Repeated measurements of paraben exposure during pregnancy in

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Ecotoxicology and Human Environmental Health

Repeated measurements of paraben exposure during pregnancy in relation to fetal and early-childhood growth Chuansha Wu, Wei Xia, Yuanyuan Li, Jiufeng Li, Bin Zhang, Tongzhang Zheng, Aifen Zhou, Hongzhi Zhao, Wenqian Huo, Jie Hu, Minmin Jiang, Chen Hu, Jiaqiang Liao, Xi Chen, Bing Xu, Shi Lu, Zongwei Cai, and Shunqing Xu Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.8b01857 • Publication Date (Web): 14 Nov 2018 Downloaded from http://pubs.acs.org on November 14, 2018

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Environmental Science & Technology

Xu, Shunqing; Tongji Medical College, Huazhong University of Science and Technology, State Key Laboratory of Environmental Health , School of Public Health

ACS Paragon Plus Environment


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Repeated measurements of paraben exposure during pregnancy in

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relation to fetal and early-childhood growth

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Chuansha Wu,†,# Wei Xia,†,# Yuanyuan Li,† Jiufeng Li,‡ Bin Zhang,§ Tongzhang Zheng,‖

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Aifen Zhou,§ Hongzhi Zhao,‡ Wenqian Huo,⊥ Jie Hu,† Minmin Jiang,† Chen Hu,† Jiaqiang

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Liao,† Xi Chen,† Bing Xu,† Shi Lu,¶ Zongwei Cai,*,‡ and Shunqing Xu*,†

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†

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

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

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Wuhan, Hubei, People’s Republic of China

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

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‡

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Chemistry, Hong Kong Baptist University, Hong Kong, SAR, People’s Republic of China

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§ Women

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Republic of China

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‖ Department

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⊥

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Zhengzhou University, Zhengzhou, Henan, People's Republic of China

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¶

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Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of

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China

State Key Laboratory of Environmental and Biological Analysis, Department of

and Children Medical and Healthcare Center of Wuhan, Wuhan, Hubei, People’s

of Epidemiology, Brown University, Providence, RI, USA

Department of Occupational and Environmental Health, College of Public Health,

Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College,

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* Corresponding author: Prof. Shunqing Xu, E-mail: [email protected], School of Public

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Health, Tongji Medical College, Huazhong University of Science and Technology, 13


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Hangkong Road, Wuhan 430030, China; Tel: 86-27-83657705; Fax: 86-27-83657781 or

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Prof. Zongwei Cai, E-mail: [email protected], Department of Chemistry, Hong Kong

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Baptist University, Hong Kong, SAR, People’s Republic of China; Tel: 852-34117070.

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# Both

authors contributed equally to this work.

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Abstract

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Parabens are potential endocrine disruptors with short half-lives in the human body. To

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date, few epidemiological studies regarding repeated paraben measurements during

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pregnancy associated with fetal and childhood growth have been conducted. Within a

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Chinese prenatal cohort, 850 mother-infant pairs from whom a complete set of maternal

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urine samples were acquired during three trimesters were included, and the levels of five

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parabens were measured. We assessed the associations of both average and trimester-

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specific urinary paraben levels with weight and height z-scores at birth, 6 months, 1, and 2

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years of age. In all infants, each doubling increase in average ethyl paraben (EtP) was

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associated with -2.82% (95% CI: -5.11%, -0.53%) decrease in weight z-score at birth,

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whereas no significant age-specific associations were identified. After stratifying by sex,

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we further observed age-specific association of average EtP with -3.96% (95% CI: -7.03%,

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-0.89%) and -3.38% (95% CI: 6.72%, -0.03%) reduction in weight z-scores at 1 and 2 years

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in males, respectively. Third-trimester EtP was negatively associated with weight z-scores

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at birth, 1 and 2 years in males. Our results suggested negative associations between

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prenatal paraben exposure and fetal and childhood growth, and the third trimester may be

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the window of susceptibility.

