Relationship of urinary bisphenol A in childhood on thyroid hormone function in adolescents: a cohort study

doi:10.21203/rs.3.rs-3144188/v1

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Relationship of urinary bisphenol A in childhood on thyroid hormone function in adolescents: a cohort study

https://doi.org/10.21203/rs.3.rs-3144188/v1

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Background

Bisphenol A (BPA) is a type of endocrine-disrupting chemical utilized in the production of plastics like epoxy resins and polycarbonate polymers. BPA exhibits weak estrogenic and potent anti-androgenic effects, and prior research has linked it to disturbances in thyroid function. This study aims to assess the potential association between early childhood exposure to urinary bisphenol A and thyroid hormone levels in pubertal children from Korea.

Methods

Participants were drawn from the Ewha Birth and Growth Cohort Study, encompassing individuals who visited Ewha Women's Mokdong Hospital between 2001 and 2005. The concentration of urinary BPA was repeatedly measured for each subject at ages 3–5 years and 7–9 years. Serum levels of free T3, free T4, and thyroid-stimulating hormone (TSH) were measured at ages 10–12 years in a subgroup of 128 out of 164 subjects who had undergone repeated BPA concentration measurements. We utilized the SAS program to analyze possible links between childhood exposure to BPA and thyroid hormone function in adolescence. Additionally, we explored how exposure to BPA during two specific periods influenced changes in thyroid hormone levels.

Results

The study observed that urinary BPA levels at ages 3–5 years were not notably linked to thyroid hormone levels in adolescents aged 10–12 years. However, BPA levels at ages 7–9 years were significantly associated with free T3 levels in girls aged 10–12 years. Conversely, exposure to BPA did not result in significant differences in thyroid hormone levels among boys. The study did not find statistically significant connections between levels of urinary BPA and the other thyroid hormones, specifically TSH and free T4. There was a significant decrease in the concentration of free T3 in girls with higher BPA concentrations.

Conclusions

BPA exposure in childhood affects thyroid function in adolescent girls. This relationship may contribute to an increased prevalence of thyroid disorders in adolescents due to environmental influences.

Bisphenol A

Endocrine disrupting chemicals

Thyroid function

Bisphenol A (BPA) is an endocrine-disrupting chemical and is mainly used as a synthetic resin and coating material inside cans for food storage. BPA is easily transferred to water, food, and air and accidentally transmitted to humans through ingestion, inhalation, or skin contact [1]. Despite the knowledge that BPA is harmful, it is still widely used, and substitute bisphenol A (BPA) and bisphenol F (BPF) cannot be considered to have no effect. BPA interferes with the actions of estrogen and thyroid hormone at various levels [2]. It has also been found that bisphenol’s analogues induce androgenic and estrogenic effects [3]. Several in vitro and animal studies have found evidence of an association between BPA exposure and the disruption of thyroid hormone [3, 4, 5]. The detailed mechanism includes the inhibition of the sodium/iodide symporter and changes to the expression of thyroid function-related genes [6].

Recently, several epidemiological studies have reported an association of BPA exposure with thyroid hormone levels. However, the results are still controversial, and there are few studies on children [1]. Children are more vulnerable than adults to environmental chemicals because they have a small body surface per weight. In addition, children do not have fully developed nervous, immune, reproductive and digestive systems and have difficulty controlling hazardous environments. Adequate thyroid hormone is essential for optimal development of children, especially in brain development and intelligence before the age of three, as well as sexual development and reproductive function [4]. Endocrine-disrupting chemical (EDC) exposure, such as BPA, in childhood can cause hormone disturbance, bring about various health problems, and have long-term effects on health in adult life [2]. Moreover, younger children had a higher BPA concentration compared to older people [7]. Therefore, it is necessary to study the endocrinologic effect of BPA on thyroid function in adolescence, which plays a hormone-disrupting role during childhood.

This study aims to investigate the relationship between urinary bisphenol A exposure in childhood and the thyroid hormone of pubertal children in Korea.

