Exposure assessment of bisphenols in Chinese women during

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Ecotoxicology and Human Environmental Health

Exposure assessment of bisphenols in Chinese women during pregnancy: a longitudinal study Jiufeng Li, Chuansha Wu, Hongzhi Zhao, Yanqiu Zhou, Guodong Cao, Zhiyi Yang, Yanjun Hong, Shunqing Xu, Wei Xia, and Zongwei Cai Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.9b01281 • Publication Date (Web): 10 Jun 2019 Downloaded from http://pubs.acs.org on June 10, 2019

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Environmental Science & Technology

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Exposure assessment of bisphenols in Chinese women during

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pregnancy: a longitudinal study

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Jiufeng Li1,#, Chuansha Wu2,#, Hongzhi Zhao1, Yanqiu Zhou1, Guodong Cao1, Zhiyi

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Yang1, Yanjun Hong1, Shunqing Xu2, Wei Xia2*, Zongwei Cai1*

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1State

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Chemistry, Hong Kong Baptist University, Hong Kong SAR, China.

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2Key

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Environmental Protection, and State Key Laboratory of Environmental Health, School

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of Public Health, Tongji Medical College, Huazhong University of Science and

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Technology, Wuhan, China

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* Corresponding author:

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Prof. Zongwei Cai

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State Key Laboratory of Environmental and Biological Analysis, Department of

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Chemistry, Hong Kong Baptist University, Hong Kong, P. R. China

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Tel.: +852-34117070

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Fax: 34117348

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E-mail: [email protected]

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Dr. Wei Xia,

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School of Public Health, Tongji Medical College, Huazhong University of Science

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and Technology, 13 Hangkong Road, Wuhan 430030, China

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E-mail: [email protected]

Key Laboratory of Environmental and Biological Analysis, Department of

Laboratory of Environment and Health, Ministry of Education & Ministry of

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# Both

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*The authors declare they have no actual or potential competing financial interests.

authors contributed equally to this work.

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ACS Paragon Plus Environment


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TOC

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ABSTRACT

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Bisphenol S (BPS) and bisphenol F (BPF) are increasingly used in manufacturing

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consumer products to replace the use of bisphenol A (BPA), but exposure data are

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limited, particularly among pregnant women. Here, we measured BPA, BPS, and BPF

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levels in urine samples, collected from 941 pregnant women over three trimesters. We

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examined the correlations, co-exposure patterns, variability, and predictors of

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bisphenols using Spearman's correlation coefficient, percentile analysis, intraclass

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correlation coefficient, and linear mixed models, respectively. We assessed health

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risks using average concentrations of bisphenols over three trimesters. The three

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bisphenols were detected in more than 50% of samples, among which BPA was the

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predominant one. Cashiers, office workers, teachers, and salespersons had elevated

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urinary BPS concentrations, while healthcare workers had relatively higher BPA

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concentrations. About 15 participants had potential health risks induced by exposure

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to bisphenol mixtures. These findings indicate that exposure to multiple bisphenols at

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low levels is common over three trimesters. Multiple measurements of urinary BPA

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and BPS concentrations are needed for more accurate evaluation of the exposure

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levels during pregnancy, while urinary BPF concentrations during pregnancy are

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moderately reliable. Occupational exposure should be taken into consideration in

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future demographic studies.

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KEYWORDS: BPA alternatives/replacements; Repeated measure; Predictors;

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Chinese

pregnant

women;

Health

risks

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INTRODUCTION

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Bisphenol A (2,2−bis−(4−hydroxyphenyl)propane; BPA) is a synthetic chemical,

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which is used as a monomer in manufacturing polycarbonate plastics and epoxy resins.

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BPA is normally applied as a plasticizer, which dominates the production of

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consumer products and food containers.1 As polymer degrades, BPA can leach from

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the products and enter the human body via ingestion, inhalation, or dermal

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contact.2 Because of its well-noted estrogenic, anti-androgenic, and thyroid hormonal

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activities,3 the usage of BPA has been banned in certain products, such as baby bottles

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and children ’ s toys, which has led to the increasing production and application of

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BPA substitutes, particularly 4,4 ′ -methylenediphenol (BPF) and 4-hydroxyphenyl

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sulfone (BPS).4 The global BPA production volume amounted to about 4.70 million

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tons in 2007, and the amount of BPA produced in China grew to 2.25 million tons in

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2010.5 The global production and consumption of bisphenols, especially those of BPS

