Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China

Environmental Pollution xxx (xxxx) xxx

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Invited paper

Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China* Shunli Jiang a, Huimin Liu a, Shuang Zhou a, Xu Zhang a, Cheng Peng a, Hao Zhou a, Yeqing Tong b, **, Qing Lu a, * a Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, #13 Hangkong Road, Wuhan, Hubei, 430030, China b Hubei Provincial Center for Disease Control and Prevention, Wuhan, 430079, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 8 September 2019 Received in revised form 5 November 2019 Accepted 16 November 2019 Available online xxx

Epidemiological studies have investigated the associations of bisphenol A (BPA) exposure with hypertension risk or blood pressure levels, but findings are inconsistent. Furthermore, the association between its alternatives bisphenol S and F (BPS and BPF) and hypertension risk are not yet known. We conducted a cross-sectional study in 1437 eligible participants without hypertension-related diseases, with complete data about blood pressure levels, hypertension diagnosis, and urinary bisphenols concentrations. Multivariable logistic and linear models were respectively applied to examine the associations of urinary bisphenols concentrations with hypertension risk and blood pressure levels. The dose-response relationship was explored by the restricted cubic spline model. Compared with the reference group of BPA, individuals in the middle and high exposure group had an adjusted odds ratio (OR) of 1.30 and 1.40 for hypertension, had a 3.08 and 2.82 mm Hg higher systolic blood pressure (SBP) levels, respectively, with an inverted “U” shaped dose-response relationship. Compared with the reference group of BPS, individuals in the second and third tertile had an adjusted OR of 1.49 and 1.48 for hypertension, had a 2.61 and 3.89 mm Hg increased levels of SBP, respectively, with a monotonic curve. No significant associations of BPF exposure with hypertension risk or blood pressure levels were found. BPA and BPS exposure were suggested to be associated with increased hypertension risk and blood pressure levels, with different dose-response relationships. Our findings have important implications for public health but require confirmation in prospective studies. © 2019 Elsevier Ltd. All rights reserved.

Keywords: Bisphenol A Bisphenols Hypertension Blood pressure

1. Introduction Bisphenol A (BPA), one of the highest volume industrial compounds in the world, is extensively used in the manufacture of polycarbonate plastics and epoxy resins (Rochester, 2013). However, due to the incomplete polymerization and degradation over time, BPA monomer can leach out and migrate into foods, water, and dust, thus causing widespread contamination (Kang et al., 2006). Humans are exposed to BPA mainly through diet ingestion, dermal absorption, and dust inhalation (Gao et al., 2016). Previous * This paper has been recommended for acceptance by Wen Chen. * Corresponding author. ** Corresponding author. E-mail address: [email protected] (Q. Lu).

studies have reported nanomolar levels of BPA in urine samples from China (median: 0.81 mg/L) (Wang et al., 2013), Korea (mean: 1.2 mg/g creatinine) (Bae et al., 2012), the USA (median: 1.28 mg/L) (Calafat et al., 2005), the UK (median: 1.3 mg/L) (Melzer et al., 2012), Denmark (median: 3.25 mg/L) (Lassen et al., 2014), and other countries (Zhang et al., 2011). Recent epidemiological studies have discovered significant associations between BPA exposure and chronic diseases such as diabetes, obesity, cardiovascular disease, and renal dysfunction (Chrysant, 2015; Lakind et al., 2014; Lang et al., 2008; Li et al., 2012; Rezg et al., 2014). Considering these adverse effects of BPA, many countries have taken measures to reduce human exposure to BPA. On the one hand, stringent regulations had been adopted such as prohibiting BPA in baby bottles and food containers, setting

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Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

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S. Jiang et al. / Environmental Pollution xxx (xxxx) xxx

migration limit of BPA from food containers and beverage cans, reducing the tolerable daily intake (TDI) of BPA from 50 to 5, then to 4 mg/kg bw/day (EFSA Panel on Food Contact Materials, 2015; Niu et al., 2015). On the other hand, all walks of life in society actively sought alternative substances to remove BPA in a myriad of applications. At present, a total of 16 bisphenol analogs have been used in the chemical industry. Among these analogs, bisphenol S (BPS) and bisphenol F (BPF) are the main substitutes of BPA and have been widely used in the production of food containers, bottles, thermal paper, and the inner protective lining for foods and beverage cans (Chen et al., 2016). Therefore, BPS and BPF can be detected in the abiotic environment and body fluid, generally in the same order of magnitude, but slightly lower than BPA concentrations (Chen et al., 2016; Ye et al., 2015). However, some literature data indicated similar or even greater hormonal activities of BPS and BPF than that of BPA (Chen et al., 2016; Rochester and Bolden, 2015). Moreover, significant associations of BPS and BPF exposure with oxidative stress, liver and thyroid function, obesity, and diabetes have been found in animal experiments and epidemiologic studies (Duan et al., 2018; Lee et al., 2019; Meng et al., 2019; Mokra et al., 2018; Zhang et al., 2019). Hypertension, a crucial global health challenge, is increasing with dramatic speed and sweep (Forouzanfar et al., 2017). It was estimated that globally 0.97 billion people had hypertension in 2000, while more than 1.56 billion individuals were projected to have hypertension in 2025 (Kearney et al., 2005). Furthermore, hypertension is the most influential risk factor for cardiovascular and kidney disease and causes the biggest global burden of disease and mortality (Poulter et al., 2015). Environmental pollution is an important but underestimated risk factor of hypertension (Landrigan et al., 2018). Some studies indicated that air pollution, heavy metals, and other environmental contaminants might be linked with the occurrence, development, and severity of hypertension (Abhyankar et al., 2012; Fuks et al., 2017; Wang and Wei, 2018). However, studies concerning the association of BPA exposure with hypertension risk are scarce and inconsistent. Based on the data from the National Health and Nutrition Examination Survey (NHANES) 2003e2004 circle, Shankar and Teppala (2012) firstly reported a significant association of BPA exposure with hypertension. Subsequently, Bae et al. (2012) documented an association of urinary BPA concentrations with hypertension in participants without a history of hypertension, especially in females. However, participants in this study all were susceptible elderly citizens (
60 years old), which may restrict the universality of the finding (Bae et al., 2012). Besides, Bae and Hong (2015) designed a randomized crossover trial in 60 elders (also
60 years old) to determine the acute effects of BPA on blood pressure by providing same beverage in different containers (glass bottle or can) to participants. Their study demonstrated that taking canned beverage can sharply increase urinary BPA concentrations and blood pressure levels. However, in a cross-sectional study in China, a negative association between BPA exposure and hypertension risk was suggested, even after multivariable adjustment (Wang et al., 2015). Collectively, we found that the association of BPA exposure with hypertension was inconclusive and the relationship of BPS and BPF exposure with hypertension was not evaluated. Therefore, we conducted this cross-sectional study to explore the association and dose-response relationship of bisphenols exposure with hypertension risk and blood pressure levels.