Study population

The subjects of this study were composed of the prospective birth cohort of the Ewha Birth and Growth Cohort Study, established at Mokdong Hospital between 2001 and 2005. The first follow-up started when subjects were 3 years of age. The follow-up observation was performed every year after 2005, and the follow-up survey is still ongoing. Details of the cohort composition and methodology are described in a previous study [8]. Of the subjects who participated in the early childhood and preadolescent follow-up, a total of 164 subjects who were able to repeat BPA measurements (3–5 years and 7–9 years old) through urine samples were selected. Among them, 128 subjects participated in the 10–12 year old check-up. All subjects and their parents or guardians agreed to participate in this study through informed consent. The Institutional Review Board on Human Subjects at Ewha Womans University approved the study protocol (SEUMC- 2019-04-035).

Exposure assessment

The concentration of urinary bisphenol A was measured repeatedly for the same subjects at 3–5 years old and 7–9 years old. Urinary bisphenol A concentrations in the subjects were determined by high-performance liquid chromatography with fluorescence detection (LC-10SPD10-AVvp system, Shimadzu, Tokyo, Japan). The limit of detection (LOD) was 0.05 µg/L, and the accuracy of the analysis and coefficient of variation (CV) were 100.05% and 1.67%, respectively. Creatinine was measured using the Jaffé method with the OSR6178 or OSR6678 reagent and an Olympus AU 680 spectrometer (Beckman Coulter, USA). We log-transformed BPA in the analysis to normalize its distribution. To compare exposures among groups, subjects were classified into tertiles based on urinary BPA concentrations at baseline. In addition, a dose-response relationship of BPA exposure with thyroid function was explored via trend analysis after the subjects were divided into tertiles based on BPA exposure concentration.

Outcome assessment

Serum Free Thyroxine (free T3), free Triiodothyronine (free T4) and thyroid-stimulating hormone (TSH) levels were measured in the thyroid function test. The analysis was performed by electrochemiluminescence immunoassay (Elecsys FT3 III, Elecsys FT4 II; Roche, Germany). Thyroid stimulating hormone (TSH) was measured using an immunoassay (E411).

Covariate

Through a review of the literature, sex, age, mother's education parents smoking and current BMI. The information for covariates was collected from the questionnaires. Current BMI was calculated using body measurements obtained during follow-up as weight (kg) divided by the square of height (m2). Height and weight were measured in 0.1-cm and 0.1-kg units using an automatic height and weight measurement system (DS-102; Dong Sahn Jenix Co., Ltd., Seoul, Korea), without shoes and in light clothing. Mother's educational level (< university or ≥ university), sex (boys or girls). A questionnaire item was used to assess each child’s exposure to secondhand smoke on follow-up at the age of 10–12 years.

Statistical analysis

In the descriptive analysis, continuous variables are presented as the mean and standard deviation when the normal distribution is satisfied and presented as the median with interquartile ranges when they are not distributed normally. Categorical data are presented as the frequency with percentage. To investigate the mean difference of thyroid function hormones between adolescents aged 3–5 and 7–9 years old according to exposure level of urinary bisphenol A, subjects were divided into three groups according to exposure level, and a generalized linear model analysis and tendency analysis were performed.

Multivariate regression analysis was used to explore the associations between urinary bisphenol A levels of the same children in early childhood and at early school age with serum free T3, free T4 and thyroid-stimulating hormone (TSH) levels at 10–12 years. Multivariate regression analysis was performed with adjustment for sex, age, mother's education, parent smoking status and current BMI.

Statistical analysis was performed using the SAS program version 9.4 (Statistical Analysis System version 9.4, SAS Institute, Cary, NC, USA).

