 443.16 71.25–2130.37

*P<0.05, there is a statistical difference compared to the same gender in the healthy control group.

P<0.05, there is a statistical difference in the same genders between the NG and PTC groups.

P<0.05, there is a statistical difference between the males and females in the PTC, NG, and control groups.

The unadjusted/adjusted UBC in the female NG group were significantly higher than those of the female control group (P=0.00/0.00) (Table 3). In addition, there was no significant difference in the unadjusted/adjusted UBC between the male NG group and the male control group.

The unadjusted/adjusted UBC in both the male PTC group (P=0.01/0.04) and the female PTC group (P=0.01/0.00) were significantly higher than those in the control group of the same gender (Table 3).

Adjusted UBC were significantly lower in the female PTC group than the female NG group (P=0.02), while there was no significant difference in unadjusted UBC between the female PTC group and the female NG group (P=0.09) (Table 3). There were no differences in unadjusted/adjusted UBC between males in the PTC and NG groups (Table 3).

Comparison of gender-specific iodine concentrations among PTC, NG, and healthy control groups

We examined and compared gender-specific UIC in all three groups. The results showed that there were no significant differences in the unadjusted/adjusted UIC between males and females in each group, or between the PTC group and the NG group of the same gender (Table 3). Higher unadjusted/adjusted UIC were found in the PTC or NG groups, compared with the healthy control group of the same gender. Specifically, unadjusted/adjusted UIC were significantly higher in the male NG group than the male healthy control group (P=0.00/0.01) (Table 3), while adjusted UIC in the female NG group were significantly higher than the female healthy control group (P=0.00) (Table 3). Unadjusted/adjusted UIC in the female PTC group were higher than the female healthy control group (P=0.00/0.02) (Table 3). However, unadjusted UIC were higher in the male PTC group than the male healthy control group (P=0.00).

Multivariate logistic regression analysis

We performed a multiple logistic analysis to examine the risk factors for NG and PTC by including age, gender, serum BPA concentration, urine creatinine, unadjusted and adjusted higher UBC, excessive iodine (unadjusted UIC), and adjusted UIC in the model. Our findings demonstrated that unadjusted higher UBC, excessive iodine intake, and age but not SBC or urine creatinine or adjusted UBC or adjusted UIC or gender were risk factors for both NG and PTC (Table 4).

Table 4. Analysis of risk factors for the PTC and NG using multivariable-adjusted logistic regression.

Group B (partial regression coefficient) Crude OR Adjusted OR 95% CI P
PTC group
  Higher urinary BPA* (>2.84 ng/ml) 1.27 3.99 3.57 1.37–9.30 0.01
  Excess iodine intake* 1.72 7.54 5.61 1.84–17.07 0.00
Age 0.09 1.09 1.09 1.05–1.13 0.00
Gender 0.91 / 2.47 0.89–6.86 0.08
NG group
  Higher urinary BPA* (>2.84 ng/ml) 1.82 5.83 6.15 2.16–17.53 0.00
  Excess iodine intake* 1.32 5.69 4.93 1.17–12.10 0.03
Age 0.12 1.11 1.12 1.08–1.17 0.00
Gender 1.31 1.68 3.72 1.27–10.89 0.02

*Unadjusted urinary concentration.

Correlation between serum and urinary BPA and iodine concentrations in PTC and NG patients

We performed a Spearman correlation analysis to examine the relationship between serum and urinary BPA and iodine concentrations in the PTC, NG, and healthy control groups. The results showed that no correlation was observed between serum and UBC, serum BPA and urinary iodine concentrations (UIC), unadjusted BPA and iodine concentrations in each group, although a significant correlation between the adjusted BPA and iodine concentrations in the PTC, NG, and healthy control groups was apparent (Table 5).

Table 5. Correlation between the urinary BPA and iodine concentrations in PTC and NTG patients.

