Effects of postnatal exposure to mixtures of bisphenol A and phthalates on children’s IQ at 5 years of age: Mothers and Children's Environmental Health (MOCEH) Study

Abstract

Background

Early childhood is important for neurodevelopment, and exposure to endocrine disruptors such as bisphenol A (BPA) and phthalates in this period may cause neurodevelopmental disorders and delays. The present study examined the association between exposure to mixtures of BPA and phthalates in early childhood and IQ at 5 years of age.

Methods

The Mother and Children's Environmental Health (MOCEH) study is a prospective birth cohort study conducted in Korea with 1751 pregnant women enrolled from 2006 to 2010. A total of 152 children was included in the analyses. We measured children’s urinary concentrations of metabolites of endocrine-disrupting chemicals (BPA, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-(2-ethyl-5-butyl) phthalate) at ages of 24 and 36 months. We evaluated the children’s IQ with the Korean Wechsler Intelligence Test at the age of 5 years. After adjusting for potential confounders, a multiple linear regression was conducted to examine the associations between individual endocrine-disrupting chemicals and the IQ of the children. Weighted Quantile Sum (WQS) regression and quantile-based g-computation were used to assess the association between IQ at age 5 and exposure to mixtures of BPA and phthalates.

Results

In the single-chemical analyses, mono-(2-ethyl-5-butyl) phthalate exposure at 36 months was adversely associated with children’s IQ (β = -4.93, 95% confidence interval (CI): -9.22, -0.64). In the WQS regression and quantile-based g-computation analyses, exposure to the mixture of BPA and phthalates was associated with lower IQ [β = -9.126 (P-value = 0.051) and β = -9.18 (P-value = 0.049), respectively]. The largest contributor to the overall association was exposure to mono-(2-ethyl-5-butyl) phthalate at 36 months.

Conclusions

In the present study, postnatal exposure to mixtures of BPA and phthalates was associated with decreased IQ of children at age 5.

Trial registration

Not applicable

Introduction

Exposure to endocrine-disrupting chemicals (EDCs) such as bisphenol A (BPA) and phthalates occurs in various ways, such as from air, dust, water, personal care products [1, 2], and food sources [3, 4]. Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) are metabolites of di(2-ethylhexyl)phthalate (DEHP), and mono-(2-ethyl-5-butyl)phthalate (MnBP) is a metabolite of di-n-butyl phthalate (DBP). Food packages and medical devices are the dominant sources of exposure to DEHP, and consumer products such as diapers for infants and toddlers, cosmetics, and drugs are dominant sources of DBP exposure [5, 6]. DBP exposure is important in children since they often come in high contact with sources of DBP [5].

EDCs can interfere with hormonal action by altering the production, release, transport, metabolism, and binding of hormones [1, 2, 7, 8]. Prior studies have demonstrated that exposure to EDCs in humans has adverse health effects such as obesity, diabetes, metabolic syndromes, reproductive cancer, and infertility [1, 2, 7–12]. Children are more susceptible to EDCs exposure due to their rapid growth, age-specific behavior, anatomy, and physiology [2, 6, 13, 14]. In earlier childhood, exposure to low doses of EDCs may cause harm to the brain, affecting the quality of life, ability to learn, memory, and neurobehavioral development and increasing the risk of unfavorable health outcomes in adulthood [2, 15, 16].

In addition, many previous studies have noted that childhood exposure to EDCs may cause neurodevelopmental problems such as attention deficit hyperactivity disorder, autism spectrum disorder, and developmental delay [16–18]. Prior studies have also investigated the associations of childhood urinary concentrations of phthalates and bisphenols with IQ [19–28]. Epidemiological studies have demonstrated that during infancy and childhood, exposure to phthalates is adversely associated with cognitive development [19–22]. However, depending on the period of exposure, specific phthalate metabolites have been inconsistently associated with childhood IQ [23–25]. With BPA, previous studies also had inconsistent results depending on exposure period and sex [26–28].