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Keywords: Parabens; Repeated measurements; Birth size; Early-childhood growth

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TOC Art

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Introduction

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Parabens are comprised of a family of antimicrobial preservatives that are added to

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personal care products, pharmaceuticals, foods, and beverages.1 Due to the extensive

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application of parabens, especially the combined utilization of methyl and propyl paraben

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(MeP and PrP, respectively), humans are widely exposed to these chemicals, mainly

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through dermal absorption, ingestion, and inhalation.2-4

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Parabens have long been regarded as endocrine disruptors and exhibit very weak

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estrogen activity both in vitro and in vivo.5 From 1984 to 2008, the US Food and Drug

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Administration (FDA) and the Cosmetic Ingredient Review (CIR) reviewed the toxicity of

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parabens and concluded that they were safe for use in cosmetic products.6, 7 However, based

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on recent accumulating evidence from experimental animal studies, prenatal exposure to

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different kinds of parabens in utero is associated with increased mortality rate, damaged

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social cognition, impaired sexual behavior, and decreased semen quality (count and

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motility), and also suggested that the aforementioned developmental toxic effects caused

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by parabens are related to their endocrine disrupting properties.8-11

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Prenatal development is a sensitive and vulnerable stage of human life, and disruptions

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during this special period may cause lifetime adverse consequences. Paraben levels in

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maternal blood are highly correlated with concentrations of parabens in cord blood or

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amniotic fluid, indicating that parabens pass through the placental barrier and thus probably

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influence the developing fetus.12-14 Moreover, the adverse impacts of exposure to

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environmental factors in utero may proceed to influence offspring growth in childhood.15-


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17

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associated with delivery measures of fetal growth and postnatal growth have been

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performed. In a French population of mother-son pairs, Philippat et al.18 did not observe

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significant associations between maternal paraben levels in a single spot urine collected

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during the early first to early third trimester and size at birth in 2012 (n = 191). Two years

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later, they enlarged the sample size to 520 pairs and still did not observe significant

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associations of prenatal paraben exposure, as measured in urine samples collected during

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22-29 gestational weeks, with anthropometric measurements at birth and in early-

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childhood.19 However, Geer et al.20 reported associations of cord blood butyl paraben (BuP)

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and PrP levels with decreased birth weight and birth length, respectively, in an immigration

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cohort study in Brooklyn, New York.

So far, few epidemiological studies concerning paraben exposure during pregnancy

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Parabens have comparatively short half-lives in the human body.18 After being

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absorbed into the body, these compounds are rapidly hydrolyzed by esterases without

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accumulation, and then mainly excreted through urine.5, 21 Thus, urinary excretion levels

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of parabens can be used as valid biomarkers of recent exposure.22 A person’s daily

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exposure level can be represented by maternal urinary paraben concentrations measured in

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a single spot urine, since medium to strong reproducibility of paraben levels were found in

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24 h urine.23 However, some previous studies reported that assessing prenatal paraben

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exposure by using a single spot urine sample may result in exposure misclassifications,18,

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19, 24

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variability during pregnancy (intraclass correlation coefficients ranged from 0.32-0.39).25,

since parabens were reported as chemicals with high within-subject temporal



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the prenatal paraben exposure levels.18

Repeatedly measured urinary paraben concentrations over trimesters may better reflect

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In this study, 850 pregnant women were repeatedly measured for urinary paraben levels

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in biospecimens collected at the early, middle, and late stage of pregnancy to further

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evaluated whether prenatal paraben exposure affected fetal as well as early-childhood

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growth; we also identified the critical window of susceptibility in which prenatal paraben

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exposure affected the growth of fetuses and children.

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Materials and Methods

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Study population

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The pregnant women in this study was recruited between March 2014 and March 2015 at

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

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Pregnant women who came to have the first prenatal care visit (before 16 weeks) were

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asked to join in the study. Eligible participants were those who were in accordance with all

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the following criteria: (1) with a singleton pregnancy; (2) living in the city of Wuhan at the

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time of enrollment and plans to reside in the region continually for the foreseeable future;

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(3) willing to donate their biospecimen during regular prenatal care; (4) giving birth at the

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study hospital. With prenatal consent, we recruited the newborns at birth and asked them

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to come back to the Department of Children’s Health at the hospital for follow-up study.

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Eight hundred and fifty six mother-infant pairs from whom a complete set of maternal urine

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samples were collected at the 1st, 2nd, and 3rd trimesters during pregnancy (13.0 ± 1.1 weeks,


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23.6 ± 3.2 weeks, and 35.9 ± 3.4 weeks, respectively) were included in the present study

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and urinary paraben levels were measured. Women who delivered neonates with a birth

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defect (n = 5) and continued to smoke during pregnancy (n = 1) were excluded. Thus, 850

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mother-infant pairs were examined in subsequent analyses (446 males and 404 females).