Group R P
PTC (unadjusted) 0.19 0.17
PTC (adjusted) 0.46 0.00
NG (unadjusted) 0.24 0.07
NG (adjusted) 0.49 0.00
Control (unadjusted) −0.06 0.66
Control (adjusted) 0.53 0.00

Discussion

In the present study, we measured the total BPA (free and conjugated) concentrations in all participants with a concentration of 7.42 ng/ml (geometry median value, GM). The detection rate was consistent with a Canadian study [27], in which free serum BPA concentrations were detected between 1.3 and 8.17 ng/ml in non-pregnant women. Free BPA in normal infants reached GM 1.70 ng/ml [28]. Considering that free BPA constitutes 20% of total serum BPA concentration, free BPA in our study subjects was GM 1.48 ng/ml, slightly lower than those in previous studies. In our study, urinary BPA was detected in 83% of participants with GM of 2.26 ng/ml. The results was consistent with the study by Zhang et al. [7], which reported urinary BPA was detectable in 84% of the Chinese adults with GM 1.01 ng/ml. In a U.S. study, urinary BPA was detectable in 93% of the participants with GM 2.6 ng/ml [29]. However, the GM of urinary BPA was 1.05 ng/ml for combined overt and subclinical hyperthyroidism and 0.63 ng/ml for combined overt and subclinical hypothyroidism patients [13]. In a Canadian population, urinary BPA was detectable in more than 90% of children and young adults, with a mean concentration of 1.3 μg/l [30]. Similar findings were demonstrated in a German population [31]. Workers constantly exposed to BPA in the BPA manufacturing factories in China have been shown to have a very high urinary BPA concentration with a median 84.6 mg/g creatinine [32]. In our study, the median adjusted urinary BPA concentration was 5.46 μg/g among study subjects. This suggests that serum and UBC may differ dramatically in different populations, geographical regions, and occupations.

We examined serum and urine BPA levels and urine iodine levels in patients with NG and PTC and found that high UIC and high UBC, but not serum TBC, were associated with NG and PTC. Unadjusted higher UBC, excessive iodine intake, and age, but not adjusted UBC or gender, were risk factors for the development of both NG and PTC. There was significant correlation between adjusted BPA and iodine concentrations, but not serum BPA and urinary iodine in the PTC, NG, and healthy control groups. These data supported the hypothesis that higher UBC and excessive iodine intake correlate and associate with PTC and NG.

In the present study, we found that BPA was detectable in all analyzed samples and no significant difference in serum TBC between males and females in each group and across PTC, NG, and healthy control groups was demonstrated, suggesting that all groups were equally exposed to BPA. This is consistent with a previous study carried out in children and pregnant women in different age groups in China [7]. Free BPA (20%), BPA disulfate (34%), and BPA glucuronide (46%) levels were found in the participants of this study [25]. Absorbed BPA is metabolized in the liver by conjugation with glucuronide and rapidly excreted in the urine within 24 h [33]. BPA entering the bloodstream is eliminated via excretion in the urine [33]. Different from serum BPA, urine BPA comprises of free BPA (32%), BPA disulfate (7%), BPA glucuronide (57%), and BPA chlorides (4%) [25]. Further, urine BPA levels relative to creatinine levels were calculated in order to eliminate errors in determining distribution of BPA. In contrast with a previous study [7], we found no association between serum and UBC.

In the present study, we found that UBC, either unadjusted or adjusted according to creatinine concentration, in the NG group and the PTC group were significantly higher than those of the healthy control group. Multivariate logistic regression analysis also showed that unadjusted higher UBC was a risk factor for both NG and PTC. Therefore, high UBC, but not serum TBC, are likely to be associated with NG and PTC. We further examined and compared gender-specific UBC in all three groups. In consistent with the overall UBC in the NG and PTC groups, UBC in the female NG group and both the male and female PTC groups are higher than those in the control group of the same gender. Adjusted UBC were significantly lower in the female PTC group than the female NG group. However, we found that there was no significant difference in unadjusted/adjusted UBC between the male NG group and the male control group, or between males in the PTC and NG groups. This gender-specific association has also been demonstrated in several studies examined in different populations [7,10]. Furthermore, unadjusted UBC in the male PTC group were higher than those in females, which is consistent with another study from China [12]. These findings suggest that higher BPA levels may pose a more significant impact on women than men with NG and PTC, as supported by the notion that BPA is estrogenic, as well as an EDC [3436].