The basic characteristics of the subjects are presented in Table 1. The study population included a total of 128 subjects, 61 boys and 67 girls. The mean age of the participants was 10.1 years. The mean BMI for boys was slightly higher than for girls. Most children in this study were not exposed to secondhand smoke. In the case of thyroid function, the mean levels of TSH, free T4 and free T3 among children were 2.95 ± 1.37 µU/mL, 1.48 ± 0.20 ng/mL, 4.59 ± 0.46 ng/mL. TSH and free T4 were present in statistically higher concentrations in boys than girls (p < 0.05). However, there was no statistical difference in the free T3 level. The urinary BPA concentration was higher in boys (0.78 µg/g creatinine) than in girls aged 3–5 years (0.60 µg/g creatinine; p = 0.06), but no obvious difference was seen in adolescents aged 7–9 years.

Table 1. Characteristics of study subjects

	Total		Boys		Girls		p
Bisphenol A
3-5years	128	0.78 (0.39-1.45)	61	0.78 (0.39-1.45)	67	0.60 (0.34-1.12)	0.06
7-9years	127	0.62 (0.38-1.17)	61	0.62 (0.38-1.17)	66	0.58 (0.36-1.07)	0.62
Thyroid function at 10-12years
TSH (ulU/mL)	128	2.76 (1.95-3.67)	61	3.02 (2.34-4.17)	67	2.53 (1.72-3.54)	0.01
Free T4	128	1.46 (1.36-1.56)	61	1.49 (1.39-1.6)	67	1.42 (1.33-1.52)	0.03
Free T3	128	4.59 ± 0.46	61	4.62 ± 0.42	67	4.57 ± 0.5	0.64

Covariate variable
Age(years)	128	10.12 ± 0.35	61	10.13 ± 0.39	67	10.1 ± 0.31	0.67
BMI(kg/m²)	128	18.14 ± 2.98	61	18.66 ± 3.12	67	17.66 ± 2.78	0.06
Secondhand Smoke	46 (36.22%)		21 (35.00%)		25 (37.31%)		0.79
Mother’s education level
Graduated from high school	28		8 (13.11%)		20 (29.85%)		0.02
Some college or higher	100		53 (86.89%)		47 (70.15%)

Abbreviation: TSH, thyroid stimulating hormone; BMI, body mass index.

Values are the mean ± SD, interquartile range and percentages.

Table 2 shows the association between log-transformed urinary BPA levels in ages 3-5 years and 7-9 years and the serum thyroid hormone at 10-12 years. The relationship between BPA at age 7-9 and free T3 was significant for girls, both in the crude model and adjusted model by sex, age, mother’s education, parent smoking status, and current BMI. Higher urinary BPA concentrations in girls aged 7-9 years were significantly associated with a lower free T3 level. There were no significant differences in the levels of thyroid hormone by the urinary BPA level in both boys and girls aged 3-5 years.

Table 2. Results of regression analysis of serum thyroid concentrations and log-transformed urinary BPA concentrations.