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Follow-up visits were consecutively conducted at the ages of 0.5, 1, and 2 years as

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described elsewhere.27 All mothers in this study signed written informed consent at

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enrollment. The research protocol was authorized by the ethics committee of Tongji

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Medical College, Huazhong University of Science and Technology, and the study hospital.

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Assessment of prenatal paraben exposure

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Maternal urine samples collected at the 1st, 2nd, and 3rd trimesters during pregnancy were

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divided into the 5-mL polypropylene bottles and instantly reserved in -20°C freezers until

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further analysis of the concentrations of MeP, ethyl paraben (EtP), PrP, BuP, and benzyl

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paraben (BzP).

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The liquid chromatography tandem mass spectrometry parameters and sample

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pretreatment procedure were detailed in a previous study from our group by Zhao et al..28

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Briefly, the target analytes were extracted from 1-mL of urine sample using liquid-liquid

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extraction, separated by ultra-high performance liquid chromatography system, and

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detected by tandem mass spectrometry. Each batch of samples included the quality control

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samples and procedural blanks. The limits of detection (LODs) were 0.01 ng/mL for EtP,

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BzP, and 0.05 ng/mL for MeP, PrP and BuP. The mean recoveries of all target analytes

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ranged from 99.6% to 108.0%. We analyzed the selected duplicate samples to acquire the



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between-assay and within-assay variation coefficients, which were both less than 10%.

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Urinary paraben concentration was adjusted for the specific gravity (SG), as measured by

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a refractometer (Atago Co., Ltd., Tokyo, Japan), to reduce the variations in urine dilution.

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Anthropometric assessments

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Within one hour after delivery, experienced obstetrical nurses measured the birth weight

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and length of infants (in grams and centimeters, respectively) using standardized

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procedures. Weight and height in early-childhood were measured by nurses in the

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Department of Children’s Health when children were 6 months (mean ± SD: 0.51 ± 0.03),

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1 (1.03 ± 0.05), and 2 (2.03 ± 0.06) years of age. Birth and early-childhood weights and

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heights were normalized to z-scores by applying WHO child growth standards specified by

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sex and age.29 The z-score for a birth size indicator or an early-childhood growth parameter

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represents the percentile of neonatal or infant size at a certain gestational age or month age.

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Covariates

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Maternal age, pregnancy history (parity), maternal weight before childbirth, and delivery

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information such as birth weight, birth length, sex, birth date, and gestational age of infants

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were all extracted from hospital medical records. Face-to-face interviews were conducted

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to retrieve the following information, including maternal demographic and socioeconomic

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characteristics (education level, household income, etc.), basic personal information

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(prepregnancy weight, parental height, etc.) and lifestyle factors (smoking and drinking,

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etc.) by well-trained nurses. We used self-reported maternal height and prepregnancy

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weight to compute prepregnancy body mass index (BMI). Pregnancy weight gain was


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defined as the value between prepregnancy weight and weight before childbirth.

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Gestational age was calculated based on 1st-trimester ultrasound estimates. Breastfeeding

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duration was retrieved from the caregivers’ questionnaires during the follow-up visits.

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Previous studies suggested that fetal and postnatal growth were associated with many

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maternal characteristics, such as prepregnancy BMI, pregnancy weight gain, parity, and

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breastfeeding duration.30-32 Forward stepwise model selection procedures were applied to

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obtain the best fit for the models. We included the covariates into the final models if they

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significantly contributed to the models (p ≤ 0.10). We adjusted models for maternal and

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paternal height (cm), self-reported prepregnancy BMI (underweight, normal weight and

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overweight), weight gain during pregnancy (kg), gestational age (weeks, in models

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including birth weight and birth length), parity (primiparous and multiparous), maternal

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age (years), maternal education level (more than high school, high school, and less than

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high school), infant sex (male and female, in models including all infants), and

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breastfeeding duration (except in models including birth size).