In the present study, we found that the adjusted UBC were significantly lower in the female PTC group than the female NG group and there was no difference in serum BPA levels, suggesting higher renal elimination of BPA in female NG groups than females in the PTC group. Absorbed BPA was metabolized in the liver by conjugation with glucuronide and excreted through urine within 24 h [33]. There was more free BPA (32% versus 20%), less BPA disulfate (7% versus 34%), BPA glucuronide (57% versus 46%), and BPA chlorides (4%) in urine than serum [25]. BPA is a potential substrate for the efflux transporters multidrug resistance-associated proteins (MRP2 and MRP3), and breast cancer-resistant protein (BCRP), and BPA glucuronide would likely enter the systemic and portal blood supply through basolateral MRP3 [37]. Whether renal expression of these transporters is differential or gender-specific and would play a differential role in renal excretion of BPA and its metabolites in female NG groups remains to be investigated in the future.

It has been established that a local reduction in iodine content in follicular lumen leads to overexpression of local thyroid-stimulating hormone receptor, which in turn excessively stimulates the regional thyroid tissue, and results in the formation of NG. Paradoxically, we found that UIC were higher in NG and PTC groups than the healthy control group, and all UIC were above 100 μg/l, which indicated no iodine deficiency in all participants, according to WHO and UNICEF guidelines [38]. Multivariate logistic regression analysis also showed that excessive iodine intake was a risk factor for both NG and PTC. This is consistent with studies in patients with PTC, with or without lymph node metastasis [39], and in patients with thyroid cancer or benign nodules [40]. Notably, studies have shown that long-term high iodine intake reduced the expression of Na+/I symporter (NIS) gene and protein and induced oxidative stress in rats [41,42]. High iodine intake increased the occurrence of T1799 BRAF mutation (69% versus 53%), which was a risk factor for PTC [43]. PTC patients with a BRAF mutation had lower NIS mRNA expression levels [44]. This suggests that high iodine results in changes in the genes such as NIS and BRAF, which may in turn cause local deficiency of iodine in the follicular lumen, as well as proliferation and heteroplasia in the thyroid gland, leading to PTC and NG. There were no gender-specific findings with respect to UIC in NG and PTC, as revealed in our present study.

Interestingly, we found that there was a significant correlation between adjusted BPA and iodine concentrations in the PTC, NG, and healthy control groups. Studies have shown that BPA increases estrogen-related receptor γ (ERRγ) mRNA and protein levels in breast cancer cells [45]. An inverse agonist of ERRγ, GSK5182, increases iodine uptake and enhances membrane localization of NIS in anaplastic thyroid cancer cells [46]. TSH also up-regulates NIS mRNA and protein levels both in vitro and in vivo [47]. Urinary BPA negatively relates to thyroid-stimulating hormone levels in adults [13]. The maternal BPA was also inversely associated with TSH in newborn girls [48]. However, in another study, urinary BPA and serum TSH had a positive association [49]. Therefore, we speculate that there was a cross-talk in the metabolic and functional pathways between BPA and iodine in PTC and NG patients.

There are several limitations to the findings in our study. First, we cannot estimate the causal relationships in the present study, as it was a cross-sectional study. Second, we only evaluated single spot urine samples, and did not determine time-course changes in urinary BPA and iodine concentrations. Third, we measured total BPA but did not measure free BPA concentrations. Free BPA is the most toxic form of BPA to humans. Fourth, our sample size was limited, and information on dietary habits, geographical location, or socioeconomic status was not incorporated. Fifth, the age of the control group was younger than the PTC and NG groups, instead of equal ages in all groups, although equal exposure of BPA in all groups was revealed by measuring serum BPA concentrations. We will address these limitations in future studies.