observational study in the physical examination center of Wuhan Union Hospital, which had been previously described in detail (Wu et al., 2018). This ongoing study endeavors to evaluate the potential impacts of daily exposure to environmental contaminations on human health. Individuals with a history of severe diseases are predisposed to alter their undesirable lifestyles and habits, thus may change the exposure levels and twist the real association between environmental exposure and the risk of diseases. Accordingly, individuals with cardiovascular diseases (e.g., coronary heart disease, cardiomyopathy, fibrillation, heart failure), stroke, diabetes, chronic obstructive pulmonary disease, renal failure, hyperthyroidism, hypothyroidism, or cancers were precluded. Therefore, only participants with normal or high blood pressure were included in the study. A semi-structured questionnaire was used to collect data by a well-trained interviewer. Information on sociodemographic factors (e.g., age, sex, educational attainment, income level), medical history, medication use, smoking status (non-smoker, current-smoker, former-smoker, pack-years of smoking), passive smoking status, alcohol consumption (non-drinker, current-drinker, formerdrinker), plastic products using frequency, and exercise frequency were gathered. Height in centimeters and weight in kilograms were measured on validated height rods and weighing scale, respectively, by qualified medical staff. Data on participants’ biochemical indexes such as cholesterol, triglyceride, and serum creatinine were acquired from their physical examination reports. Besides, body mass index (BMI) and estimated glomerular filtration rate (eGFR) were calculated, and hyperlipidemia status was defined accordingly. Detailed information for covariates definition, categorization, and calculation were displayed on the Supplemental Materials, Part A. According to the aforementioned criteria, from May 2016 to May 2018, we finally enrolled 1546 participants in our study. After excluding 65 participants with insufficient urine volume for bisphenols or creatinine analysis, 27 with incomplete information on smoking or drinking, and 17 with missing information on blood pressure levels, we finally included 1437 (92.9%) participants in the present analysis. All participants offered informed consent. Every part of the study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. 2.2. Blood pressure and hypertension

2. Methods

Blood pressure levels were measured by a skilled medical technologist, according to the 2010 Chinese guidelines for the management of hypertension (Liu, 2011). Briefly, after a 5-min rest in a sitting position, two or three blood pressure readings were recorded by a calibrated mercury sphygmomanometer with a proper size cuff placed on the right upper arm. Systolic and diastolic blood pressure (SBP and DBP) were assigned as the average of the corresponding readings. Pulse pressure (PP) was calculated as the difference between SBP and DBP. Mean arterial pressure (MAP) was calculated as (SBPþ2  DBP)/3. Mid blood pressure (MBP) was calculated as (SBP þ DBP)/2. MBP was suggested as the most informative blood pressure index to predict the stroke and ischemic heart disease mortality, partly due to any random measurement errors that only influenced SBP or DBP were halved in the calculation (Collaboration, 2002). Participants were considered as hypertensive if they had SBP
140 mm Hg, DBP
90 mm Hg, a selfreported physician diagnosis, or current use of antihypertensive medications (Liu, 2011).

2.1. Study population

2.3. Urine sample collection

The

study

population

was

derived

from

the

ongoing

After a detailed explanation and demonstration, single morning

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

S. Jiang et al. / Environmental Pollution xxx (xxxx) xxx

midstream urine samples from participants during their physical examination were collected into cylindrical polypropylene containers, which were previously confirmed to be bisphenols-free. All the urine samples were gathered from 09:00 a.m. to 11:00 a.m. to decrease the diurnal variation. All samples were packed into a cooler and delivered to the laboratory within 3 h. Urine samples were frozen in a refrigerator at 20  C until further analysis. 2.4. Urine bisphenols determination 2.4.1. Reagents and sources Certified reference material BPA and its internal standard BPAd16 were purchased from Sigma-Aldrich Laboratories, Inc. (St. Louis, MO, USA); BPS and BPF were purchased from AccuStandard, Inc. (New Haven, CT, USA); BPS-d8 and BPF-13C6 were purchased from Toronto Research Chemicals (Toronto, Ontario, Canada). b-glucuronidase/sulfatase (from abalone, aqueous solution), HPLC grade ethyl acetate, and LC-MS grade methanol were purchased from ANPEL Laboratory Technologies (Shanghai) Inc. (Shanghai, China). The purified water (18.2 MU cm) was obtained from a Milli-Q A10 system (Millipore, Bedford, MA, USA). 2.4.2. Sample preparation and determination We modified a liquid-liquid extraction method according to previous studies (Liao and Kannan, 2012; Wang et al., 2019). After thawing and centrifugation at 4000 rpm for 10 min, 1000 mL of urine sample was transferred into a 1.5-mL polypropylene tube. Then, 20 mL of b-glucuronidase/sulfatase solution was added into a sample, and samples were incubated in a thermostat water bath at 37  C for 12 h for thorough enzymolysis. The digested sample was spiked with 20 mL of the mixed internal standard working solution (100 mg/L), vortexed vigorously for 30 s, then centrifuged at 12000 rpm for 10 min. After that, all the supernatant was transferred into a 15-mL polypropylene tube and extracted by 4 mL of ethyl acetate. The mixed liquor was vortexed at 2500 rpm for 10 min then centrifuged at 4000 rpm for 10 min. The upper-layer extract was transferred into a 10-mL glass tube, concentrated to near-dryness under a gentle nitrogen stream at 35  C, and reconstituted with 100 mL of 50% (v/v) methanol aqueous solution. The separation of bisphenols was processed on an Agilent 1260 HPLC system (Agilent Technologies Inc., Santa Clara, CA, USA) serially equipped with an Agilent Eclipse XDB-C18 guard column (4.6  12.5 mm, 5 mm) and an Agilent ZORBAX Eclipse XDB-C18 analytical column (4.6  150 mm, 5 mm). A volume of 5 mL of the prepared sample was injected into the system with a mobile phase comprising water (A) and methanol (B) at a flow rate of 200 mL/min. The column temperature was set at 35  C. In the separation, the following gradient (A/B, v/v) was used: equilibrate the column at 50/50 for 2.0 min, 45/65 to 0/100 from 2.1 to 10.0 min, stay at 0/100 for 4 min, then change to initial condition 50/50 at 14.1 min and equilibrate the column until 22.0 min. The retention time for BPA, BPS, and BPF was 11.35, 4.91, and 9.39 min, respectively. The quantitative analysis was carried out on an Agilent 6540 UHD accurate-mass quadrupole time-of-flight (Q-TOF) mass spectrometer equipped with an electrospray ionization with Agilent jet stream technology (Dual AJS ESI) under negative mode. 2.4.3. Method validation and quality control The method validation including the linearity of the standard curve, the limit of detection, the limit of quantification (LOQ), rate of recovery, intra- and inter-day precision, reagent blank, procedural blank and matrix effects. The determination coefficient of each analyte was > 0.995. The LOQ for BPA, BPS, and BPF all was 0.1 mg/L. The detection rate (N% > LOQ) for BPA, BPS, and BPF was 61.59%, 83.86% and 66.04%, respectively. The recovery rate for BPA,

3

BPS, and BPF was 102.89%e111.14%, 94.30%e104.88%, and 79.63%e 100.86%, respectively. The intra- and inter-day relative standard deviation was 6.01% and 4.81%, respectively. We measured the purified water, b-glucuronidase/sulfatase, ethyl acetate, and methanol for potential reagent contaminations. Additionally, we packed the purified water into the cylindrical polypropylene tube at the beginning of the study (May 2016) to examine that if bisphenols can be released from the container. Furthermore, purified water as a procedural blank in each batch was analyzed. All the concentrations of the three bisphenols in reagents and procedural blanks were under the LOD. Matrix refers to the components of a sample other than the targeted analyte of interest. In a biological matrix such as urine, the matrix can have a potential effect on the quality of the testing results (Van Eeckhaut et al., 2009). We appraised the matrix effects by comparing the response value of the standards in synthetic urine and in the mobile phase. The matrix effects of BPA, BPS, and BPF was 100.97%, 114.16%, and 120.07%, respectively, which were basically in the permissible range (85%e115%). Methods of quality control including: a) we recoded the sample number before analyzing, thus, the lab personnel in sample preparation, instrument operation, and data extraction were blinded to sample types; b) a series of the aforementioned experiments for method validation were conducted to assure the reliability of data; c) we performed the mass calibration every day before the analysis to assure the mass accuracy; d) we measured one mobile phase sample and one procedural blank before each run to evaluate instrument performance and check potential laboratory contaminations; e) we measured one methanol sample and one quality control sample (1.0 mg/L, reference materials) for every 20 samples to monitor the random drift error and the real-time precision of the instrument, and reset the standard curve for each 60 samples; f) we detected some urine samples and quality control samples on another mass spectrometer (Thermo Scientific Q Exactive), with good consistency. Detailed information about the measurement was presented in the Supplemental Materials, Part B. 2.5. Urine creatinine and specific gravity determination To account for urine dilution, urinary creatinine concentrations were determined on an automatic biochemical analyzer (Mindray BS200, Mindray Medical International Ltd., Shenzhen, China), based on the sarcosine oxidase method. Urine specific gravity (USG) was also measured to adjust for urinary bisphenols concentrations as a sensitivity method, using a calibrated handheld refractometer (LHY12, Lohand Biological Technologies Inc., Hangzhou, China). 2.6. Statistical analysis We performed descriptive analyses for the characteristics of the study population. Continuous variables were presented as mean ± standard deviation (SD) or median (interquartile range), according to their distributions; categorical variables were presented as numbers (percentage). Student’s t-test, Mann-Whitney U test, and chi-square test were applied to compare the differences between non-hypertension and hypertension group. Spearman’s rank correlation test was used to assess the correlations between urinary bisphenols concentrations and blood pressure levels. Urine samples with analyte concentrations < LOQ were imputed as LOQ/2. We calculated the estimated daily intake (EDI) of bisphenols to compare that with the TDI of BPA. We adopted a simple pharmacokinetic equation based on urinary bisphenol concentrations as: EDI ¼ Cu  Vu/W. Cu is the bisphenol concentration in urine (mg/L); Vu is the daily urine excretion volume (L/ day); W is the body weight of the individual (kg). Urine volume was considered to be 1.6 L/day for adult males and 1.2 L/day for adult