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Statistical analysis

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The total paraben concentration (SumP) was computed as the sum of the molar

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concentrations (μmol/L) of the five measured parabens. The value of urinary paraben

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concentrations below the LOD were assigned a value of the LOD/ 2.33 Paraben

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concentrations were log2-transformed to bring down the effects of extremums on the

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regression coefficients (βs) and to compute the Pearson’s correlation coefficients and

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interclass correlation coefficients (ICCs). We calculated ICCs to evaluate the



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reproducibility of urinary paraben concentrations over the three trimesters of pregnancy.

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We also computed Pearson’s correlation coefficients between pairs of the log2-transformed

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paraben concentrations measured in urine collected during the three trimesters.

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MeP, EtP, PrP, and SumP (detection rate > 90%) were log2-transformed, whereas BuP

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and BzP (detection rate < 40%) were treated as binary variables (detected vs. undetected).

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Since parabens have relatively short biological half-lives,34 we first used the average SG-

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adjusted paraben concentrations measured in the three trimesters of pregnancy to provide

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reasonable estimates of exposure during pregnancy. Initially, general linear models were

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constructed to estimate the associations of average paraben concentrations with birth size

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(including weight and length at birth, and z-scores for weight and height at birth), as well

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as the age-specific associations of average paraben concentrations with weight and height

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z-scores at each time point (6 months, 1, and 2 years) in early childhood. Then, mixed linear

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models were used to examine z-scores for weight and height on average from birth to 2

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years of age in relation to prenatal paraben exposure. The age of infants at follow-up were

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also added to the mixed linear models as a categorical variable in addition to the

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confounders mentioned above. Fixed effect coefficient estimations were calculated to

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interpret the average effects of prenatal paraben exposure on z-scores for weight and height

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started from birth to 2 years. An interaction term of the age of infants at follow-up

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(categorical variable: birth, 6 months, 1, and 2 years) × paraben exposure were used to

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estimate the differences in association over time. A statistically significant interaction was

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defined if the p-value of the interaction term was less than 0.10.


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Furthermore, generalized estimating equation models with a linear link function were

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applied to assess the associations of trimester-specific urinary parabens concentrations with

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birth size and early-childhood growth (weight and height z-scores at birth, 6 months, 1 year

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and 2 years), as well as to identify the windows of susceptibility. The significance of

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interaction terms between prenatal paraben exposure and the trimester were estimated to

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assess the differences in associations over trimester. All βs represented the percent change

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in the z-score for each doubling increase in maternal urinary paraben concentrations and

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the β was multiplied by 100 to become a percentage. Sex-stratified analyses were

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conducted for prenatal exposure levels of parabens in relation to all fetal as well as early-

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childhood anthropometric assessments due to the hormonally active property of parabens.

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In the models including measurements of fetal and early-childhood growth as dependent

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variables, infant sex × paraben exposure were inserted to examine the potential interactions

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between infant sex and paraben exposure.

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Statistical Analysis System (SAS) version 9.4 (SAS Institute Inc., Cary, NC, USA) was

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applied to perform statistical analyses. All tests were two-sided and significance levels

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were set at α = 0.05.

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Results

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Study population

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Maternal baseline characteristics and infant anthropometric measurements of the study

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population are provided in Table 1. The mothers were approximately 28.6 years of age



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(ranged from 20 to 44 years) and were primarily primiparous (85.9%). The majority of the

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mothers were well-educated (78.4% for more than high school) and had a normal

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prepregnancy BMI (68.2%). The average weight gain during pregnancy was 16.5 ± 4.6

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(4.0−33.0) kg. A large proportion of the infants (69.5%) were breastfed for more than 6

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months.

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Maternal urinary concentrations of parabens and their reproducibility

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Table 2 shows the detection rate and ICCs during the three trimesters, along with the

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distribution of average unadjusted and SG-adjusted urinary paraben concentrations of our

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study population. Concentrations of MeP, EtP and PrP were detected in more than 90% of

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the urine samples, whereas the detection rates of BuP and BzP were less than 40%. ICCs

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were low (< 0.4; EtP: 0.37, PrP: 0.36, BuP: 0.38, BzP: 0.33) to moderate (0.4–0.6; MeP:

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0.41) and of comparable magnitude for all 5 parabens and their sum (ICC = 0.38).