In conclusion, we demonstrated that UBC and UIC were higher in NG and PTC groups compared with healthy controls. Higher UBC and excessive iodine intake were risk factors for NG and PTC development. Association of high UBC and UIC with NG and PTC is gender-dependent. There may, therefore, be a potential cross-talk in the metabolic and functional pathways between BPA and iodine in the pathogenesis and progression of NG and PTC.

Abbreviations

BPA

bisphenol A

EDC

endocrine disrupting chemical

ERRγ

estrogen-related receptor γ

LOQ

limit of quantification

NG

nodular goiter

PTC

papillary thyroid carcinoma

RSD

relative standard deviation

TBC

total BPA concentrations

UBC

urinary BPA concentrations

AUC

area under the curve

UIC

urinary iodine concentrations

Funding

This work was supported by the National Natural Science Foundation of China [grant number 81272181]; the Science and Technology Development Project of Shandong Province [grant number 2012GSF11851]. The authors thank Xiangfeng Chen, Hanzhu Xing, and Meizhen Fu in Shandong Province Analysis and Test Center for their assistance in experiments.

Author Contribution

Ling Jiang and Zhenzhen Zhou conceived and designed the experiments. Zhenzhen Zhou and Jin Zhang performed the experiments and analyzed the data. Yan Xie, Fan Jiang and Xiaochen Zhang collected the participants.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