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

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females as suggested (Zhang et al., 2013). Because BPA (61.59%) and BPF (66.04%) were not detected in over two thirds of the samples, an ordinal three-category variable was constructed as: individuals with analyte concentrations < LOQ were classified as the low exposure group, individuals with detectable levels (>LOQ) were equally divided into the middle and high exposure group. BPS concentrations (83.86%) in urine were equally categorized into tertiles in the analysis. We summed the mass concentration of BPA, BPS, and BPF to represent the total concentrations of bisphenols (SBPs). The associations of bisphenols exposure with the odds of hypertension and the changes in blood pressure levels were assessed by multivariable logistic and multivariable linear regression models, respectively. Linear trend test was performed by modeling the median value of each exposure category as a continuous variable in the models. Antihypertensive medication use reduces blood pressure levels and might blunt the effect of bisphenols exposure on blood pressure levels. Consequently, a constant of 10 mm Hg and 5 mm Hg was added on the SBP and DBP levels, respectively, for participants using antihypertensive drugs (Levy et al., 2009). To explore the dose-response relationship of bisphenols exposure with the risk of hypertension and blood pressure levels, the restricted cubic spline (RCS) model was constructed on a SAS macro (Desquilbet and Mariotti, 2010). The 10th, 50th, and 90th percentiles of the logarithmic transformed urinary bisphenols concentrations were set as knots, with the 10th percentile was considered as the reference value. The p-value for overall association < 0.05 in the RCS model manifested a significant association, whatever the shape of the dose-response curve was. The p-value for non-linear association < 0.05 indicated a nonmonotonic dose-response (NMDR) curve, otherwise, a monotonic relationship was suggested. A covariate was included in the regression model if it caused >10% change in the estimated exposure-effect [odds ratio (OR) or coefficient] or had biological relevance with hypertension (Greenland, 1989). Finally, covariates including age, sex, BMI, smoking, pack-years of smoking, passive smoking status, drinking, exercise frequency, educational attainment, income level, hyperlipidemia status, and eGFR level were included in the model. In view that our previous studies and other epidemiological research have suggested the harmful effects of heavy metals on the cardiovascular system, urinary cadmium, mercury, lead, and arsenic concentrations were further adjusted in the model (Chowdhury et al., 2018; Wu et al., 2018; Wu et al., 2019). In the end, urinary creatinine levels were compulsively included in all the models to correct urine dilution. We compared the differences in urinary bisphenols concentrations in different subgroups of the selected covariates. For covariates (age, BMI, and income) with significantly different bisphenols concentrations in subgroups, we further performed subgroup analysis and constructed an interaction term to explore the modification effect. Sex was considered in the subgroup analysis for potential hormone effects and sex differences. Furthermore, the effects of medication treatment, antihypertensive types, and the duration year of hypertension on the associations were considered. We performed sensitivity analyses to examine the robustness of our results. First, we repeated the regression models while not adding a constant to the blood pressure levels for antihypertensive users, or excluding individuals with antihypertensive treatment. Second, to diminish the potential impacts of extreme urine samples, we separately performed the analysis after excluding samples with urine creatinine <0.3 or >3 g/L, or excluding the outliers of the urinary bisphenols (beyond the range of mean ± 3SD). Third, we adopted different methods to correct for urine dilution: a) not adjusting for urinary creatinine concentrations; b) dividing the urinary bisphenols concentrations by the creatinine

concentrations; c) using USG to adjust for urine dilution (Barr et al., 2004). Fourth, time-dependent factors such as daily ambient temperature may affect blood pressure levels (Bae and Hong, 2015). Besides, bisphenols exposure levels might change over time. Therefore, we adjusted for the date, daily minimum temperature ( C), particulate matter 2.5, and particulate matter 10 of the enrollment day in the models. Additionally, we further adjusted for hyperuricemia (yes/no) and impaired fasting glucose status (yes/ no) in the aforementioned models. We performed all statistical analyses on the Statistical Package for the Social Sciences (SPSS), version 22.0 (IBM SPSS Institute, Inc., New York, USA). A two-tailed p-value < 0.05 was considered to have a statistical difference. 3. Results 3.1. Characteristics of the study population Table 1 shows the characteristics of the study population. Among the 1437 participants, 30.1% (433/1437) were diagnosed with hypertension. The mean age was 60 years for the hypertension group and 55 years for the non-hypertension group. Participants with hypertension had high BMI, and low eGFR levels; they were more likely to be smokers and drinkers; they were predisposed to have hyperlipidemia. In participants with hypertension, only 61.9% were under medications. 3.2. Distribution of the urinary bisphenols The median of unadjusted BPA (0.710 mg/L) and BPS (0.334 mg/L) concentrations in hypertension group was significantly higher than that in non-hypertension group (BPA, 0.576 mg/L; BPS, 0.243 mg/L) (Table 2). Similar distributions also can be found in creatinine and USG adjusted BPA and BPS concentrations, and in their EDI levels. The EDI level of BPA (median: 0.013 mg/kg bw/day) in our study was three orders of magnitude less than the TDI (50 mg/kg bw/day). No significant difference for urinary BPF concentrations in hypertension and non-hypertension group was found. Participants with high BMI and high income levels were likely to have high urinary BPA concentrations while elder participants were prone to have high urinary BPS concentrations (Fig. S1). Spearman rank correlation test showed that urinary BPA concentrations were significantly correlated with urinary BPF concentrations, but not with BPS (Table S1). Urinary BPS concentrations were significantly associated with all the blood pressure indexes. 3.3. Bisphenols exposure and hypertension risk Urinary BPA and BPS concentrations were significantly associated with the risk of hypertension, even after adjustment for multiple confounders and four heavy metals (Table 3). Compared with the reference group of BPA, individuals in the middle and high exposure group had an adjusted OR of 1.30 (95% CI: 0.95, 1.78) and 1.40 (95% CI: 1.03, 1.91) for hypertension, with a significant linear trend (ptrend ¼ 0.035). Compared with the reference group of BPS, individuals in the second and third tertile had a 1.49-fold (95% CI: 1.09, 2.06) and 1.48-fold (95% CI: 1.07, 2.05) increased risk of having hypertension, with no significant linear trend (ptrend ¼ 0.100). No significant associations of BPF and SBPs exposure with the risk of hypertension can be found. In the RCS model, significant doseresponse relationships for BPA and BPS were suggested (Fig. 1A). We observed a significant association of BPA with the risk of hypertension in hypertensive participants with medication treatment, especially with diuretics, while a significant association between BPS and hypertension risk was found in hypertensive participants without treatment. Additionally, a significant