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Pearson’s correlation coefficients were weak to medium (ranged from 0.26 to 0.51, see

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Table S1), which showed the similar patterns with ICCs. Among all 5 parabens, the highest

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concentration was observed for the short-chain alkyl paraben MeP (SG-adjusted median:

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32.06 ng/mL), whereas EtP showed the lowest concentration (SG-adjusted median: 0.80

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ng/mL).

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Average prenatal exposure levels of parabens and birth size

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For all infants, each doubling increase in average urinary EtP concentrations was associated

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with reduction in weight [β = -9.10, 95% confidence interval (CI): -17.77, -0.44] and z-

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score for weight at birth (percent change = -2.82%, 95% CI: -5.11%, -0.53%) (Table 3).


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Similarly, more evident associations were identified in males, with β values of -10.62 (95%

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CI: -19.95, -1.29) for birth weight and a percent change of -3.61% (95% CI: -6.74%, -

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0.48%) for birth weight z-score. In females, prenatal EtP concentrations tended to be

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negatively associated with birth weight and birth weight z-score (β = -8.76, 95% CI: -21.62,

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4.10, and percent change = -2.34%, 95% CI: -5.74%, 1.06%, per doubling increase in EtP

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concentrations) (Table 3). For all infants, prenatal MeP exposure showed a nonsignificant

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inverse association with birth length and its z-score (β = -0.03, 95% CI; -0.07, 0.01, and

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percent change = -2.47%, 95% CI: -5.32%, 0.38%, per doubling increase in MeP

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concentrations) (Table 3). In females, birth length reduced by -0.07 cm (95% CI: -0.13, -

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0.01) and height z-score at birth reduced by -5.08% (95% CI: -9.12%, -1.04%) with each

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doubling increase in MeP concentrations, whereas the associations observed for males

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were approximately zero (Table 3).

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Average prenatal exposure levels of parabens and early-childhood growth

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The associations between average paraben levels and age-specific weight z-scores in early-

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childhood were nonsignificant. (Table 4). After stratifying by sex, each doubling increase

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in EtP concentration was associated with decrease in z-scores for weight at 1 year (percent

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change = -3.96%, 95% CI: -7.03%, -0.89%) and 2 years (percent change = -3.38%, 95%

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CI: -6.72%, -0.03%) in males (Table 4). However, we did not observe the same inverse

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association among females, and evidence for a modulatory effect of sex was observed (p

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for interaction = 0.03 and 0.06, respectively) (Table 4). We did not observe significant

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associations between average paraben levels and age-specific z-scores for height during



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early-childhood in all children or in sex-stratified analyses (Table S2).

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Among all children, average urinary EtP level was inversely associated with average z-

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score for weight over the early-childhood, where each doubling increase in exposure was

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associated with a -2.81% (95% CI: -4.94%, -0.68%) decrease in weight z-score on average

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throughout childhood (Table 5). Likewise, males exhibited a similar result, with a more

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prominent percent change of -3.64% (95% CI: -6.64%, -0.64%, per doubling increase in

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EtP concentration) (Table 5). In females, prenatal EtP tended to be associated with

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decreased z-score for weight on average throughout early-childhood (percent change = -

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1.80%, 95% CI: -4.86%, 1.25%, per doubling increase in EtP concentration) (Table 5). We

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did not identify significant interactions between prenatal paraben exposure and follow-up

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age (p > 0.10) (Table 5). Additionally, each doubling increase in MeP concentrations was

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negatively associated with height z-score on average, with a -2.95% decrease (95% CI: -

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5.77%, -0.13%) in all infants (Table 5). In females, height z-score on average decreased by

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-5.24% (95% CI: -9.18%, -1.30%) in association with each doubling increase in MeP

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concentrations, whereas the association in males was approximately zero (Table 5).

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Significant interactions with follow-up age for prenatal MeP were found for all infants and

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females only (p = 0.04) (Table 5).

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Trimester-specific prenatal exposure levels of parabens and size at birth and early-

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childhood growth

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The 3rd-trimester EtP concentration was negatively associated with z-score for birth

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weight in all infants, as well as male and female infants (percent change = -3.31%, 95%


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CI: -5.30%, -1.33% for all infants; percent change = -3.41%, 95% CI: -6.17%, -0.66% for

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male infants; percent change = -3.49%, 95% CI: -6.33%, -0.64% for female infants) (Figure

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1). Moreover, each doubling increase in the 3rd-trimester EtP concentration was associated

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with reduced weight z-scores at 1 year and 2 years in males only (percent change = -2.65%,

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95% CI: -5.31%, -0.01% and -3.04%, 95% CI: -5.72%, -0.36%, respectively) (Figure 1).