References

  • 1.Derwahl M. and Nicula D. (2014) Estrogen and its role in thyroid cancer. Endocr. Relat. Cancer 21, 273–283 [DOI] [PubMed] [Google Scholar]
  • 2.Kumar A., Klinge C.M. and Goldstein R.E. (2010) Estradiol-induced proliferation of papillary and follicular thyroid cancer cells is mediated by estrogen receptors alpha and beta. Int. J. Oncol. 36, 1067–1080 [DOI] [PubMed] [Google Scholar]
  • 3.Liu J., Chen G., Meng X.Y., Liu Z.H. and Dong S. (2014) Serum levels of sex hormones and expression of their receptors in thyroid tissue in female patients with various types of thyroid neoplasms. Pathol. Res. Pract. 210, 830–835 [DOI] [PubMed] [Google Scholar]
  • 4.Tunbridge W.M., Evered D.C., Hall R., Appleton D., Brewis M., Clark F. et al. (1977) The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. (Oxf) 7, 481–493 [DOI] [PubMed] [Google Scholar]
  • 5.Park J.S., Oh K.K., Kim E.K., Son E.J., Chang H.S., Hong S.W. et al. (2007) Sonographic detection of thyroid cancer in breast cancer patients. Yonsei Med. J. 48, 63–68 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Michalowicz J. (2014) Bisphenol A–sources, toxicity and biotransformation. Environ. Toxicol. Pharmacol. 37, 738–758 [DOI] [PubMed] [Google Scholar]
  • 7.Zhang T., Sun H. and Kannan K. (2013) Blood and urinary bisphenol A concentrations in children, adults, and pregnant women from china: partitioning between blood and urine and maternal and fetal cord blood. Environ. Sci. Technol. 47, 4686–4694 [DOI] [PubMed] [Google Scholar]
  • 8.Stahlhut R.W., Welshons W.V. and Swan S.H. (2009) Bisphenol A data in NHANES suggest longer than expected half-life, substantial nonfood exposure, or both. Environ. Health Perspect. 117, 784–789 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Vandenberg L.N., Hauser R., Marcus M., Olea N. and Welshons W.V. (2007) Human exposure to bisphenol A (BPA). Reprod. Toxicol. 24, 139–177 [DOI] [PubMed] [Google Scholar]
  • 10.Calafat A.M., Ye X., Wong L.Y., Reidy J.A. and Needham L.L. (2008) Exposure of the U.S. population to bisphenol A and 4-tertiary-octylphenol: 2003–2004. Environ. Health Perspect. 116, 39–44 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Frederiksen H., Aksglaede L., Sorensen K., Nielsen O., Main K.M., Skakkebaek N.E. et al. (2013) Bisphenol A and other phenols in urine from Danish children and adolescents analyzed by isotope diluted TurboFlow-LC-MS/MS. Int. J. Hyg. Environ. Health 216, 710–720 [DOI] [PubMed] [Google Scholar]
  • 12.He Y., Miao M., Herrinton L.J., Wu C., Yuan W., Zhou Z. et al. (2009) Bisphenol A levels in blood and urine in a Chinese population and the personal factors affecting the levels. Environ. Res. 109, 629–633 [DOI] [PubMed] [Google Scholar]
  • 13.Wang T., Lu J., Xu M., Xu Y., Li M., Liu Y. et al. (2013) Urinary bisphenol a concentration and thyroid function in Chinese adults. Epidemiology 24, 295–302 [DOI] [PubMed] [Google Scholar]
  • 14.Bhan A., Hussain I., Ansari K.I., Bobzean S.A., Perrotti L.I. and Mandal S.S. (2014) Bisphenol-A and diethylstilbestrol exposure induces the expression of breast cancer associated long noncoding RNA HOTAIR in vitro and in vivo. J. Steroid Biochem. Mol. Biol. 141, 160–170 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Ptak A., Hoffmann M., Gruca I. and Barc J. (2014) Bisphenol A induce ovarian cancer cell migration via the MAPK and PI3K/Akt signalling pathways. Toxicol. Lett. 229, 357–365 [DOI] [PubMed] [Google Scholar]
  • 16.Diamanti-Kandarakis E., Bourguignon J.P., Giudice L.C., Hauser R., Prins G.S., Soto A.M. et al. (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr. Rev. 30, 293–342 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Moriyama K., Tagami T., Akamizu T., Usui T., Saijo M., Kanamoto N. et al. (2002) Thyroid hormone action is disrupted by bisphenol A as an antagonist. J. Clin. Endocrinol. Metab. 87, 5185–5190 [DOI] [PubMed] [Google Scholar]