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and BPF, have tended to increase.6 BPS is mostly applied in products for industrial

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uses and thermal papers, while BPF is commonly found in consumer products, such

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as adhesives plastics, dental sealants, pipelines, and coatings.7 The production volume

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of BPS applied in thermal paper has nearly doubled between 2016 and 2017

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according to a recent survey from the European Chemicals Agency (ECHA).8 BPS

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has been detected in receipts and paper money,9 while BPF is mainly applied to make

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epoxy resin in China.6 Also, BPS and BPF have been detected in many personal care

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products and food.10 Nowadays, BPA alternatives are widely detected in dust,11

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water,12 sediment,13 foodstuffs,14 human urine,15 blood,16 and seminal plasma.17

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Recently, in vitro and animal studies have shown that BPF and BPS may exhibit

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similar toxicity to or higher than BPA.7, 18 Several studies, although limited in number,

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have evaluated the health effects of BPA alternatives on pregnant women or fetuses.

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Wan et al. (2018) observed that prenatal exposure to BPS was associated with

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increased gestational age among girl infants,19 whereas Aung et al. (2018) found that

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BPS exposure during the third trimester increased the risks of preterm birth.20 The

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inconsistent findings may be caused by urinary concentrations, which were measured

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at different time points in pregnancy. Considering the rapid elimination of

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bisphenols21,

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urinary bisphenol measurements during pregnancy are essential to more accurately

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assess the exposure levels of bisphenols and further to help address the potential

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adverse health effects of maternal bisphenol exposure on mothers or fetuses.15 Health

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risks caused by BPA exposure have been investigated thoroughly in general

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population23 and children.9 However, a limited number of studies have evaluated the

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health hazards induced by exposure to mixtures of bisphenols.

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22

and relatively long gestation period (about 40 weeks), the repeated

Additionally, urinary concentrations of bisphenols are associated with a variety of 6


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factors, such as demographic factors, socioeconomic levels, and lifestyles.24, 25 Thus,

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understanding the relationships between predictors and exposure levels of bisphenols

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might help to reduce bisphenol exposures. However, predictors varied across study

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populations, study designs, sampling years, and assessment approaches. It is a

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necessity to investigate the exposure characterization of bisphenols among Chinese

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pregnant women.

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In this study, we measured BPA and its two most common alternatives, BPS and

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BPF, in urine samples collected from 941 mothers at three trimesters. We aimed to

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profile exposure patterns, to evaluate the correlations of analytes, and to investigate

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the variations and variability of three bisphenols over three trimesters. In addition, we

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explored the associations between urinary bisphenol concentrations and demographic

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factors to obtain the predictors of exposure to bisphenols. We also assessed the health

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risks caused by exposure to bisphenol mixtures based on the average concentrations

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of three bisphenols over the three trimesters.

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MATERIALS AND METHODS

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Study Population

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Between 2014 and 2015, we recruited pregnant women who aged 18 years or older,

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whose first visit time was before 16 gestational weeks and had a singleton delivery at

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Wuhan Women and Children Medical and Healthcare Center in Hubei Province,

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China. All participants in this study at enrollment signed written informed consent at

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enrollment and filled up the questionnaires. The detailed information of population

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was introduced in our previous work.26 Finally, 941 mothers provided a complete

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series of urine samples at three trimesters: first (T1: 13.0 ± 1.1 weeks), second (T2:

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23.6 ± 3.2 weeks) and third trimester (T3: 35.9 ± 3.4 weeks). The research protocol

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was approved by the ethics committee of Tongji Medical College, Huazhong

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University of Science and Technology.

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Data Collection

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The information (e.g., weight, height, jobs, and vomiting or not) was collected by

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nurses. Participants were categorized as cashiers, healthcare workers (e.g., nurses and

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physical therapists), teachers (including other faculty or staff working at a school),

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office workers, salespersons, others, and unemployed (reference). Pre-pregnancy body

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mass index (BMI: kg/m2) was calculated using the self-reported weight and height

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before pregnancy. Participants were divided into four pre-pregnancy BMI groups

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(kg/m2): underweight (< 18.5), normal (18.5 - 23.9), overweight (24 - 27.9), and obese

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(≥ 28). The population was stratified into four groups of gestational weight gain (kg):

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below 10, between 10 and 15, between 16 and 19, and above 20. Additionally, women

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were divided into three groups (inadequate, recommended, and excessive) by 8


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comparing their gestational weight gain with Institute of Medicine (IOM)

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recommendations.27 Babies born at less than 37 weeks (preterm birth) and 37 to 38

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weeks (early-term birth) may have more health problems than those born between 39

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and 42 weeks.28 Therefore, we divided participants into two groups according to the

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length of gestation: < 39 weeks and 39 - 42 weeks.

