Bisphenol A (BPA) is one of the highest volume chemicals in production today.1 It has been used primarily in the manufacture of plastics including polycarbonate plastics and epoxy resins that coat food cans, and in dental sealants.1 The human population is widely and continuously exposed to BPA through food, drinking water, dermal exposures, and inhalation of dusts.2 In the 2003–2004U.S. National Health and Nutrition Examination Survey (NHANES), BPA was detected in 93% of the 2517 participants age 6 years or older.3
BPA exposure has been reported to relate to metabolic disorders such as type 2 diabetes, obesity, insulin resistance, and albuminuria,4–8 and recent experimental studies suggest that BPA exposure may affect thyroid function. BPA can bind to the thyroid hormone receptor and play an important part in reducing triiodothyronine-mediated gene expression by reducing triiodothyronine binding to the nuclear thyroid hormone receptors and recruiting nuclear receptor corepressor to the thyroid hormone receptor.9 Moreover, Kaneko etal10 reported that BPA affects the release of thyroid-stimulating hormone (TSH). Studies focusing on the association between urinary BPA and serum thyroid hormones in humans are limited and the results are inconsistent. Urinary BPA was inversely associated with serum TSH in 167 men recruited through an infertility clinic11; however, this association was not seen in the NHANES 2007–2008.12 We investigated the association between urinary BPA and thyroid function in Chinese adults age 40 years or older.
Details about the study have been published previously.5–7 Briefly, in June and July 2008, we performed an investigation in a population selected from Songnan Community, Baoshan District, Shanghai metropolitan area, China. As our major interest was focused on the effects of BPA exposure on chronic diseases, we conducted the investigation in residents age 40 years or older. A total of 10,185 participants were included in the screening examination.
Participants were classified into one of three groups according to fasting plasma glucose levels: normal glucose regulation (defined as a fasting plasma glucose level <5.6 mmol/l and no history of diabetes); impaired glucose regulation (defined as a fasting plasma glucose level of 5.6 to <7.0mmol/l and no history of diabetes); and diabetes (defined as a fasting plasma glucose level ≥7.0 mmol/l or a history of diabetes). From June through August 2009, participants were randomly selected from these groups for further investigation, which included a detailed questionnaire, anthropometric measurement, a 75-g oral glucose tolerance test, and blood and urine sampling. Our sampling was on a ratio of 1.0 (diabetes):1.2 (impaired glucose regulation):1.44 (normal glucose regulation) because subjects with lower glucose levels were expected to have a lower participation rate than those with higher glucose levels.
A total of 4012 participants were randomly selected from the three groups and received a comprehensive survey. Among 3455 study participants with blood and urine samples in the second survey, we excluded those who met the following criteria: (1) history of overt hyperthyroidism, hypothyroidism, or thyroiditis and taking, or had previously taken, thyroid hormones or antithyroid drugs (n = 12); (2) taking medications affecting thyroid function (including amiodarone, lithium, antipsychotic drugs such as chlorpromazine and risperidone, and antiepileptic drugs such as phenytoin sodium and carbamazepine) (n = 5); (3) history of thyroidectomy (n = 2); and (4) insufficient serum for thyroid measurements (n = 42). Thus, a total of 3394 subjects were included in the present analysis of the association between BPA exposure and thyroid function. The participants (3394 subjects) and the nonparticipants (6791 subjects) did not differ by age and sex. The Committee on Human Research at Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine approved the study protocol, and all study participants provided written informed consent.
Interviews about sociodemographics, medication history, family history, and lifestyle factors were conducted by trained personnel. Weight and height were measured according to a standard protocol by experienced nurses.
Plasma and serum were obtained, and blood glucose and lipid profile were measured within 2 hours. Serum was immediately removed into Eppendorf tubes and stored at −80°C for the measurement of thyroid function. First-morning urines were also collected and stored at −80°C. Measurements of urinary creatinine, lipid profile (total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides) were performed with an autoanalyzer (ADVIA-1650 Chemistry System, Bayer Corporation, Germany).