In real-world situations, we are ubiquitously exposed to EDCs [1–4]. Moreover, mixtures of EDCs can be harmful to human health even when individual chemical exposure doses are under the estimated level of observable effect [2, 29–31]. However, few studies have examined the associations of EDC mixtures on cognitive development [32–35].

Identifying period of susceptibility to EDCs is important to minimize their effects. Previous studies have reported that exposure during pregnancy to EDC mixtures was associated with lower IQ in children [32–34]. However, the results regarding postnatal exposure are limited [16].

To address these research gaps, the present study evaluated the associations between exposure to mixture of BPA and phthalates in early childhood on children’s IQ at 5 years of age.

Methods

Measurement Of BPA And Phthalate Exposure

We measured children’s urinary concentrations of BPA, MEOHP, MEHHP, and MnBP at ages of 24 and 36 months. Samples of spot urine in 100-mL sterile cups were kept in freezers at − 20°C until they were delivered to the laboratory. The measurement method used to achieve accuracy and reliability of metabolite measurements is described in the Centers for Disease Control and Prevention Manual of Laboratory Procedures [38, 39]. The limits of detection (LODs) of BPA, MEOHP, MEHHP, and MnBP were 0.275, 0.65, 0.53, and 0.87 µg/L. None of the 4 chemicals samples contained levels below the LOD. Quality control analysis was conducted using functional materials from a German External Quality Assessment Scheme for phthalates and BPA in the laboratory. Urine creatinine concentrations were used to convert BPA and phthalate concentrations [36, 40].

Cognitive Assessment

Trained physicians measured the children’s IQ with the Korean Wechsler Preschool and Primary Scale of Intelligence, fourth edition (K-WPPSI-IV) at age 5 years. The K-WPPSI-IV is the most common test for comprehensive assessment of cognitive function of children in Korea. The K-WPPSI-IV consists of 15 subdomains, five basic indicators, and four additional indicators [41]. The MOCEH database management system validated answers and numerical data entry with a web-based database program using a mechanized screening system.

Potential Confounding Factors

Potential confounding factors were selected a priori from the literature, and a directed acyclic graph was used to select covariates included in the models. Information on child sex was collected from delivery room records. Maternal age, education level, household income level, and child’s exposure to secondhand smoke were collected through a questionnaire at the planned visits. Maternal IQ was obtained with the Korean Wechsler Adult Intelligence Scale, fourth edition, at the pre- or postnatal period for those who agreed to take the test, and there were no significant differences in characteristics of those who did or did not take the test (Table S1). The following variables were considered as categorical variables: maternal education level (below bachelor’s degree, bachelor’s degree, higher than bachelor’s degree), household monthly income level (< KRW 2,000,000, KRW 2,000,000–4,000,000, > KRW4,000,000), child sex (boy or girl), and exposure to secondhand smoke (yes or no). The variables considered as continuous were maternal age and IQ and child’s age. Smoking during pregnancy was not included because none of the mothers were smokers.

Results

The general characteristics of the participants and those who were excluded are shown in Table 1. There was no statistically significant difference between the participants and those who were excluded. The mean child’s IQ was 104.68 ± 14.47.

Children’s urinary concentrations of chemical metabolites are presented in Table S2. Figure S1 is a correlation matrix of exposure to metabolites of endocrine-disrupting chemicals at 24 and 36 months. The strongest correlations were detected with the MEOHP and MEHHP concentrations at 24 and 36 months. Correlation coefficients for BPA at 24 and 36 months were − 0.05.

Table 2 shows the association between exposure to individual chemical metabolites and child’s IQ. After adjusting for potential confounders, MnBP at 36 months was adversely associated with child’s IQ. After further adjusting for mother’s IQ, MEHHP and MEOHP at 36 months were adversely associated with child’s IQ.