Total			TSH (ulU/mL)		Free T4 (ng/dL)		Free T3 (ng/dL)
Total			PE(95%CI)	p	PE(95%CI)	p	PE(95%CI)	p
Crude	Bisphenol A at 3-5 years	Total	0.07 (-0.18, 0.33)	0.56	0.03 (-0.00, 0.07)	0.07	0.06 (-0.03, 0.14)	0.20
Model		Boys	0.05 (-0.31, 0.41)	0.8	0.01 (-0.05, 0.06)	0.85	0.04 (-0.08, 0.15)	0.53
		Girls	-0.04 (-0.41, 0.34)	0.85	0.05 (-0.00, 0.1)	0.07	0.07 (-0.07, 0.21)	0.30
	Bisphenol A at 7-9 years	Total	0.09 (-0.17, 0.34)	0.51	0.00 (-0.04, 0.04)	0.98	-0.09 (-0.18, -0.01)	0.04
		Boys	-0.00 (-0.40, 0.39)	0.98	0.02 (-0.04, 0.08)	0.56	-0.03 (-0.16, 0.09)	0.61
		Girls	0.12 (-0.21, 0.46)	0.46	-0.02 (-0.06, 0.03)	0.53	-0.14 (-0.26, -0.02)	0.03
Adjusted	Bisphenol A at 3-5 years	Total	0.08 (-0.19, 0.35)	0.55	0.03 (-0.01, 0.07)	0.13	0.07 (-0.03, 0.16)	0.16
Model 1		Boys	0.20 (-0.19, 0.59)	0.32	0.02 (-0.04, 0.08)	0.55	0.09 (-0.04, 0.21)	0.17
		Girls	0.06 (-0.32, 0.44)	0.74	0.05 (-0.01, 0.1)	0.08	0.04 (-0.10, 0.18)	0.60
	Bisphenol A at 7-9 years	Total	0.09 (-0.16, 0.34)	0.46	-0.00 (-0.04, 0.04)	0.92	-0.10 (-0.19, -0.01)	0.03
		Boys	0.04 (-0.35, 0.43)	0.82	0.02 (-0.04, 0.08)	0.50	-0.02 (-0.15, 0.10)	0.73
		Girls	0.18 (-0.16, 0.51)	0.30	-0.02 (-0.06, 0.03)	0.53	-0.15 (-0.28, -0.03)	0.01
Adjusted	Bisphenol A at 3-5 years	Total	0.09 (-0.17, 0.34)	0.51	0.03 (-0.01, 0.07)	0.13	0.07 (-0.03, 0.16)	0.15
Model 2		Boys	0.22 (-0.16, 0.60)	0.25	0.02 (-0.05, 0.08)	0.61	0.09 (-0.03, 0.22)	0.13
		Girls	0.05 (-0.33, 0.42)	0.81	0.05 (-0.00, 0.1)	0.06	0.04 (-0.11, 0.18)	0.62
	Bisphenol A at 7-9 years	Total	0.10 (-0.15, 0.34)	0.44	-0.00 (-0.04, 0.03)	0.91	-0.10 (-0.18, -0.01)	0.03
		Boys	0.04 (-0.34, 0.43)	0.83	0.02 (-0.04, 0.08)	0.50	-0.02 (-0.15, 0.10)	0.71
		Girls	0.18 (-0.14, 0.51)	0.27	-0.02 (-0.06, 0.03)	0.50	-0.15 (-0.28, -0.03)	0.01

Abbreviations: 95% CI, 95% confidence intervals; TSH, thyroid stimulating hormone.

Adjusted Model 1 adjusted for sex, age, mother's education, and parent smoking status.

Adjusted Model 2 adjusted for sex, age, mother's education, parent smoking status, and current BMI.

Table 3 shows the relationship between urinary BPA tertiles and serum thyroid hormone levels. To investigate the possible dose-response relationship of BPA exposure and thyroid hormone function, a trend analysis was performed and p for the trend was presented. In early school age, 7-9 years old, the free T3 level decreased significantly as the concentration of BPA increased (p for trend = 0.01), and the dose-dependent relationships were more evident in girls than in boys. At age 3-5, early childhood, thyroid hormone had no significant association with an increase in the BPA concentration (p for trend = 0.31).

Table 3. The relationship between urinary bisphenol A concentration and serum thyroid hormone level.