Measurements of Thyroid Function
Thyroid measurements were determined by the Clinical Laboratory for Endocrinology, Shanghai Institution of Endocrine and Metabolic Diseases, which was certified by College of American Pathologists. Serum free triiodothyronine, free thyroxine, and TSH were determined by chemiluminescent microparticle immunoassay by the Architect system (Abbott Laboratories, Abbott Park, IL). The laboratory reference ranges were 2.62–6.49 pmol/l for free triiodothyronine (with an interassay coefficient of variation [CV] of 4.7–8.0%), 9.01–19.04 pmol/l for free thyroxine (with an interassay CV of 2.6–5.3%), and 0.35–4.94 μIU/ml for TSH (with an interassay CV of 3.1–3.4%). Serum thyroid peroxidase antibodies and thyroglobulin antibody were tested using Architect Anti-TPO and Anti-TG (Chemiluminescent Microparticle Immunoassay) on the Architect i System (Abbott Laboratories). The laboratory reference range for thyroid peroxidase antibodies was <5.61 IU/ml (with an interassay CV of 4.3–6.8%) and for thyroglobulin antibody was <4.11 IU/ml (with an interassay CV of 3.2–5.2%). We classified subjects according to measurements of serum free thyroid hormone and TSH concentrations as follows13: (1) overt hyperthyroidism—free thyroxine >19.04 pmol/l and free triiodothyronine >6.49 pmol/l, or free triiodothyronine >6.49 pmol/l, with serum TSH <0.35 μIU/ml; (2) subclinical hyperthyroidism—normal free thyroxine (9.01–19.04 pmol/l) and free triiodothyronine (2.62–6.49 pmol/l), with serum TSH <0.35 μIU/ml; (3) euthyroid—normal serum TSH (0.35–4.94 μIU/ml); (4) subclinical hypothyroidism: normal free thyroxine and TSH >4.94 μIU/ml; (5) overt hypothyroidism—free thyroxine <9.01 pmol/l and TSH >4.94 μIU/ml. High-normal thyroid function was defined as, in subjects with euthyroid, free triiodothyronine >5.23 pmol/l (90% cut-point) and free thyroxine >16.34 pmol/l (90% cut-point) or TSH <0.74 μIU/ml (10% cut-point).
Quantification of BPA
Total (free and conjugated) urinary BPA concentrations were measured in spot morning urine samples at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Levels were determined after enzymatic hydrolysis by a sensitive and selective high-performance liquid chromatography-tandem mass spectrometry method. Details about the quantification of urinary BPA concentration have been reported previously.5 The standard curve ranged from 0.30 to 100ng/ml for BPA using weighted (1/x 2) least-squares linear regression mode. Both the intraday and interday relative standard deviations, calculated from quality control samples at three levels (0.80, 10.0, and 80.0ng/ml), were <8.7%, and the accuracy ranged from 98.0% to 98.5%. The interday relative error as determined from quality control samples was within 2.5%. The lower limit of detection (LOD) for BPA was 0.30ng/ml; for BPA levels below this limit, a value of 0.15ng/ml was assigned for the purpose of analysis.14 The results of stability experiments showed substantial degradation during sample incubation, chromatography, or extraction processes for BPA in urine samples (deviating no more than 7.4% at low and high nominal concentrations). The analytic data demonstrated excellent reproducibility, specificity, sensitivity, and precision for measurement of urinary BPA concentrations.
We performed statistical analysis using SAS software, version 9.2 (SAS Institute, Cary, NC). The values of urinary BPA and creatinine, serum triglycerides, free triiodothyronine, free thyroxine, TSH, thyroid peroxidase antibodies, and thyroglobulin antibody were log 10-normal-transformed to achieve normal distributions. We summarized demographic and laboratory characteristics as medians and interquartile ranges (IQRs) for continuous variables, or numbers and percentages for categorical variables. Thyroid measures were summarized as geometric means and 95% confidence intervals (CIs) for the urinary BPA quartiles.
We used multivariate linear regression analysis to test for trend of the changes of variables across the quartiles of urinary BPA and to estimate the association between adjusted urinary BPA and serum thyroid measures. We applied two models in the linear regression analyses: the age-adjusted and urinary creatinine-adjusted model and the multivariate model, which was additionally adjusted for body mass index (BMI), education attainment (≤6, 6.1–8.9, and ≥9 years), occupation (production, service, management, retirement, and others), smoking status (never-smoker, former smoker, and current smoker), alcohol consumption (never-drinker, former drinker, and current drinker), total cholesterol, triglycerides, HDL-C, LDL-C, thyroglobulin antibody, and thyroid peroxidase antibodies.