In the WQS regression (Table 3), a one-quartile increase in the WQS index decreased the child’s IQ by 1.392 points, which was not a significant change. The largest contributor to the overall association was MEOHP exposure at 24 months and the second was BPA at 36 months (mean weight: 0.499 and 0.155, respectively). After adjusting for mother’s IQ, a one-quartile increase of the WQS index was significantly associated with a 9.126-point decrease in child’s IQ. The largest contributor to the overall association was MnBP exposure at 36 months and the second largest was BPA at 24 months (mean weight: 0.399 and 0.199, respectively).

Figure 2 shows the associations between exposure to a mixture of BPA and phthalates and child’s IQ analyzed with quantile-based g-computation. In model 1, a mixture of BPA and phthalates at 24 and 36 months was adversely associated with child’s IQ at age 5 years (-2.20 points per a quartile), but the association was not significant. In model 2, high exposure to such a mixture at 24 and 36 months was adversely associated with child’s IQ (-9.18 points per quartile, P-value = 0.049).

No metabolites of a single chemical were significantly associated with IQ in the sex-stratified analyses (Table S3). In WQS regression (Table S4), a one-quartile increase in the WQS index was associated with a 2.48-point increase in boys’ IQ, but the change was not significant. The largest contributor to the overall association in boys’ IQ was BPA exposure at 36 months and the second largest was MEHHP exposure at 24 months (mean weight: 0.412 and 0.170, respectively). In contrast, a one-quartile increase in the WQS index was associated with a 5.58-point decrease in girls’ IQ, but the association was not significant. The largest contribution to the overall association was MnBP exposure at 36 months and the second largest was MnBP exposure at 24 months (mean weight: 0.454 and 0.286, respectively).

Figure S2 shows associations between exposure to a mixture of BPA and phthalates and boys’ and girls’ IQ analyzed with quantile-based g-computation. A one-quartile increase of a mixture at 24 and 36 months was adversely associated with boys’ and girls’ IQ at age 5 years, leading to a difference of -0.68 points and − 3.96 points, respectively, which was not statistically significant.

Discussion

We observed significant association between postnatal exposures at the age of 24 and 36 months to mixtures of BPA and phthalates and lower child's IQ at the age of 5 years in a prospective birth cohort. The largest contributor to the overall association was MnBP exposure at 36 months, which was also significantly and adversely associated with child’s IQ in an individual chemical analysis.

We could not find any previous study analyzing the effect of postnatal exposure to a mixture of BPA and phthalates on children's IQ using multiple exposure analyses. Only a few studies have found an effect of prenatal exposure to EDCs on children's IQ [32–34]. Our findings are consistent with the results of previous studies assessing the effects of prenatal exposure to EDC mixtures on children’s cognitive abilities [32–34]. A Dutch study found an association of prenatal exposure to chemical mixtures of phthalates, bisphenols, and organophosphate pesticides with children’s IQ at the age of 6 years using quantile-based g-computation. Fetuses with higher exposure to EDC mixtures during pregnancy were associated with lower nonverbal child IQ, with phthalates being the most critical component, particularly among girls [32]. A Swedish population-based study of a pregnancy cohort used WQS regression and found that prenatal exposure to a mixture of EDCs (26 compounds in urine, serum, and plasma) was related to lower levels of cognitive function at age 7, particularly among boys, and bisphenol F had the largest contribution [33]. Using a Bayesian kernel machine regression, a Chinese study found an adverse association between prenatal exposure to a mixture of chemicals (heavy metals, pesticides, and phenols) and children's boys’ IQ at 7 years of age among boys, and BPA and Pb were the largest contributors [34].

The association between exposure to EDCs and neurodevelopment can be explained by potential biological mechanisms, although this is not completely understood [2, 45–48]. Part of our brain functions as an endocrine gland, with the hypothalamus helping the body adapt to its environment and regulating the peripheral endocrine system. In this aspect, the brain is targeted by EDCs in two ways, through disturbances of the endocrine system of the hypothalamus and through the EDC influence on pathways of hormone production via steroid hormone receptors. These effects lead to changes in molecular structures through alterations in generation, maintenance, and death of neurons and glial cells. They also cause changes in regulation of the brain's neurotransmitter system, leading to functional consequences such as neurobehavioral disorder [2].