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Urinary Concentrations of Bisphenols

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BPA, BPS, and BPF were purchased from Sigma-Aldrich Chemical Co. (St. Louis,

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USA). 13C12-BPA (99%, 100 μg/mL in methanol) and 13C12-BPS (98%, 100 μg/mL in

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methanol) were brought from Sigma-Aldrich and Cambridge Isotope Laboratories

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(Andover, MA, USA), respectively.

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13C-BPA

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property.

13C-BPF

was not purchased in this work.

was used for the quantification of BPF, considering its similar structural

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We applied liquid-liquid extractions for sample preparation according to our

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previous study.29 In brief, urine (1 mL) was digested with β-glucuronidase/sulfatase

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overnight, the mixture was extracted, and supernatants were combined, evaporated,

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and reconstituted for instrumental analysis. Bisphenols were separated by Ultimate

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3000 UHPLC system (Dionex, Sunnyvale, CA, USA) equipped with a Betasil C18

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column (2.1 mm × 100 mm, 3 μm, Thermo) using a mobile phase gradient with water

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and acetonitrile, and detected by a Triple Quadrupole Mass Spectrometer (Thermo 9



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Scientific, San Jose, CA) in negative-ion electrospray ionization mode.

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This method performed satisfactory accuracy (9.8% - 12.6%) and precision (
72%) and BPS (> 63%). Wilcoxon tests found no significant difference in

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bisphenol concentrations across the three trimesters. Weak correlations between

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time-points of BPA and BPS levels were observed (r < 0.45). Urinary concentrations

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of BPF between time-points were moderately correlated (r: 0.538 - 0.706).

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Figure S1 presents the proportions of urinary concentrations of each bisphenol

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(BPF, BPA, or BPS) in the total concentrations of three bisphenols. BPA dominated

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the exposure by covering more than 45% of the total bisphenol concentrations,

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followed by BPF (32.1% - 33.1%) and BPS (21.7% - 22.7%), which indicated that 14


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BPA was the predominant bisphenol in the study population, although its application

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has been forbidden in many products. In addition, we found no significant variations

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of exposure patterns over the three trimesters.

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The bisphenol levels in this study and those in previous studies are compared in

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Table 3. There are a number of studies, which have evaluated BPA concentrations

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among pregnant women worldwide. The median BPA concentration (1.18 ng/mL) in

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our study was comparable with those in the United States (0.6 - 1.8 ng/mL),21

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Denmark (1.38 ng/mL),36 Canada (1.19 ng/mL),24 and the Netherlands (1.6 ng/mL).37

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When comparing with our results, higher BPA levels were observed among pregnant

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women in Spain (2.2 ng/mL),38 Ohio, USA (1.3 - 2 ng/mL),39 Puerto Rico (2.5

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ng/mL),22 France (2.7 ng/mL)40, and Israel (2.0 ng/mL).15

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However, exposure data of other bisphenols are scarce, especially for pregnant

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women. The median concentration of BPS (0.34 ng/mL) in this study was comparable

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with that reported in the Netherlands (0.36 ng/mL),37 but lower than that (0.59 ng/mL)

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in Canada.24 Compared with the previous study conducted in Wuhan, China (0.16

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ng/mL) between 2012 and 2014,19 our participants had elevated BPS levels, which

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indicated BPS exposure increased among the population of Wuhan. When comparing

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with general population, BPS levels in this work were higher than those in India (0.06

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ng/mL), South Korea (0.01 ng/mL), Kuwait (0.37 ng/mL), Malaysia (0.08 ng/mL), 15



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Vietnam (0.16 ng/mL), and the United States (0.26 ng/mL), but lower than those in

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Japan (1.04 ng/mL) 4 and Saudi Arabia (4.92 ng/mL).41

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BPF detection rate in the present work was relatively higher than that among

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pregnant women in the Netherlands in 2004 – 2005 (40.2%)37 and that in samples

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collected from American adults in 2014 (88%),42 but lower than that in non-pregnant

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women from Cyprus and Romania in 2013 - 2015 (100%).43 The detection rates of