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Additionally, the 3rd-trimester MeP exposure was inversely associated with height z-score

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at birth (percent change = -3.32%, 95% CI: -6.23%, -0.41%) in females only (Figure S1),

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and the 3rd-trimester SumP was inversely associated with z-score for birth weight (percent

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change = -2.58%, 95% CI: -5.03%, -0.13%) in all infants (Figure S5). Apart from these

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findings, no significant associations of trimester-specific prenatal PrP, BuP, or BzP

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exposure with size at birth or early-childhood growth were observed either in overall

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population or in sex-stratified analyses (Figures S2-4).

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Discussion

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As far as we know, our study is the first to explore repeated measurements of paraben

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exposures during pregnancy in relation to multiple growth measures starting from birth to

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2 years. Among all infants, inverse associations were identified between average prenatal

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EtP exposure and weight z-score at birth and weight z-score on average throughout

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childhood. In sex stratified analyses, the same associations were found in males, with more

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evident estimated effect, and a nonsignificant association with consistent direction was

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observed in females. In addition, age-specific negative associations were identified



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between the average prenatal EtP exposure and weight z-scores in 1 year- and 2 year-old

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males. Similarly, 3rd-trimester EtP were inversely associated with z-scores for weight at

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birth, 1 and 2 years in males. Besides, the average prenatal MeP and 3rd-trimester MeP

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were associated with reduced height z-score at birth among female infants.

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More than 90% of the pregnant women in this study were detected for MeP, EtP, and

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PrP, indicating the prevalent exposure of paraben in our study population. BuP and BzP

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were measured at a far lower rate (less than 40%), probably because BuP and BzP are used

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at a much lower dosage in personal care products in China.35 The patterns of detection rates

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for different parabens were similar to those reported in the common population in Belgium

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as well as the pregnant women in Greece.36, 37 Compared to the common population in the

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U.S. and Denmark (LOD for EtP: 0.1 and 0.4 ng/mL, respectively), our population had a

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higher detection rate for EtP, probably due to the lower LOD of EtP in the present study

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(LOD for EtP: 0.01 ng/mL).22, 38 In addition, the highest paraben exposure levels occurred

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in the first trimester, with a decreasing trend in later trimesters. Similarly, the median

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urinary paraben concentrations observed in the 2nd and 3rd-trimesters were lower than in

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the 1st-trimester among pregnant women in Boston.26 The explanation may involve the

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tendency of pregnant women to reduce the consumption of cosmetic and skin care products,

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which are the major routes of human exposure to paraben, as the pregnancy progresses.23

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We compared the urinary paraben concentrations and ICCs in our population with

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previous studies (Table S3). The temporal variability in urinary paraben concentrations, as

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indicated by ICCs that were low to moderate in our study population, is probably attributed


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to the rapid metabolism of parabens. In this study, the ICCs of urinary concentrations of

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paraben were comparable to the ICCs through three trimesters in pregnant women in Puerto

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Rico and Boston (MeP: 0.41 vs. 0.39 and 0.38, respectively; PrP: 0.36 vs. 0.32 and 0.36,

328

respectively).25, 26 However, the ICCs calculated in the present study were somewhat lower

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than the ICCs of paraben concentrations over three trimesters among pregnant women in

330

New York (MeP: 0.41 vs. 0.61; EtP: 0.37 vs. 0.48; PrP: 0.36 vs. 0.55; BuP: 0.38 vs. 0.56),39

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probably because of the differences in individual application of personal care products

332

containing parabens and diverse lifestyle characteristics. Our study population had

333

comparable median concentrations of unadjusted urinary parabens (ng/mL) compared with

334

the common population in developed countries, such as male and female adults in the USA

335

and female adults in Belgium (MeP: 28.4 vs. 43.9 and 32.4; EtP: 0.7 vs. 1.0 and 1.9; PrP:

336

2.2 vs. 9.1 and 3.3; BuP:

Repeated measurements of paraben exposure during pregnancy in

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