Gender differences have been observed in most previous studies of neurodevelopmental effects of EDC exposure [49]. Estrogen, a steroid hormone, acts on the hypothalamus and plays a critical role in gender-dimorphic behaviors that develop in childhood [45]. This study demonstrated sex-specific changes to the brain’s monoaminergic systems. Changes in dopamine, serotonin, and norepinephrine levels caused by exposure to EDCs lead to gender differences in neurodevelopment [50]. However, previous studies show no clear evidence of specific gender effects on cognitive neurodevelopment in association with exposure to mixtures of EDCs due to inconsistency in the exposure windows and substances [2, 32–34, 49].

The present study has limitations. The sample size was small, due to which we could not adjust maternal IQ in the sex-stratified analyses. In addition, the small sample size might be the cause of some of the non-significant associations. Second, we adjusted all available potential confounding factors, but there may be additional or residual confounders. Third, although there are many phthalates, only three metabolites (MEHHP, MEOHP, and MnBP) were included in the present study. These three phthalates were selected because they were considered representative markers for quantifying phthalate exposure in the human body [51]. Finally, spot urine collection was performed only once each visit, which might lead to misclassification. This misclassification is most likely non-differential, and the random variation of the concentration of chemical metabolites would have made the observed association closer to the null. Additionally, the BPA and phthatlates concentrations of spot urine collection are mostly consistent with 24-hour concentration despite the short half-lives and high variability[52, 53].

In summary, our results provide additional evidence on adverse effects of postnatal exposure to the BPA and phthalates on children’s cognition. This suggests the importance of avoiding child exposure to BPA and phthalates of children in susceptible age windows.

Abbreviations

BPA: bisphenol A

CI: confidence intervals

DBP: di-n-butyl phthalate

DEHP: di(2-ethylhexyl)phthalate

EDCs: endocrine-disrupting chemicals

K-WPPSI-IV: Korean Wechsler Preschool and Primary Scale of Intelligence, fourth edition

KRW: Korean Won

IQ: Intelligence Quotient

MEOHP: mono-(2-ethyl-5-oxohexyl) phthalate

MEHHP: mono-(2-ethyl-5-hydroxyhxyl) phthalate

MnBP: mono-(2-ethyl-5-buyl) phthalate

MOCEH: Mother and Children's Environmental Health

WQS: Weighted Quantile Sum

Declarations

Ethics approval and consent to participate

The Institutional Review Boards approved this study at Ewha Woman’s University (IRB No. 12-07B-15), Dankook University Hospital (IRB No. 2011-09-0340), and Ulsan University Hospital (IRB No. 06-29).

Consent for publication

Not applicable

Availability of data and material

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request

Competing interests

The authors declare they have no conflicts of interest to disclose.

Funding

Not applicable

Authorship contribution

Da Jeong Ham: Conceptualization, Visualization, Software, Formal analysis Roles/Writing - original draft; Writing - review & editing. Mina Ha: Supervision, Investigation, Resources, Data Curation, Writing - review & editing. Hyesook Park: Supervision, Investigation, Resources, Data Curation, Writing - review & editing. Yun-Chul Hong: Supervision, Investigation, Resources, Data Curation, Writing - review & editing. Yangho Kim: Supervision, Investigation, Resources, Data Curation, Writing - review & editing. Eunhee Ha: Supervision, Investigation, Resources, Data Curation, Writing - review & editing. Sanghyuk Bae: Supervision, Validation, Investigation, Resources, Data Curation, Writing - review & editing.

Acknowledgments

Dajeong Ham was supported as a trainee of the environmental health training program which was provided by the Environmental Health Centre of the Catholic University of Korea, funded by the Ministry of Environment, Republic of Korea (2022). Mothers and Children's Environmental Health Study (MOCEH) was supported by the Ministry of Environment, Republic of Korea.

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