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BPF have increased over the past two decades, probably as a result of the increased

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usage of this BPA alternative in industry. Andrianou et al. suggested that microwave

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use might be a significant predictor of BPF urinary levels.43 Consistent with our

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findings, Yamazaki et al. found that BPF was the major bisphenol in rivers, and its

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levels were higher than those of BPA in China.44 High detection rates in vegetables

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and seafood in China may be one reason for the common occurrence of BPF exposure

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among our studied population.4 In addition, the high consumption of condiment,

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mustard, and preserved bamboo shoots among the Chinese population may be another

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explanation.10 Further assessments of BPF exposure are needed considering the lack

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of information on the dietary habits of participants. Participants in our study had

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similar BPF concentration (median: 0.59 ng/mL) with those in the Netherlands study

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(0.57 ng/mL),37 but slightly higher than the study participants in Israel (0.4 ng/mL).15

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Compared with our results, the urinary concentration of BPF was lower in the general 16


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population of Saudi Arabia (2.16 ng/mL).43

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The difference in exposure levels of bisphenols may result from the variations in

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lifestyle (dietary habits and personal care products usage) and industrial application of

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bisphenols-containing products. In addition, BPA levels have decreased in recent

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years, due to the increasing concerns on its well-noted harmful effects, efforts of

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nongovernmental organizations on reducing the usage of BPA-containing products,

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and legislative measures introduced in different countries.

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Correlations of Bisphenols

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The correlations for both unadjusted and SG-adjusted concentrations of bisphenols

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were evaluated (Table 4). BPA, BPF, and BPS were weakly correlated with each

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other (r < 0.45), indicating that the major exposure sources of these bisphenols may

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be different. BPA is mainly applied as a plasticizer in the production of plastics and

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resins.1 BPS is mostly used in thermal receipt papers,8 and BPF is increasingly used in

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epoxy resin.6 In addition, a study conducted by Liao et al. observed higher BPA

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concentrations in canned food, higher BPS concentrations in meat products and higher

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BPF concentrations in vegetable products.14 Consistent with our findings, Liu et al.

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(2018) reported that different sources dominated BPA and BPS exposure.24 Since the

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information on dietary habits and usage of bisphenol-containing personal care

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products has not been collected in this work, it is difficult to characterize the exposure 17



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sources of three bisphenols.

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Exposure to Individual or Three Bisphenols at Single or Three Trimesters

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Several studies have evaluated the simultaneous exposure to BPA, BPS, and BPF,37

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but limited studies have investigated the patterns of co-exposure to three bisphenols at

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one trimester or exposure to one bisphenol over three trimesters. The percentages of

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participants whose urinary concentrations were greater than certain percentiles (25th,

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50th, or 75th percentile) of the distributions are evaluated and shown in Figure 1. For

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all three bisphenols, 48%, 49%, and 48% of the study population were exposed to

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above the 25th percentile at each trimester, but only 3%, 4%, and 3% were above the

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75th percentile. For three trimesters, about 50%, 51%, and 57% of the population were

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exposed to above the 25th percentages of BPS, BPA, and BPF, respectively. Lower

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than 10% of participants were exposed to higher than the 75th percentile of BPA, BPS,

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or BPF. Our results suggest that exposure to multiple bisphenols at one point or one

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bisphenol at multiple points tend to occur at low levels.

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Variability of Bisphenols

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Several studies have evaluated the variability and predictors of urinary BPA during

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pregnancy; yet, studies of BPA alternatives were limited, particularly among pregnant

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women. To evaluate the variability of the targeted bisphenols, the intraclass

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correlation coefficient (ICC) is calculated through dividing the between-person 18


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variations of bisphenol concentrations by the between-person variations and

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within-person variations in the study population (Table 5). As low ICC indicates high

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within-person variations and relatively low between-person variations, ICC values

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ranging from 0.247 to 0.479 indicated these bisphenols had moderate to high

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within-person variability. Consistent with these findings, as found in the present study,

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the variations of urinary concentrations over three trimesters on basis of median

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concentrations are not significant. The ICC values for BPA and BPS (BPS: ICC =

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0.312; BPA: ICC = 0.247) indicated a high variability of two bisphenols. The result

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(ICC = 0.479) also suggested that BPF was relatively reliable throughout the

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collection period. The ICC of BPA in our work was comparable with that of pregnant

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women in Puerto Rico (ICC: 0.24),22 but somewhat higher than the results of two US