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

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Table 1 General characteristics among the study population (N ¼ 1437)a. Variable

All subjects (N ¼ 1437)

Non-hypertension (N ¼ 1004)

Hypertension (N ¼ 433)

p-valueb

Age, year Sex, male, N (%) Smoking status, N (%) Non-smoker Current smoker Former smoker Pack-years of smoking Passive smoking, N (%) Drinking status, N (%) Non-drinker Current drinker Former drinker Exercise, N (%) <1 time/week 1-3 times/week >3 times/week Education, N (%) < high school high school > high school Income, RMB, yuan/month, N (%) <5000 5000e10000 >10000 BMI, kg/m2 eGFR, mL/min/1.73 m2 Hyperlipidemia, N (%) Antihypertensive use, N (%) SBP, mmHg DBP, mmHg PP, mmHg MAP, mmHg MBP, mmHg

56 ± 9 855 (59.5)

55 ± 8 546 (54.4)

60 ± 10 309 (71.4)

< 0.001 < 0.001

1049 (73.0) 291 (20.2) 97 (6.8) 5.93 ± 12.97 631 (43.9)

749 (74.6) 201 (20.0) 54 (5.4) 5.79 ± 12.99 441 (43.9)

300 (69.3) 90 (20.8) 43 (9.9) 6.25 ± 12.93 190 (43.9)

898 (62.5) 499 (34.7) 40 (2.8)

649 (64.6) 330 (32.9) 25 (2.5)

249 (57.5) 169 (39.0) 15 (3.5)

0.033

440 (30.6) 363 (25.3) 634 (44.1)

314 (31.3) 267 (26.6) 423 (42.1)

126 (29.1) 96 (22.2) 211 (48.7)

0.055

174 (12.1) 330 (23.0) 933 (64.9)

125 (12.5) 216 (21.5) 663 (66.0)

49 (11.3) 114 (26.3) 270 (62.4)

0.135

574 (39.9) 682 (47.5) 181 (12.6) 23.62 ± 2.88 103.77 ± 22.28 350 (24.4) 268 (18.6) 127 ± 18 79 ± 11 49 ± 13 95 ± 12 103 ± 13

411 (40.9) 467 (46.5) 126 (12.6) 23.20 ± 2.69 105.67 ± 22.15 227 (22.6) 0 (0.0) 119 ± 12 75 ± 8 45 ± 10 90 ± 9 97 ± 9

163 (37.6) 215 (49.7) 55 (12.7) 24.56 ± 3.07 99.40 ± 22.00 123 (28.4) 268 (61.9) 146 ± 16 88 ± 11 58 ± 15 107 ± 10 117 ± 11

0.005 0.531 0.988

0.483 < 0.001 < 0.001 0.019 e < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; MAP, mean arterial pressure; MBP, mid blood pressure; eGFR, estimated glomerular filtration rate. a Continuous variables were presented as mean ± standard deviation or median (interquartile range), according to its distribution; categorical variables were presented as numbers (percentage). b p-values were calculated by Student’s t-test or chi-square test for different variables.

Table 2 Urinary bisphenols concentrations among the study population (N ¼ 1437). Chemicals

p-valuea

All subjects (N ¼ 1437)

Non-hypertension (N ¼ 1004)

Hypertension (N ¼ 433)

GM

GM

Median (25th-75th)

GM

Median (25th-75th)

0.304 0.290 0.197 1.264

0.576 (ND.-0.943) 0.243 (0.127e0.678) 0.259 (ND.-0.454) 1.28 (0.725e2.199)

0.370 0.377 0.206 1.461

0.710 0.334 0.262 1.425

(ND.-0.998) (0.160e0.760) (ND.-0.437) (0.914e2.397)

0.011 < 0.001 0.721 0.011

0.263 0.251 0.171 1.096

0.368 0.225 0.217 1.109

(0.041e1.054) (0.093e0.635) (0.041e0.528) (0.490e2.642)

0.294 0.300 0.164 1.163

0.436 0.262 0.189 1.084

(0.050e0.969) (0.122e0.678) (0.037e0.516) (0.550e2.501)

0.332 0.038 0.570 0.606

0.307 0.293 0.199 1.277

0.397 0.272 0.244 1.355

(0.050e1.188) (0.107e0.717) (0.050e0.583) (0.596e2.950)

0.398 0.406 0.222 1.573

0.591 0.361 0.243 1.440

(0.067e1.34) (0.166e0.916) (0.067e0.714) (0.766e3.600)

0.005 < 0.001 0.201 0.005

0.007 0.006 0.004 0.028

0.013 0.006 0.006 0.029

(0.001e0.021) (0.003e0.015) (0.001e0.010) (0.016e0.050)

0.008 0.008 0.004 0.032

0.016 0.007 0.006 0.030

(0.001e0.021) (0.003e0.017) (0.001e0.010) (0.020e0.053)

0.076 0.001 0.937 0.059

Median (25th-75th)

Unadjusted bisphenols concentrations (mg/L) BPA 0.322 0.598 (ND.-0.970) BPS 0.314 0.274 (0.137e0.705) BPF 0.200 0.260 (ND.-0.453) SBPs 1.321 1.333 (0.799e2.277) Creatinine adjusted bisphenols concentrations (mg/g) BPA 0.272 0.387 (0.042e1.028) BPS 0.265 0.237 (0.101e0.641) BPF 0.169 0.208 (0.039e0.525) SBPs 1.116 1.099 (0.517e2.613) Urine specific gravity adjusted bisphenols concentrations (mg/L) BPA 0.332 0.459 (0.067e1.224) BPS 0.323 0.295 (0.123e0.755) BPF 0.206 0.243 (0.050e0.633) SBPs 1.360 1.396 (0.649e3.116) Estimated daily intake of bisphenols (mg/kg bw/day) BPA 0.007 0.013 (0.001e0.021) BPS 0.007 0.006 (0.003e0.015) BPF 0.004 0.006 (0.001e0.010) SBPs 0.029 0.029 (0.018e0.051)

Abbreviations: BPA, bisphenol A; BPS, bisphenol S; BPF, bisphenol F; SBPs, the mass sum of the three bisphenols; GM, geometric mean; ND., not detectable. a p-values for comparisons of the differences between the non-hypertension and hypertension group using the Mann-Whitney U tests, p-value in bold indicates significance at p < 0.05.

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Table 3 Associations of urinary bisphenols concentrations with hypertension and blood pressure levels (N ¼ 1437).a Outcomes

Odds Ratios/Coefficients (95%CIs) T1 (< 33.3rd)

Hypertension BPA 1.00 BPS 1.00 BPF 1.00 SBPs 1.00 SBP BPA 1.00 BPS 1.00 BPF 1.00 SBPs 1.00 DBP BPA 1.00 BPS 1.00 BPF 1.00 SBPs 1.00 PP BPA 1.00 BPS 1.00 BPF 1.00 SBPs 1.00 MAP BPA 1.00 BPS 1.00 BPF 1.00 SBPs 1.00 MBP BPA 1.00 BPS 1.00 BPF 1.00 SBPs 1.00

ptrend

T2 (33.3rd-66.7th)

T3 (> 66.7th)

(reference) (reference) (reference) (reference)

1.30 (0.95, 1.78) 1.49 (1.09, 2.06) 1.25 (0.91, 1.73) 1.18 (0.86, 1.61)

1.40 (1.03, 1.91) 1.48 (1.07, 2.05) 0.91 (0.66, 1.26) 1.22 (0.89, 1.67)

0.035 0.100 0.403 0.269

(reference) (reference) (reference) (reference)