To study the association between BPA exposure and thyroid dysfunction, we first compared the urinary BPA concentration (which was summarized as geometric means with 95% CIs) in categories of thyroid function status. Given the low prevalence of overt or subclinical hyperthyroidism in this general population, we combined overt hyperthyroidism, subclinical hyperthyroidism, and high-normal thyroid function as the “high thyroid function” group. We carried out logistic regression analyses to evaluate the odds ratios (ORs) and 95% CIs of having high thyroid function for each BPA quartile compared with the first quartile.
The median urinary BPA concentration was 0.81ng/ml (IQR = 0.47–1.43ng/ml). Basic characteristics of the participants are presented in Table 1. Compared with women, the men were older; had higher levels of education; were more likely to be smokers and drinkers; and had higher levels of serum free triiodothyronine and urinary BPA and lower levels of BMI, serum total cholesterol, LDL-C, HDL-C, TSH, thyroglobulin antibody, thyroid peroxidase antibodies, and urinary creatinine. Associations between the covariates and urinary BPA are shown in the eTable 1(http://links.lww.com/EDE/A649).
Serum thyroid measures across urinary BPA quartiles are presented in Table 2. In both men and women, serum free triiodothyronine gradually increased and serum TSH gradually decreased with increasing urinary BPA quartiles (unadjusted and age-adjusted and urinary creatinine-adjusted tests for trend, P < 0.01). No obvious trends in serum free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibodies were found.
Multivariable-adjusted regression analysis of urinary BPA and measurements of thyroid function showed that urinary BPA was directly associated with serum free triiodothyronine and inversely associated with serum TSH in both men and women (Table 3). For example, for the median level of serum free triiodothyronine (4.70 pmol/l) and TSH (1.22 μIU/ml) among 1354 men, each one-quartile increase in urinary BPA was associated with a 0.068 pmol/l increase in serum free triiodothyronine (95% CI = 0.065 to 0.071) and a 0.084 μIU/ml decline in serum TSH (95% CI = −0.099 to −0.069).
Thyroid function status is shown in Table 4. Given the limited number of cases of overt hypothyroidism (n = 2) and overt hyperthyroidism (n = 13), we combined overt and subclinical hypothyroidism as one group and combined overt and subclinical hyperthyroidism as another group. The Figureshows urinary BPA in the three thyroid function groups. The geometric means of urinary BPA were 0.63ng/ml (95% CI = 0.52 to 0.77ng/ml) for combined overt and subclinical hypothyroidism, 0.81ng/ml (0.78 to 0.83ng/ml) for euthyroid, and 1.05ng/ml (0.84 to 1.32ng/ml) for combined overt and subclinical hyperthyroidism. Compared with subjects who were euthyroid or with overt or subclinical hypothyroidism, those with overt or subclinical hyperthyroidism had higher urinary BPA (combined overt and subclinical hyperthyroidism vs. euthyroid, P = 0.035; overt or subclinical hyperthyroidism vs. overt or subclinical hypothyroidism, P = 0.005), controlling for age, sex, and urinary creatinine. Compared with subjects who were euthyroid, those with overt or subclinical hypothyroidism had lower urinary BPA (P = 0.068).
We found that 432 (13%) participants had high thyroid function (median free triiodothyronine = 4.75 pmol/l [IQR = 4.39–5.21 pmol/l]; median free thyroxine = 14.75 pmol/l [13.66–16.35 pmol/l]; and median TSH = 0.60 μIU/ml [0.45–0.69 μIU/ml]). Logistic regression analyses (Table 5) produced ORs for high thyroid function that increased across urinary BPA quartiles. Compared with the first quartile, the OR for the fourth quartile was 1.66 (95% CI = 1.23 to 2.25) after adjusting for age, sex, and urinary creatinine. After full adjustment, the association was not substantially changed (1.71 [1.26 to 2.32]). When overt and subclinical hypothyroidism were combined as low thyroid function, there was a negative association between high BPA exposure and low thyroid function (for quartile 4 vs. 1, OR = 0.52 [0.30 to 1.01]) (data not shown).