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studies in Ohio (0.11)39 and in New York (0.11).21 The urine samples for the study in

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Ohio were collected at 16 gestational weeks, 26 gestational weeks, and 24 hours after

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delivery, which is very different from the present study (13.0 weeks, 23.6 weeks, and

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35.9 weeks). Furthermore, BPA concentrations in urine samples collected during 24

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hours after delivery were clearly lower than those collected during pregnancy in this

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American study. In addition, ICC was calculated on the basis of creatinine-adjusted

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concentrations in the Ohio study, which is different from our work using SG-adjusted

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concentrations. The variability of BPA alternatives (BPF and BPS) was lacking 19



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among pregnant women in previous works. Wang et al. investigated the variability of

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BPF in healthy adult men and found that the ICC of BPF was low (< 0.06).45 Vernet

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et al. found the variability of BPS was relatively high among pregnant women, with

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ICC values 0.14 to 0.50.46 Therefore, repeated measurements of bisphenols in

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multiple time points are required due to the lesser reliability of bisphenols.

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Characterizing variability of bisphenols is critical to interpreting the epidemiology

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results and to evaluating potential methodology errors.

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Demographic Factors Associated with Urinary Bisphenols

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Since environmental exposures might be associated with sociodemographic and

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lifestyle factors, we investigated the differences in SG-adjusted concentrations of

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bisphenols in stratified groups (Table 6). We found that urinary concentrations of

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bisphenols varied by sampling seasons. Concentrations of BPF, BPS, and BPA were

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higher in summer than in winter. The reason may be that the high temperature in

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summer can increase the migration of bisphenols from products,2 and cause heavier

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bisphenol exposure.

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We observed the elevated urinary BPS concentrations in women who are

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cashiers, office workers, salespersons, and teachers. BPS was the substitute of BPA

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mainly used in most paper products.7 Thayer et al. found that BPS levels increased

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after handling BPS-containing receipts.47 Dermal absorption of BPS-containing 20


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products may be the main exposure source for BPS. In addition, we found participants

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who worked in healthcare sectors had higher BPA levels. Workers can be exposed to

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BPA via breathing or skin absorption through using the medical devices containing

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polymer materials, for BPA is widely applied in the manufacturing of medical care

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equipment and dental sealants,7 and it can be released from these medical products

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into the environment. The exposure from the workplace is a considerable factor in

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evaluating the exposure levels of BPA and BPA-alternatives.

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Mothers who reported vomiting after conception had lower BPS concentrations

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than those did not vomit. The reason may be that BPS has potential estrogenic

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disrupting activities,48 which can disturb hormone homeostasis and cause adverse

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effects on BPS-exposed person. Lee et al. found that pregnant women who

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experienced vomiting had higher estradiol levels due to its effects on gastric smooth

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muscle.49 Vinas and Watson observed BPS had the same or higher estrogen

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effectiveness than estradiol;48

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estradiol in the membrane-mediated pathway,

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could change the expression of aromatase, which is the key enzyme in the estradiol

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synthesis.51 Considering the non-monotonic dose responses and low-dose effects of

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hormone and bisphenols, relationships among BPS exposure, hormone levels, and

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vomiting need further clarification.

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Johanna et al. found BPS had the similar potency to 7

and Kinch et al. observed that BPS

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We observed that women who gave birth in a short gestational period (less than

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39 weeks) had higher BPA concentrations. Consistent with our results, Cantonwine et

376

al. found that maternal BPA levels were associated with the increased risks of preterm

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birth.52,53 We found that mothers with inadequate or excessive gestational weight gain

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had significantly elevated urinary BPF concentrations when compared with those who

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gained recommend weight. In addition, elevated urinary BPS concentrations were

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observed in mothers with inadequate gestational weight gain. There was no significant

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difference in urinary BPA levels among GWG groups (inadequate, normal, and

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excessive). One possible explanation was the main dietary sources of BPS (meat and

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meat products), BPF (vegetable products and seafood), and BPA (canned food) were

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different.14 Dietary lifestyles and preferences may influence the exposure levels of

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three bisphenols. Since information on food consumption habits (e.g. packaged food,

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fast food, etc.) and cosmetic usage were not collected in this work, it is hard to stratify

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the exposure to bisphenols, because the both are significant sources for exposures to

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bisphenols. Another possible reason was that BPS and BPF have the ability to disturb

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thyroid hormonal homeostasis and induce the energy imbalance. Both BPS and BPF

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can affect lipid metabolism and adipogenesis.54,

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Higashihara et al. observed that BPF and BPS exposures were associated with the

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decreased body weight.56 This work also found that obese women had lower BPF

55

An animal study conducted by

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levels than women with normal pre-pregnancy BMI. Since limited research has

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investigated the associations between BPA alternatives and weight gains or BMI

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among mothers, additional works are expected to explore the relationships between

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bisphenol exposure and hormone homeostasis.