3.08 (0.76, 5.40) 2.61 (0.26, 4.95) 1.78 (0.65, 4.21) 2.49 (0.15, 4.83)

2.82 (0.50, 5.15) 3.89 (1.49, 6.29) 0.64 (3.02, 1.74) 2.29 (0.06, 4.64)

0.016 0.006 0.426 0.112

(reference) (reference) (reference) (reference)

1.57 (0.18, 2.96) 1.13 (0.28, 2.54) 1.05 (0.4, 2.51) 1.85 (0.45, 3.25)

1.59 (0.20, 2.99) 1.70 (0.26, 3.14) 0.18 (1.61, 1.24) 0.92 (0.49, 2.33)

0.024 0.046 0.616 0.438

(reference) (reference) (reference) (reference)

1.51 1.47 0.73 0.64

3.09) 3.08) 2.39) 2.24)

1.23 (0.36, 2.82) 2.20 (0.56, 3.84) 0.45 (2.08, 1.17) 1.37 (0.24, 2.98)

0.124 0.024 0.468 0.099

(reference) (reference) (reference) (reference)

2.07 (0.48, 3.66) 1.62 (0.01, 3.23) 1.30 (0.37, 2.96) 2.06 (0.46, 3.67)

2.00 (0.41, 3.60) 2.43 (0.79, 4.07) 0.34 (1.97, 1.30) 1.38 (0.23, 2.99)

0.013 0.013 0.496 0.220

(reference) (reference) (reference) (reference)

2.33 (0.58, 4.07) 1.87 (0.11, 3.63) 1.42 (0.41, 3.24) 2.17 (0.42, 3.93)

2.21 (0.46, 3.95) 2.80 (1.00, 4.60) 0.41 (2.20, 1.38) 1.61 (0.16, 3.37)

0.012 0.009 0.465 0.171

(0.08, (0.13, (0.93, (0.96,

Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure, PP, pulse pressure; MAP, mean arterial pressure; MBP, mid blood pressure; BPA, bisphenol A; BPS, bisphenol S; BPF, bisphenol F; SBPs, the mass sum of the three bisphenols. a Model 3 was adjusted for urinary creatinine, age, sex, BMI, smoking status, packyears of smoking, passive smoking, drinking status, exercise frequency, education, income level, hyperlipidemia, eGFR, and urinary lead, cadmium, mercury and arsenic concentrations.

association between BPA exposure and hypertension risk was observed in participants with a history of hypertension over two years (Table S2). 3.4. Bisphenols exposure and blood pressure levels The associations of urinary bisphenols concentrations with the changes in blood pressure levels were explored in the multivariable linear regression models (Table 3). Compared with the reference group of BPA, the significant increase levels of SBP, DBP, MAP, and MBP in the high exposure group were slightly lower than those in the middle exposure group. Correspondingly, significant inverted “U” shaped dose-response relationships between BPA exposure and these blood pressure indexes in the RCS model were suggested (Fig. 1A and B). Urinary BPS concentrations were linearly associated with the increased blood pressure levels in the second and third tertile (all ptrend < 0.05). Compared with the reference group of BPS, participants in the second and third tertile had a 2.61 (95% CI: 0.26, 4.95) and 3.89 (95% CI: 1.49, 6.29) mm Hg increased SBP levels, and a 1.13 (95% CI: 0.28, 2.54) and 1.70 (95% CI: 0.26, 3.14) mm Hg increased DBP levels, respectively. The RCS model manifested a coherent monotonic dose-response relationship between BPS exposure and blood pressure levels. 3.5. Subgroup analysis and sensitivity analysis We conducted subgroup analyses and modeled interaction terms to examine the modification effects of sex, age, BMI, and

income levels on the association of bisphenols exposure with hypertension risk and blood pressure levels (Tables S3eS6). When stratified by sex, the associations of BPA and BPS exposure with the risk of hypertension were more prominent in males than females. The significant associations of BPA and BPS exposure with hypertension risk were found in participants with high BMI and high income levels. In addition, modification effects of sex on BPF exposure and income levels on BPS exposure with hypertension risk and blood pressure levels were suggested. The magnitude and direction of the associations of bisphenols exposure with hypertension risk and blood pressure levels remained robust in most sensitivity analyses (Tables S7eS15). The method of not adding a constant to participants with antihypertensive use slightly weakened these associations, while excluding extreme urine samples, using different standardization methods for diuresis, further adjusting for potential confounders caused no substantial changes. 4. Discussion In the present study, after adjustment for potential confounders and four heavy metals, BPA and BPS exposure, even far below the TDI, were positively associated with the hypertension risk and blood pressure levels, but with different dose-response relationships. All these associations remained unchanged in most sensitivity analyses. Furthermore, significant associations of BPA and BPS exposure with hypertension risk were more pronounced in males and participants with high BMI and high income levels. We determined bisphenols levels in urine and shown a comparison of that in the present study and previously published studies in Table S16. The urinary BPA concentrations [median: 0.60 mg/L, geometrical mean (GM): 0.32 mg/L] in our population were in the same order of magnitude as that among general residents from Shanghai (median: 0.81 mg/L) and Tianjin (median: 0.66 mg/L), but were notably lower than that in adults from India (GM: 1.59 mg/L), Korea (GM: 2.0 mg/L), the USA (median: 1.24 mg/L), the UK (median: 1.24 mg/L), and Denmark (median: 3.25 mg/L) (see references in Table S16). The urinary BPS concentrations (GM: 0.31 mg/L; median: 0.27 mg/L) in our study were comparable with that in the USA (GM: 0.30 mg/L); were high than that in India (GM: 0.07 mg/L) and Korea (GM: 0.03 mg/L); were lower than that in Japan (GM: 1.18 mg/L), especially in Saudi Arabia (median: 4.92 mg/L) (see references in Table S16). Similar distributions about urinary BPF concentrations in adults from different countries also can be found. The comparison indicated the regional, ethnic, and lifestyle differences in the sources and extent of bisphenols exposure. We questioned participants on plastic products’ use frequency (see Table S17). A total of 98.7% and 83.9% of our participants consumed canned food and beverage less than one time per week, which may partly explain the low bisphenols levels in their urine. We found a declining trend of BPA and BPS in 2017 while their levels were a resurgence in 2018 (see Fig. S2 and Table S18). However, BPF exposure levels were increasing over time. We only enrolled 37 participants in 2018, which might not be able to spot long term trends. More years of monitoring were needed to confirm the changing trend of bisphenols. In this study, consistent with other studies, we found that urinary BPA concentrations were associated with increased hypertension risk. Using the NHANES 2003e2004 data, a significant association between BPA exposure, reflected in urinary BPA concentrations, and the risk of having hypertension was firstly reported (Shankar and Teppala, 2012). The multivariable-adjusted risk for hypertension associated with the highest versus lowest tertile of urinary BPA concentrations was 1.50 (95% CI: 1.12, 2.00). In the subgroup analysis, the positive association of BPA exposure

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

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7

Fig. 1. A. The dose-response relationships of urinary bisphenols concentrations with the risk of hypertension and the difference in SBP and DBP. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; BPA, bisphenol A; BPS, bisphenol S; BPF, bisphenol F; SBPs, the mass sum of the three bisphenols. Models were adjusted for urinary

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

Fig. 1. (continued).