		TSH (ulU/mL)		Free T4 (ng/dL)		Free T3 (ng/dL)
		LS Mean (95% CI)	P (P for trend)	LS Mean (95% CI)	P (P for trend)	LS Mean (95% CI)	P (P for trend)
Bisphenol A at 3-5 years
Total	Q1	2.26 (1.32, 3.21)	0.89 (0.75)	1.44 (1.29, 1.58)	0.83 (0.59)	4.62 (4.28, 4.96)	0.27 (0.31)
	Q2	2.14 (1.14, 3.15)		1.45 (1.30, 1.6)		4.55 (4.19, 4.91)
	Q3	2.14 (1.15, 3.12)		1.46 (1.31, 1.61)		4.72 (4.37, 5.07)
Boys	Q1	2.25 (1.09, 3.41)	0.31 (0.57)	1.53 (1.34, 1.72)	0.78 (0.63)	4.55 (4.18, 4.93)	0.18 (0.07)
	Q2	2.92 (1.72, 4.13)		1.48 (1.28, 1.67)		4.62 (4.23, 5.01)
	Q3	2.49 (1.38, 3.60)		1.49 (1.30, 1.67)		4.81 (4.45, 5.17)
Girls	Q1	2.56 (1.90, 3.21)	0.09 (0.59)	1.36 (1.26, 1.45)	0.31 (0.15)	4.68 (4.42, 4.94)	0.8 (0.94)
	Q2	1.77 (1.05, 2.48)		1.42 (1.32, 1.53)		4.59 (4.30, 4.88)
	Q3	2.46 (1.77, 3.16)		1.43 (1.33, 1.54)		4.68 (4.41, 4.96)
Bisphenol A at 7-9 years
Total	Q1	1.90 (0.92, 2.89)	0.3 (0.23)	1.46 (1.31, 1.61)	0.5 (0.31)	4.77 (4.42, 5.12)	0.05 (0.01)
	Q2	2.33 (1.39, 3.28)		1.46 (1.32, 1.60)		4.64 (4.30, 4.98)
	Q3	2.23 (1.25, 3.21)		1.41 (1.26, 1.56)		4.52 (4.17, 4.87)
Boys	Q1	2.03 (0.85, 3.22)	0.11 (0.82)	1.49 (1.29, 1.69)	0.69 (0.72)	4.71 (4.31, 5.11)	0.45 (0.35)
	Q2	2.88 (1.79, 3.97)		1.53 (1.35, 1.71)		4.76 (4.39, 5.12)
	Q3	2.13 (1.02, 3.23)		1.47 (1.28, 1.66)		4.59 (4.21, 4.96)
Girls	Q1	2.04 (1.37, 2.70)	0.27 (0.12)	1.43 (1.33, 1.52)	0.48 (0.28)	4.83 (4.58, 5.08)	0.06 (0.02)
	Q2	2.21 (1.44, 2.98)		1.42 (1.31, 1.53)		4.63 (4.33, 4.92)
	Q3	2.65 (1.96, 3.35)		1.36 (1.26, 1.46)		4.48 (4.22, 4.74)

Abbreviations: 95% CI, 95% confidence intervals; ls means, least-squares means; TSH, thyroid stimulating hormone.

Adjusted for sex, age, mother's education, parent smoking status, and current BMI.

The interaction between urinary BPA tertiles at two time points on serum free T3 level were examined by ANOVA, which is presented in Figure 1. We did not find any significant interaction between the two periods of early childhood and school-aged children. We found that the comparison of free T3 level according to the BPA tertiles (T1 lowest, T2 middle, T3 highest) provided statistically significant results (p = 0.02).

In this study, we evaluated the effects of BPA exposure in childhood on thyroid hormone function around puberty, at 10-12 years old. The BPA level at 3-5 years had no significant relationship with thyroid hormone at 10-12 years. As the BPA exposure increased at 7-9 years, the free T3 level of girls aged 10-12 years significantly decreased. The higher the concentration of BPA in school-age children of 7-9 years, the larger the adverse effect on thyroid hormone in girls. Our data indicates that there were no significant effects of BPA exposure in early childhood on later health, but exposure at an early school age had a significant effect on thyroid hormone. It could be said that the period of 7-9 years of age had a larger impact on thyroid hormone because the children were exposed close to the time of the testing. These results show that exposure to BPA close to puberty can affect thyroid hormone in adolescence.

In a previous study, the association of prenatal BPA and early childhood BPA, BPF, and BPS exposure with thyroid function in 6-year-old children was investigated [2]. In this study, as the concentration of bisphenol F increased, the free T4 level of girls decreased. In addition, a large cohort study of 6003 adults through the KNEHS (Korean National Environmental Health Survey) found that the higher the BPA exposure concentration, the lower the TSH level [9]. In China’s prospective cohort study, maternal exposure to BPA affected fetal thyroid hormone, significantly reduced T3 level in cord blood, and increased behavioral problems, as it affected neurobehavioral development between ages 2 and 4. [10]. The results of this study also showed that TSH increased, free T4 decreased, and free T3 decreased significantly according to the exposure amount in ages 7-9, which were similar results to previous studies.