We did sensitivity analysis in 2975 participants with a urinary BPA equal to or greater than the limit of detection (0.3ng/ml). Multivariate regression analyses found that the relationship of urinary BPA remained after full adjustment for serum free triiodothyronine (for men: β = 0.076 [SE = 0.005]; for women, 0.058 [0.004]) and for serum TSH (for men, −0.059 [0.027]; for women, −0.11 [0.028]). In addition, fully adjusted logistic regression analyses indicated that the association between high urinary BPA level and high thyroid function (for quartile 4 vs. 1, OR = 1.60 [95% CI = 1.10 to 2.32]) was not substantially changed.
In this study of 3394 middle-aged and elderly Chinese, urinary BPA was directly associated with serum free triiodothyronine and inversely associated with serum TSH in both men and women. Moreover, compared with subjects who were euthyroid, those with overt or subclinical hyperthyroidism had increased urinary BPA.
Thyroid hormone is essential for fetal and child growth and brain development, for the control of metabolism and energy balance, and for many aspects of normal physiology, including nervous, cardiovascular, pulmonary, and reproductive systems.15,16 Changes in the function of the thyroid gland or interference with the ability of thyroid hormone to exert its action may produce effects on development, metabolism, or physiology.15 Previous studies have demonstrated that BPA is able to disrupt thyroid function in rodent models, although the exact effect remains controversial. Zoeller et al17 reported that dietary exposure of BPA to Sprague-Dawley rats during pregnancy and lactation caused an increase of serum total thyroxine in pups, whereas the serum TSH was not altered. Xu et al18 showed that perinatal BPA exposure at a very low level (0.1mg/l) would produce transient hypothyroidism in female pups, whereas male pups were found to have transient hyperthyroidism followed by hypothyroidism.18 Another study19 reported that in utero and lactational exposure to BPA (4–40mg/kg/day, from gestation day 6 through postnatal day 20) did not affect thyroid function in the F1 generation of male and female rats.19 The inconsistent results of animal experiments might be due to different BPA dosages, different animal ages, routes of BPA exposure, and duration of BPA exposure. Furthermore, it is difficult for animal studies to mimic the physiological exposure of BPA in human beings, mainly because the metabolism pathway of BPA in rodents differs from metabolic endpoints in humans.20,21 For example, orally absorbed BPA is metabolized in the liver and then enters the blood stream in humans, whereas oral doses of BPA in rodents are excreted through the bile with reabsorption via the gut—a process that does not occur in humans. Moreover, acute exposures to relatively high doses in animals cannot reflect the situation in humans, where BPA exposure is more likely to be chronic and low level.
Even though animal studies have shown that BPA is a thyroid hormone disruptor, epidemiologic data on the relationship between BPA exposure and thyroid measures in human are limited and inconsistent. Meeker et al11 reported a negative association between BPA and TSH in 167 men recruited from an infertility clinic, but they observed no corresponding associations of BPA with either free thyroxine or total triiodothyronine. One recent study, by Meeker and Ferguson,12 using data from NHANES 2007–2008, reported no relation between urinary BPA and free triiodothyronine (β = 0.0021, P = 0.66) and TSH (β = 0.001, P = 0.96) in 1346 adults (age 20 years or older).12 Our findings of an inverse relationship between BPA and TSH were consistent with the results of Meeker et al11; moreover, we reported a corresponding direct relationship between BPA and free triiodothyronine. Our results may differ from those of NHANES because of differences in sample size, age, clinical characteristics, or BPA exposure. The NHANES study included 1346 American adults (age 20 years or older) and 329 American adolescents (age 12–19 years); the geometric mean of urinary BPA was 2.03ng/ml (IQR = 1.17–3.33ng/ml) in adults and 1.88ng/ml (1.10–2.93ng/ml) in adolescents.12 Our study was conducted in 3394 Chinese adults age 40 years or older, and we found a geometric mean of urinary BPA of 0.81ng/ml (IQR = 0.47–1.43ng/ml). This low concentration of urinary BPA is similar to those in a previous study of Chinese workers and their families that reported a geometric mean urinary BPA of 0.87ng/ml (IQR = <LOD to 5.26ng/ml), with urinary BPA undetectable for 50%.14 Our results are in line with the evidence from experimental studies indicating that BPA binds to the thyroid hormone receptor as a weak ligand and acts as a thyroid hormone antagonist on thyroid hormone receptor; it also blocks TSH secretion at the pituitary level and suppresses the release of TSH.9,10,22