creatinine, age, gender, BMI, smoking status, pack-years of smoking, passive smoking, drinking status, exercise frequency, education, income level, hyperlipidemia, eGFR, and urinary lead, cadmium, mercury and arsenic concentrations. The solid red lines represented the ORs of hypertension or differences in blood pressure indexes, and the long dashed gray lines indicated corresponding 95% CIs. The short dashed green lines indicated the reference value (the 10th percentile) and the red dots represented the knots at 10th, 50th and 90th percentiles of log 2 transformed urinary bisphenols concentrations (mg/L). The p-value for overall association <0.05 manifested a significant association, whatever the shape of the dose-response curve was. The p-value for non-linear association <0.05 indicated a nonmonotonic dose-response (NMDR) curve, otherwise, a monotonic relationship was suggested. B. The dose-response relationships of urinary bisphenols concentrations with the difference in PP, MAP and MBP. Abbreviations: PP, pulse pressure; MAP, mean arterial pressure; MBP, mid blood pressure; BPA, bisphenol A; BPS, bisphenol S; BPF, bisphenol F; SBPs, the mass sum of the three bisphenols. Models were adjusted for urinary creatinine, age, gender, BMI, smoking status, pack-years of smoking, passive smoking, drinking status, exercise frequency, education, income level, hyperlipidemia, eGFR, and urinary lead, cadmium, mercury and arsenic concentrations. The solid red lines represented the differences in blood pressure indexes, and the long dashed gray lines indicated corresponding 95% CIs. The short dashed green lines indicated the reference value (the 10th percentile) and the red dots represented the knots at 10th, 50th and 90th percentiles of log 2 transformed urinary bisphenols concentrations (mg/L). The p-value for overall association <0.05 manifested a significant association, whatever the shape of the dose-response curve was. The p-value for non-linear association <0.05 indicated a nonmonotonic dose-response (NMDR) curve, otherwise, a monotonic relationship was suggested.

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

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with hypertension remained significant in non-smoker individuals and participants with prediabetes or diabetes. However, urinary BPA concentrations in the 2003e2004 circle (GM: 2.49 mg/L) were notably higher than that in other circles (2005e2006, GM: 1.79 mg/ L) and other countries (Melzer et al., 2010). Following that, Bae et al. (2012) found an association of urinary BPA concentrations with hypertension, particularly in female participants without a history of hypertension. However, participants in their study all were elders (mean age > 70 years) who are more susceptible to environmental contaminants and subjected to have degenerative diseases. A randomized crossover trial conducted by Bae and Hong (2015) drew more direct evidence about BPA exposure and hypertension risk than cross-sectional studies. Compared with participants drinking glass bottled soy milk, urinary BPA concentrations dramatically increased by 16 times and SBP acutely increased by 5 mm Hg in participants who consumed canned soy milk. Their trial discovered the acute effects of high BPA intake on blood pressure levels (Bae and Hong, 2015). Nevertheless, elderly participants and unbalanced sex composition (56 females and 4 males) might restrict the extrapolation of the finding. A study in Thailand found that serum BPA concentrations, independent of estradiol level, was associated with the prevalence of hypertension in women (Aekplakorn et al., 2015). Contrarily, a large-scale cross-sectional study in Shanghai, China, found an inverse association between urinary BPA concentrations and the odds of hypertension with a linear trend (Wang et al., 2015). However, we noticed that about one-third of participants (1023/3246) in their study had been diagnosed with diabetes, which may cover up the true effects of BPA exposure on hypertension. In our study, after excluding participants with diseases, we still found significant associations of BPA and BPS exposure with increased hypertension risk. Our results and other studies together given more evidence to support bisphenols’ adverse effects on blood pressure levels. In our study, significant NMDR (inverted “U” shaped) relationships of BPA exposure with blood pressure levels were suggested. The occurrence of NMDR relationship is not an exception and perhaps more common than the monotonic dose-response relationship. Calabrese and Baldwin (2001) assessed that almost 40% of eligible studies satisfied the inclusion criteria for an NMDR relationship. The mechanisms of NMDR including but not limited to cytotoxicity, receptor specificity and selectivity, receptor downregulation and desensitization, receptor competition, and negative feedback loops disruption (Schug et al., 2011; Vandenberg et al., 2012; Vandenberg et al., 2009). The current regulations and safety limit of BPA are based on monotonicity. However, under the NMDR curve of BPA, the reaction at low exposure levels cannot be predicted by the effects observed at a high dose. Fundamental reform in chemical safety testing for BPA is needed to protect the ecosystem and human health. Some reviews had made comparisons between BPA and its analogs, but mainly found their similarity, not the disparity (Chen et al., 2016; Rochester and Bolden, 2015; Usman and Ahmad, 2016). BPS has less estrogenic and antiandrogenic ability than BPA and BPF while exerts the largest efficacy on 17a-hydroxyprogesterone among the three bisphenols. BPS was predicted to be a substrate of CYP2C9 while BPA and BPF of CYP3A4 (Rosenmai et al., 2014). BPS has a higher percutaneous absorption rate and a longer half-life than BPA, thus BPS might contribute to more substantial body burden under the same dose (Usman and Ahmad, 2016). Moreover, a recent article indicated that after an equal molar dose oral administration, the systemic bioavailability of BPS was 250 times higher than that for BPA, which suggested that small differences in chemical structure could lead to distinct metabolic pathways (Gayrard et al., 2019). More solid evidence is needed to confirm the difference between the three bisphenols.

9

Despite the exact mechanism of how bisphenols lead to blood pressure rise and subsequent hypertension is unclear, the estrogen signaling pathway may play a role. Estrogen is considered to have protective effects on the cardiovascular system, mainly via estrogen receptor a (ERa) mediated increase in endothelial nitric oxide synthase, cyclooxygenase, and vascular endothelial growth factor (Bae et al., 2012). BPA has dual actions for ERa via playing as agonist and antagonist but only acts as agonist for estrogen receptor b (ERb). Hence, bisphenols may disrupt the transcription of target genes of estrogen via binding to ERs. Moreover, bisphenols also can bind to membrane-bound ER and G protein-coupled receptor 30, thus activating a cascade of intracellular signaling pathways including the mitogen-activated protein kinase pathway, phosphoinositide 3-kinase pathway, calcium mobilization, nitric oxide synthesis, and cyclic adenosine monophosphate production, and controlling a series of gene transcription and subsequent biological functions (Meyer et al., 2009; Thomas and Dong, 2006). Besides, bisphenols exposure was associated with insulin resistance, adiponectin release, oxidative stress, inflammatory response, endothelial dysfunction, autonomic nervous system disorder, as well as liver, renal, and thyroid dysfunction. All these deleterious effects of bisphenols might lead to their hypertensive effects (Bae et al., 2012; Carwile and Michels, 2011; Lang et al., 2008; Li et al., 2012; Melzer et al., 2010; Stahlhut et al., 2009; Wang et al., 2013). We observed sex difference in the magnitude and significance of associations between bisphenols exposure and hypertension risk. BPA and BPS exposure showed more effects on hypertension risk in males than females. There exist sex differences in the expression and function of sex steroid hormones and their receptors (Bae et al., 2012; Mendelsohn and Karas, 2005). Estrogen exerts vasodilation effects via affecting the renin-angiotensin-aldosterone system, endothelin system, and sympathetic nervous system, while androgen causes vasoconstriction, water-sodium retention, and blood pressure elevation (Mendelsohn and Karas, 2005; Sampson et al., 2012). Intriguingly, the expression of angiotensin receptor is higher in female kidney than that in males, thus contributing to better blood pressure control in females (Hilliard et al., 2013). Besides, female exhibits high antioxidant gene expression to help
s et al., 2003). counteract bisphenols induced oxidative stress (Borra Furthermore, males in our study had a high proportion of smoking and drinking, and they were prone to have hyperlipidemia, high mean age, high BMI, and low eGFR (see Table S19). All these unfavorable factors may aggravate bisphenols’ adverse effects on blood pressure (Carwile and Michels, 2011; Lang et al., 2008; Li et al., 2012). The inverse association of BPF exposure with hypertension and blood pressure may due to residual confounding or other unknown mechanisms. Hence, hypothesis-promoted research for BPF is required. Besides, we observed modification effects of income levels on the association of BPS exposure with hypertension risk. Individuals’ income levels are closely related to their social status and educational levels (Shavers, 2007). Knowledge and education motivated behavior changes, from BPA-based products to BPA-free but BPS-manufactured commodities, may be a reason (Rochester and Bolden, 2015). We aimed to explore the associations of bisphenols exposure with hypertension risk and blood pressure levels in the crosssectional study. Standardized quality controls in covariates collection, blood pressure measurement, and laboratory analysis, eligible participants without hypertension-related diseases, and multiple sensitivity analyses were the strengths of the study. Nevertheless, several limitations should be considered. Firstly, restricted by the cross-sectional nature, we could not confirm the causality between bisphenols exposure and hypertension risk or blood pressure levels. However, a randomized trial had indicated that BPA exposure increased blood pressure levels (Bae and Hong, 2015; Bae et al.,