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Cumulative Health Risk Assessment

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Considering the moderate to high variability of bisphenols, we used the average of

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urinary concentrations at three trimesters to assess the health risks induced by the

400

exposure to bisphenols. The estimated daily intakes (EDI) and the health risks by

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comparing EDI with TDI are shown in Table 7. The percentages of the participants

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with health risks caused by the exposure to bisphenols were as follows: BPA (1.17%)

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> BPS (0.43%) > BPF (0%). About 15 (1.6%) participants were at the risk from

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exposure to BP mixtures. Of those, 4 participants had risks (HI > 1) driven by BPS,

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while 11 could be harmed by BPA. The 75th percentiles of the daily intakes of BPS,

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BPA, BPF, and ∑ BPs were 0.22, 0.51, 0.20, and 1.16 nmol/kg body weight/day,

407

respectively, which do not exceed the TDI for BPA (18 nmol/kg body weight/day).

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To the best of our knowledge, this is the first study to investigate the health risks of

409

bisphenol mixtures using urinary concentrations collected at multiple time points

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among Chinese pregnant women. The exposure to high levels of bisphenols over

411

trimesters, although in a small part of participants, points the need for regulation to 23



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eliminate the exposure to BPA and its alternatives.

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We evaluated the frequency (% in the group) of participants with HI > 1 and

414

distributions of HI divided by occupation groups (Table S1). No significant difference

415

in HI among jobs was observed, although the higher frequency of HI > 1 is found in

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teachers. Compared with the frequency of HI > 1 in participants who were

417

unemployed, workers had higher health risks with HI > 1. Hence, occupational

418

standards are urgently called for to protect workers from adverse health impacts

419

induced by exposure in China.

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The repeated measurement of urinary bisphenols at different trimesters enabled

421

us to evaluate the exposure levels and exposure patterns at multiple point times.

422

Additionally, we assessed BPA and its two most common substitutes, BPF and BPS,

423

in our study to give an investigation of bisphenol exposure after the regulation of BPA.

424

Furthermore, we assessed the health risks caused by exposure to three bisphenols

425

using average concentrations over three trimesters, which more accurately reflect

426

bisphenol levels during gestation. However, our study also had a number of

427

limitations. First, we did not collect information on dietary factors and the usage of

428

personal care products before sampling date, which may affect urinary concentrations

429

of bisphenols. Second, we measured total concentrations (free and conjugated

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metabolites), while free bisphenols may be more toxic. These limitations merit

431

attention in future research.

432

In summary, exposure to BPA, BPS, and BPF is ubiquitous among the study

433

population. BPA is still the dominating bisphenol, although its application has been

434

restricted in certain products. Exposure sources for BPA, BPS, and BPF vary. Urine

435

samples collected at multiple time points are essential to assess the exposure levels of

436

bisphenols throughout pregnancy. Only a few participants experienced exposure to

437

high levels of multiple bisphenols over trimesters and had potential health risks

438

stemming from this exposure. This work highlights the occupational exposure and

439

fills a gap in the biomonitoring of exposure to BPA alternatives among pregnant

440

women.

441 442

SUPPORTING INFORMATION

443

(Figure S1) Exposure patterns of three bisphenols (distributions of concentrations and

444

composition profiles) among 941 participants over three trimesters (first trimester: T1,

445

second trimester: T2, third trimester: T3); (Table S1) Frequency (% in group) of

446

participants with HI>1 and distributions of HI divided by occupation groups.

447 448

ACKNOWLEDGMENTS

25



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449

This study was supported by grants from the National Natural Science Foundation of

450

China (21437002 and 21505111) and the General Research Fund (GRF 12301915 and

451

12319716) from the Research Grants Council (RGC) of Hong Kong, China.

26


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Table 1. Demographic characteristics of the participants (N = 941) Variables

N (%)

Gestational weight gain (GWG, kg)

Exposure assessment of bisphenols in Chinese women during

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