  • 18.Laurberg P., Bulow Pedersen I., Knudsen N., Ovesen L. and Andersen S. (2001) Environmental iodine intake affects the type of nonmalignant thyroid disease. Thyroid 11, 457–469 [DOI] [PubMed] [Google Scholar]
  • 19.Laurberg P., Jorgensen T., Perrild H., Ovesen L., Knudsen N., Pedersen I.B. et al. (2006) The Danish investigation on iodine intake and thyroid disease, DanThyr: status and perspectives. Eur. J. Endocrinol. 155, 219–228 [DOI] [PubMed] [Google Scholar]
  • 20.Yu X., Fan C., Shan Z., Teng X., Guan H., Li Y. et al. (2008) A five-year follow-up study of goiter and thyroid nodules in three regions with different iodine intakes in China. J. Endocrinol. Invest. 31, 243–250 [DOI] [PubMed] [Google Scholar]
  • 21.Feldt-Rasmussen U. (2001) Iodine and cancer. Thyroid 11, 483–486 [DOI] [PubMed] [Google Scholar]
  • 22.Harach H.R. and Williams E.D. (1995) Thyroid cancer and thyroiditis in the goitrous region of Salta, Argentina, before and after iodine prophylaxis. Clin. Endocrinol. (Oxf) 43, 701–706 [DOI] [PubMed] [Google Scholar]
  • 23.Dong W., Zhang H., Zhang P., Li X., He L., Wang Z. et al. (2013) The changing incidence of thyroid carcinoma in Shenyang, China before and after universal salt iodization. Med. Sci. Monit. 19, 49–53 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Harach H.R. and Ceballos G.A. (2008) Thyroid cancer, thyroiditis and dietary iodine: a review based on the Salta, Argentina model. Endocr. Pathol. 19, 209–220 [DOI] [PubMed] [Google Scholar]
  • 25.Liao C. and Kannan K. (2012) Determination of free and conjugated forms of bisphenol A in human urine and serum by liquid chromatography-tandem mass spectrometry. Environ. Sci. Technol. 46, 5003–5009 [DOI] [PubMed] [Google Scholar]
  • 26.Zhou F., Zhang L., Liu A., Shen Y., Yuan J., Yu X. et al. (2013) Measurement of phenolic environmental estrogens in human urine samples by HPLC-MS/MS and primary discussion the possible linkage with uterine leiomyoma. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 938, 80–85 [DOI] [PubMed] [Google Scholar]
  • 27.Aris A. (2014) Estimation of bisphenol A (BPA) concentrations in pregnant women, fetuses and nonpregnant women in Eastern Townships of Canada. Reprod. Toxicol. 45, 8–13 [DOI] [PubMed] [Google Scholar]
  • 28.Chen L.H., Shi J.R., Fang Y.L., Liang L., Chen W.Q. and Chen X.Z. (2014) Serum Bisphenol A Concentration and Premature Thelarche in Female Infants Aged 4-month to 2-year. Indian J. Pediatr. 82, 221–224 [DOI] [PubMed] [Google Scholar]
  • 29.Lakind J.S. and Naiman D.Q. (2008) Bisphenol A (BPA) daily intakes in the United States: estimates from the 2003-2004 NHANES urinary BPA data. J. Exposure Sci. Environ. Epidemiol. 18, 608–615 [DOI] [PubMed] [Google Scholar]
  • 30.Findlay L.C. and Kohen D.E. (2015) Bisphenol A and child and youth behaviour: Canadian Health Measures Survey 2007 to 2011. Health Rep. 26, 3–9 [PubMed] [Google Scholar]
  • 31.Becker K., Goen T., Seiwert M., Conrad A., Pick-Fuss H., Muller J. et al. (2009) GerES IV: phthalate metabolites and bisphenol A in urine of German children. Int. J. Hyg. Environ. Health 212, 685–692 [DOI] [PubMed] [Google Scholar]
  • 32.He Y., Miao M., Wu C., Yuan W., Gao E., Zhou Z. et al. (2009) Occupational exposure levels of bisphenol A among Chinese workers. J. Occup. Health 51, 432–436 [DOI] [PubMed] [Google Scholar]
  • 33.Volkel W., Colnot T., Csanady G.A., Filser J.G. and Dekant W. (2002) Metabolism and kinetics of bisphenol a in humans at low doses following oral administration. Chem. Res. Toxicol. 15, 1281–1287 [DOI] [PubMed] [Google Scholar]