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639

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S. Jiang et al. / Environmental Pollution xxx (xxxx) xxx

2012). Thus, it was more reasonable to speculate that bisphenols exposure increases blood pressure and ascribes to subsequent hypertension, not vice versa. Secondly, the participants of our study were enrolled from a physical examination center, selection bias might limit the extrapolation of our findings. Given the exploratory intention of this study, such a study design contributed to high participation rate and strict quality control. Thirdly, single morning urine samples were used to determine the exposure levels of bisphenols, which might lead to exposure misclassification (Lakind et al., 2014). However, some studies have reported that a single urine sample could classify individuals into tertiles with moderate sensitivity (Chen et al., 2016; Mahalingaiah et al., 2007). Furthermore, changeless lifestyles, consumption habits, and living environments of individuals, as well as the restricted urine collection time will mitigate the variability of bisphenols. Since our findings remained significant in different statistical models and sensitivity analyses, reasons preceded chances in the associations. 5. Conclusions In the present study, we explored the association of BPA and its alternatives BPS and BPF exposure with the odds of hypertension and blood pressure levels in a Chinese general population. We found that environmental exposure to BPA and BPS, even far below the TDI, might be associated with increased hypertension risk and elevated blood pressure levels. Given that the ubiquitous bisphenols exposure for the general population and high prevalence of hypertension, our findings highlight a notable public health issue and help managers at all levels of governments make more informed regulations on the presence of bisphenols. However, our findings need to be confirmed in studies with prospective or randomized controlled designs. Declaration of competing interest The authors declare that they have no potential conflicts of interest. Acknowledgments We sincerely thank all the participants in this study. This research was supported by the National Natural Science Foundation of China (81573237). Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.envpol.2019.113639. References Abhyankar, L.N., Jones, M.R., Guallar, E., Navas-Acien, A., 2012. Arsenic exposure and hypertension: a systematic review. Environ. Health Perspect. 120, 494e500. Aekplakorn, W., Chailurkit, L.O., Ongphiphadhanakul, B., 2015. Association of serum bisphenol a with hypertension in Thai population. Int. J. Hypertens. 2015, 594189. Bae, S., Hong, Y.C., 2015. Exposure to bisphenol A from drinking canned beverages increases blood pressure: randomized crossover trial. Hypertension 65, 313e319. Bae, S., Kim, J.H., Lim, Y.H., Park, H.Y., Hong, Y.C., 2012. Associations of bisphenol A exposure with heart rate variability and blood pressure. Hypertension 60, 786e793. Barr, D.B., Wilder, L.C., Caudill, S.P., Gonzalez, A.J., Needham, L.L., Pirkle, J.L., 2004. Urinary creatinine concentrations in the US population: implications for urinary biologic monitoring measurements. Environ. Health Perspect. 113, 192e200.
s, C., Sastre, J., García-Sala, D., Lloret, A., Pallardo
, F.V., Vin ~ a, J., 2003. MitoBorra chondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic. Biol. Med. 34, 546e552. Calabrese, E.J., Baldwin, L.A., 2001. The frequency of U-shaped dose responses in the

toxicological literature. Toxicol. Sci. 62, 330e338. Calafat, A.M., Kuklenyik, Z., Reidy, J.A., Caudill, S.P., Ekong, J., Needham, L.L., 2005. Urinary concentrations of bisphenol A and 4-nonylphenol in a human reference population. Environ. Health Perspect. 113, 391e395. Carwile, J.L., Michels, K.B., 2011. Urinary bisphenol A and obesity: NHANES 20032006. Environ. Res. 111, 825e830. Chen, D., Kannan, K., Tan, H., Zheng, Z., Feng, Y.L., Wu, Y., et al., 2016. Bisphenol analogues other than BPA: environmental occurrence, human exposure, and toxicity-A review. Environ. Sci. Technol. 50, 5438e5453. Chowdhury, R., Ramond, A., O’Keeffe, L.M., Shahzad, S., Kunutsor, S.K., Muka, T., et al., 2018. Environmental toxic metal contaminants and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 362, k3310. Chrysant, S.G., 2015. Association of exposure to bisphenol A and incidence of cardiovascular disease and hypertension. J. Clin. Hypertens. 17, 737e739. Collaboration, P.S., 2002. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903e1913. Desquilbet, L., Mariotti, F., 2010. Dose-response analyses using restricted cubic spline functions in public health research. Stat. Med. 29, 1037e1057. Duan, Y., Yao, Y., Wang, B., Han, L., Wang, L., Sun, H., et al., 2018. Association of urinary concentrations of bisphenols with type 2 diabetes mellitus: a casecontrol study. Environ. Pollut. 243, 1719e1726. EFSA Panel on Food Contact Materials E Flavourings Aids P, 2015. Scientific opinion on the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA Journal 13, 3978. Forouzanfar, M.H., Liu, P., Roth, G.A., Ng, M., Biryukov, S., Marczak, L., et al., 2017. Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm Hg, 1990-2015. J. Am. Med. Assoc. 317, 165e182. Fuks, K.B., Weinmayr, G., Basagana, X., Gruzieva, O., Hampel, R., Oftedal, B., et al., 2017. Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). Eur. Heart J. 38, 983e990. Gao, C., Liu, L., Ma, W., Zhu, N., Jiang, L., Ren, N., et al., 2016. Bisphenol A in urine of Chinese young adults: concentrations and sources of exposure. Bull. Environ. Contam. Toxicol. 96, 162e167. Gayrard, V., Lacroix, M.Z., Grandin, F.C., Collet, S.H., Mila, H., Viguie, C., et al., 2019. Oral systemic bioavailability of bisphenol A and bisphenol S in pigs. Environ. Health Perspect. 127, 77005. Greenland, S., 1989. Modeling and variable selection in epidemiologic analysis. Am. J. Public Health 79, 340e349. Hilliard, L.M., Sampson, A.K., Brown, R.D., Denton, K.M., 2013. The "his and hers" of the renin-angiotensin system. Curr. Hypertens. Rep. 15, 71e79. Kang, J.H., Kondo, F., Katayama, Y., 2006. Human exposure to bisphenol A. Toxicology 226, 79e89. Kearney, P.M., Whelton, M., Reynolds, K., Muntner, P., Whelton, P.K., He, J., 2005. Global burden of hypertension: analysis of worldwide data. Lancet 365, 217e223. Lakind, J.S., Goodman, M., Mattison, D.R., 2014. Bisphenol A and indicators of obesity, glucose metabolism/type 2 diabetes and cardiovascular disease: a systematic review of epidemiologic research. Crit. Rev. Toxicol. 44, 121e150. Landrigan, P.J., Fuller, R., Acosta, N.J.R., Adeyi, O., Arnold, R., Basu, N.N., et al., 2018. The Lancet Commission on pollution and health. Lancet 391, 462e512. Lang, I.A., Galloway, T.S., Scarlett, A., Henley, W.E., Depledge, M., Wallace, R.B., et al., 2008. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. J. Am. Med. Assoc. 300, 1303e1310. Lassen, T.H., Frederiksen, H., Jensen, T.K., Petersen, J.H., Joensen, U.N., Main, K.M., et al., 2014. Urinary bisphenol A levels in young men: association with reproductive hormones and semen quality. Environ. Health Perspect. 122, 478e484. Lee, S., Kim, C., Shin, H., Kho, Y., Choi, K., 2019. Comparison of thyroid hormone disruption potentials by bisphenols A, S, F, and Z in embryo-larval zebrafish. Chemosphere 221, 115e123. Levy, D., Ehret, G.B., Rice, K., Verwoert, G.C., Launer, L.J., Dehghan, A., et al., 2009. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 41, 677. Li, M., Bi, Y., Qi, L., Wang, T., Xu, M., Huang, Y., et al., 2012. Exposure to bisphenol A is associated with low-grade albuminuria in Chinese adults. Kidney Int. 81, 1131e1139. Liao, C., Kannan, K., 2012. Determination of free and conjugated forms of bisphenol A in human urine and serum by liquid chromatographyetandem mass spectrometry. Environ. Sci. Technol. 46, 5003e5009. Liu, L., 2011. 2010 Chinese guidelines for the management of hypertension. Chin. J. Cardiol. 39, 579e615. Mahalingaiah, S., Meeker, J.D., Pearson, K.R., Calafat, A.M., Ye, X., Petrozza, J., et al., 2007. Temporal variability and predictors of urinary bisphenol A concentrations in men and women. Environ. Health Perspect. 116, 173e178. Melzer, D., Osborne, N.J., Henley, W.E., Cipelli, R., Young, A., Money, C., et al., 2012. Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Circulation 125, 1482e1490. Melzer, D., Rice, N.E., Lewis, C., Henley, W.E., Galloway, T.S., 2010. Association of urinary bisphenol a concentration with heart disease: evidence from NHANES 2003/06. PLoS One 5, e8673. Mendelsohn, M.E., Karas, R.H., 2005. Molecular and cellular basis of cardiovascular gender differences. Science 308, 1583e1587. Meng, Z., Tian, S., Yan, J., Jia, M., Yan, S., Li, R., et al., 2019. Effects of perinatal exposure to BPA, BPF and BPAF on liver function in male mouse offspring