Most (95%; 3,236/3,394) of the participants in our study were euthyroid and <1% had clinical hyperthyroidism or hypothyroidism; thus the differences in serum free triiodothyronine and TSH in relation to varying levels of BPA were small. Even in persons with subclinical hypothyroidism, euthyroid, and subclinical hyperthyroidism, serum free triiodothyronine levels did not vary greatly. We observed that urinary BPA was higher in the participants with overt or subclinical hyperthyroidism compared with those who were euthyroid. Given the low prevalence of thyroid dysfunction in this general population, we further defined high thyroid function and found that higher levels of BPA were associated with high thyroid function. The NHANES study demonstrated that BPA could be associated with cardiovascular disease.4,23 Recently, Melzer and colleagues24 also found positive associations between higher BPA exposure and incident coronary artery disease during >10 years of follow-up in England. Furthermore, high thyroid function (including overt hyperthyroidism, subclinical hyperthyroidism, and high-normal thyroid function) has been shown to be a risk factor for cardiovascular disease.13,25,26 Therefore, although the differences in serum free triiodothyronine and TSH by BPA categories are small, they may be clinically important and not simply evidence of a benign biological effect. Moreover, we added a sensitivity analysis attempting to exclude people with a “traditional” lifestyle free of BPA exposure, and the association remained for those with a BPA exposure of at least 0.3ng/ml (which is the LOD of urinary BPA concentration), thus demonstrating a dose-response relation within the BPA-exposed population.
The associations of urinary BPA with thyroid measures and high thyroid function were independent of thyroglobulin antibody and thyroid peroxidase antibodies, suggesting that the effect of BPA on thyroid dysfunction might be independent of thyroid autoimmunity. We found an association for free triiodothyronine and TSH but not for free thyroxine. The reason for the discrepancy in the results for free triiodothyronine or free thyroxine is unclear. It might be related to the origin of triiodothyronine and the stronger physiological activity of free triiodothyronine than free thyroxine.27,28 Nevertheless, the mechanism of BPA’s action on thyroid hormone is complex and remains unclear. BPA alters global developmental timing through a thyroid hormone pathway.22 BPA has been shown to bind to thyroid hormone receptor and directly activate or inhibit the action of endogenous triiodothyronine in various cell lines.9 This action may occur by influencing the interaction of thyroid hormone receptors with various cofactors such as N-CoR or SRC-1. In addition, BPA may cause thyroid hormone receptor to exhibit a different affinity for the thyroid hormone receptor response element and to suppress transcriptional activity that is stimulated by triiodothyronine in a dose-dependent manner in the transient gene expression experiments.9 Thus, it seems reasonable that BPA would not produce patterns of effects or diseases that simply mimic thyroid hormone insufficiency or excess.17
The strengths of our study include the large community-based population and the control of potential confounders in multivariate-adjusted analysis. Several limitations of our study must also be considered. First, our study is cross-sectional, and no causal relationships can be established. We cannot exclude the possibility that thyroid function might alter BPA metabolism. However, there is no experimental evidence for an effect of thyroid function on BPA metabolism. Second, urinary BPA was determined on a single morning urine specimen, and intraindividual variation could attenuate the observed associations. Although direct immunoassays for the measurement of free triiodothyronine and free thyroxine have been universally applied in clinical and research studies,12,29,30 this method has some limitations.31 Recently, ultrafiltration liquid chromatography-tandem mass spectrometry has been recommended as a better standard,32 and studies adopting this method may be warranted. Third, we did not collect data on socioeconomic status or diet. In the absence of reliable dietary measures, confounding cannot be dismissed. Fourth, due to the community-based nature of our sample, the prevalence of thyroid dysfunction was relatively low. We applied cut-points of thyroid hormones to define a high thyroid function to increase statistical power.
In conclusion, in 3394 Chinese age 40 years or older, urinary BPA was directly associated with serum free triiodothyronine and inversely associated with serum TSH. We also found that increased urinary BPA was related to high thyroid function. Our findings support and extend results from experimental and human studies.
We thank the field staff for their contribution and the participants for their cooperation.
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