  • 34.Huang Y., Dong W., Li J., Zhang H., Shan Z. and Teng W. (2014) Differential expression patterns and clinical significance of estrogen receptor-alpha and beta in papillary thyroid carcinoma. BMC Cancer 14, 383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Dong W., Li J., Huang Y., Zhang H., Shan Z. and Teng W. (2012) Differential expression patterns of estrogen receptor (ER)-beta splice variants between papillary thyroid cancer and nodular thyroid goiter. Med. Sci. Monit. 18, BR351–BR355 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Fan D., Liu S.Y., van Hasselt C.A., Vlantis A.C., Ng E.K., Zhang H. et al. (2015) Estrogen receptor alpha induces prosurvival autophagy in papillary thyroid cancer via stimulating reactive oxygen species and extracellular signal regulated kinases. J. Clin. Endocrinol. Metab. 100, E561–E571 [DOI] [PubMed] [Google Scholar]
  • 37.Mazur C.S., Marchitti S.A., Dimova M., Kenneke J.F., Lumen A. and Fisher J. (2012) Human and rat ABC transporter efflux of bisphenol a and bisphenol a glucuronide: interspecies comparison and implications for pharmacokinetic assessment. Toxicol Sci. 128, 317–325 [DOI] [PubMed] [Google Scholar]
  • 38.WHO (2007) Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme managers.
  • 39.Wang F., Wang Y., Wang L., Wang X., Sun C., Xing M. et al. (2014) Strong association of high urinary iodine with thyroid nodule and papillary thyroid cancer. Tumour Biol. 35, 11375–11379 [DOI] [PubMed] [Google Scholar]
  • 40.Kim H.J., Kim N.K., Park H.K., Byun D.W., Suh K., Yoo M.H. et al. (2016) Strong association of relatively low and extremely excessive iodine intakes with thyroid cancer in an iodine-replete area. Eur. J. Nutr. 56, 965–971 [DOI] [PubMed] [Google Scholar]
  • 41.Hussein Ael A., Abbas A.M., El Wakil G.A., Elsamanoudy A.Z. and El Aziz A.A. (2012) Effect of chronic excess iodine intake on thyroid function and oxidative stress in hypothyroid rats. Can. J. Physiol. Pharmacol. 90, 617–625 [DOI] [PubMed] [Google Scholar]
  • 42.Man N., Guan H.X., Shan Z.Y., Li Y.S., Fan C.L., Guo X.J. et al. (2006) Long-term effects of high iodine intake: inhibition of thyroid iodine uptake and organification in Wistar rats. Zhonghua Yi Xue Za Zhi 86, 3420–3424 [PubMed] [Google Scholar]
  • 43.Guan H., Ji M., Bao R., Yu H., Wang Y., Hou P. et al. (2009) Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer. J. Clin. Endocrinol. Metab. 94, 1612–1617 [DOI] [PubMed] [Google Scholar]
  • 44.Morari E.C., Marcello M.A., Guilhen A.C., Cunha L.L., Latuff P., Soares F.A. et al. (2011) Use of sodium iodide symporter expression in differentiated thyroid carcinomas. Clin. Endocrinol. (Oxf) 75, 247–254 [DOI] [PubMed] [Google Scholar]
  • 45.Zhang X.L., Liu N., Weng S.F. and Wang H.S. (2016) Bisphenol A increases the migration and invasion of triple negative breast cancer cells via oestrogen-related receptor gamma. Basic Clin. Pharmacol. Toxicol. 119, 389–395 [DOI] [PubMed] [Google Scholar]
  • 46.Singh T.D., Jeong S.Y., Lee S.W., Ha J.H., Lee I.K., Kim S.H. et al. (2015) Inverse agonist of estrogen-related receptor gamma enhances sodium iodide symporter function through mitogen-activated protein kinase signaling in anaplastic thyroid cancer cells. J. Nucl. Med. 56, 1690–1696 [DOI] [PubMed] [Google Scholar]
  • 47.Filetti S., Bidart J.M., Arturi F., Caillou B., Russo D. and Schlumberger M. (1999) Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism. Eur. J. Endocrinol. 141, 443–457 [DOI] [PubMed] [Google Scholar]
  • 48.Romano M.E., Webster G.M., Vuong A.M., Thomas Zoeller R., Chen A., Hoofnagle A.N. et al. (2015) Gestational urinary bisphenol A and maternal and newborn thyroid hormone concentrations: the HOME Study. Environ. Res. 138, 453–460 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Andrianou X.D., Gangler S., Piciu A., Charisiadis P., Zira C., Aristidou K. et al. (2016) Human exposures to bisphenol A, bisphenol F and chlorinated bisphenol A derivatives and thyroid function. PLoS One 11, e0155237. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Bioscience Reports are provided here courtesy of Portland Press Ltd

RESOURCES