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S. Jiang et al. / Environmental Pollution xxx (xxxx) xxx involving in oxidative damage and metabolic disorder. Environ. Pollut. 247, 935e943. Meyer, M.R., Haas, E., Prossnitz, E.R., Barton, M., 2009. Non-genomic regulation of vascular cell function and growth by estrogen. Mol. Cell. Endocrinol. 308, 9e16. Mokra, K., Wozniak, K., Bukowska, B., Sicinska, P., Michalowicz, J., 2018. Low-concentration exposure to BPA, BPF and BPAF induces oxidative DNA bases lesions in human peripheral blood mononuclear cells. Chemosphere 201, 119e126. Niu, Y., Zhang, J., Duan, H., Wu, Y., Shao, B., 2015. Bisphenol A and nonylphenol in foodstuffs: Chinese dietary exposure from the 2007 total diet study and infant health risk from formulas. Food Chem. 167, 320e325. Poulter, N.R., Prabhakaran, D., Caulfield, M., 2015. Hypertension. Lancet 386, 801e812. Rezg, R., El-Fazaa, S., Gharbi, N., Mornagui, B., 2014. Bisphenol A and human chronic diseases: current evidences, possible mechanisms, and future perspectives. Environ. Int. 64, 83e90. Rochester, J.R., 2013. Bisphenol A and human health: a review of the literature. Reprod. Toxicol. 42, 132e155. Rochester, J.R., Bolden, A.L., 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environ. Health Perspect. 123, 643e650. Rosenmai, A.K., Dybdahl, M., Pedersen, M., Alice van Vugt-Lussenburg, B.M., Wedebye, E.B., Taxvig, C., et al., 2014. Are structural analogues to bisphenol a safe alternatives? Toxicol. Sci. 139, 35e47. Sampson, A.K., Jennings, G.L., Chin-Dusting, J.P., 2012. Y are males so difficult to understand?: a case where "X" does not mark the spot. Hypertension 59, 525e531. Schug, T.T., Janesick, A., Blumberg, B., Heindel, J.J., 2011. Endocrine disrupting chemicals and disease susceptibility. J. Steroid Biochem. Mol. Biol. 127, 204e215. Shankar, A., Teppala, S., 2012. Urinary bisphenol A and hypertension in a multiethnic sample of US adults. J. Environ. Public Health 2012, 481641. Shavers, V.L., 2007. Measurement of socioeconomic status in health disparities research. J. Natl. Med. Assoc. 99, 1013e1023. Stahlhut, R.W., Welshons, W.V., Swan, S.H., 2009. Bisphenol A data in NHANES suggest longer than expected half-life, substantial nonfood exposure, or both. Environ. Health Perspect. 117, 784e789. Thomas, P., Dong, J., 2006. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 102, 175e179. Usman, A., Ahmad, M., 2016. From BPA to its analogues: is it a safe journey? Chemosphere 158, 131e142.

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Van Eeckhaut, A., Lanckmans, K., Sarre, S., Smolders, I., Michotte, Y., 2009. Validation of bioanalytical LC-MS/MS assays: evaluation of matrix effects. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 877, 2198e2207. Vandenberg, L.N., Colborn, T., Hayes, T.B., Heindel, J.J., Jacobs Jr., D.R., Lee, D.-H., et al., 2012. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr. Rev. 33, 378e455. Vandenberg, L.N., Maffini, M.V., Sonnenschein, C., Rubin, B.S., Soto, A.M., 2009. Bisphenol-A and the great divide: a review of controversies in the field of endocrine disruption. Endocr. Rev. 30, 75e95. Wang, Q., Wei, S., 2018. Cadmium affects blood pressure and negatively interacts with obesity: findings from NHANES 1999-2014. Sci. Total Environ. 643, 270e276. 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, 295e302. Wang, T., Xu, M., Xu, Y., Lu, J., Li, M., Chen, Y., et al., 2015. Association of bisphenol A exposure with hypertension and early macrovascular diseases in Chinese adults: a cross-sectional study. Medicine (Baltim.) 94, e1814. Wang, Y.-X., Liu, C., Shen, Y., Wang, Q., Pan, A., Yang, P., et al., 2019. Urinary levels of bisphenol A, F and S and markers of oxidative stress among healthy adult men: variability and association analysis. Environ. Int. 123, 301e309. Wu, W., Jiang, S., Zhao, Q., Zhang, K., Wei, X., Zhou, T., et al., 2018. Environmental exposure to metals and the risk of hypertension: a cross-sectional study in China. Environ. Pollut. 233, 670e678. Wu, W., Liu, D., Jiang, S., Zhang, K., Zhou, H., Lu, Q., 2019. Polymorphisms in gene MMP-2 modify the association of cadmium exposure with hypertension risk. Environ. Int. 124, 441e447. Ye, X., Wong, L.Y., Kramer, J., Zhou, X., Jia, T., Calafat, A.M., 2015. Urinary concentrations of bisphenol A and three other bisphenols in convenience samples of U.S. Adults during 2000-2014. Environ. Sci. Technol. 49, 11834e11839. Zhang, T., Sun, H., 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, 4686e4694. Zhang, Y., Dong, T., Hu, W., Wang, X., Xu, B., Lin, Z., et al., 2019. Association between exposure to a mixture of phenols, pesticides, and phthalates and obesity: comparison of three statistical models. Environ. Int. 123, 325e336. Zhang, Z., Alomirah, H., Cho, H.S., Li, Y.F., Liao, C., Minh, T.B., et al., 2011. Urinary bisphenol A concentrations and their implications for human exposure in several Asian countries. Environ. Sci. Technol. 45, 7044e7050.

Please cite this article as: Jiang, S et al., Association of bisphenol A and its alternatives bisphenol S and F exposure with hypertension and blood pressure: A cross-sectional study in China, Environmental Pollution, https://doi.org/10.1016/j.envpol.2019.113639