Several in vitro and animal studies have provided evidence for an association between BPA exposure and the disruption of thyroid hormone [11]. Bisphenols can disrupt thyroid hormone signaling and action by altering the transcription of thyroid function-related genes such as TSH-ß, TRs and deiodinase. It is likely that BPA alters the relationship of the TR to various co-modulatory molecules. Specifically, BPA can antagonize T3 action at the transcriptional level, which suggests that BPA and analogues of BPA derivatives interfere with thyroid hormone signaling during development [12]. The biological mechanism through which BPA and thyroid hormone function are related is currently ill-defined and warrants further detailed investigation [4, 13].

Despite previous studies with subjects of various ages and both sexes, such as early childhood, adults and pregnant females, our study differs from other studies in that it investigates thyroid hormone function in adolescence [14, 15, 16, 17, 18]. During puberty, thyroid function changes and thyroid volume increases by adaptation to sexual development. It is not yet clear how much thyroid hormone changes due to certain puberty stages or specific pubertal development patterns [19]. In addition, in this study, thyroid hormone dysfunction was more pronounced in girls, which is consistent with previous findings on 6-year-old children [1]. In boys, no significant differences in thyroid hormone levels were observed by exposure to BPA. These results show that BPA affects thyroid hormones differently according to sex. Thyroid disease has a higher prevalence among females than males in adulthood, and epidemiologic reports have revealed the potential mechanisms of estrogen on thyroid function and growth regulation [20]. A previous study revealed that BPA clearance was faster in females than in males [21]. Another study also reported a sex difference in serum BPA levels due to differences in androgen-associated BPA metabolism [22]. An animal study suggested that sex differences may be associated with sex hormone-related markers because BPA functions as an estrogen analogue [23].

Free T3, instead of total T3, was measured in this study. The free portion of T3 is considered more relevant to the biological action than total T3 [24]. Another strength of our study is that birth cohort data were used to prospectively assess causal relationships between BPA exposure and the thyroid function test. Our results were significant even after adjustment for various covariates. Another strength is that our study measured BPA exposure at two points and evaluated the effects on subjects at the same time.

There are several limitations to our study. First, BPA exposure was measured with a single spot urine sample, which may not represent the average long-term exposure due to short half-life and body variability of bisphenols [11, 25]. Second, this study included a limited number of bisphenols. Although BPA is one of the most well-known raw materials for production of plastics and epoxy resin, BPF and BPS have also recently been reported to have toxic effects on reproduction, development, and aging. Third, the relatively small sample size of the study may lower the accuracy of our results.

In conclusion, our findings add important information regarding how BPA exposure in childhood affects thyroid hormone function in adolescent girls. Among the two points, exposure close to adolescence can affect the endocrine system in puberty, which might be related to an increase in thyroid disorder in adolescents according to environmental effects. A long-term follow-up of the affected children with their endocrine profiles, growth and neurocognitive development should be considered.

Acknowledgements

None.

Authors’ contributions

JC, EC, HK, and HP were involved in the design and execution of the study. SL, BP wrote the ethical application to IRB. Data were collected by EC, HL, HK, and HP. (Ewha cohort). EL, HL, and HP performed the analysis. All other authors were involved in the final consensus process of the protocol, interpretation of the data and revised the manuscript critically for important intellectual content. JC, EC, YH, EH drafted the manuscript and all other authors read, edited and approved the final manuscript for publication. EC prepared the tables, HP prepared the flow chart

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data Availability

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

Ethical approval and consent to participate For the Ewha cohort, we obtained informed parental consent in all cases. The Institutional Review Board on Human Subjects at Ewha Womans University approved the study protocol (SEUMC- 2019-04-035). The protocol was performed in accordance with the relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests

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No competing interests reported.

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Relationship of urinary bisphenol A in childhood on thyroid hormone function in adolescents: a cohort study

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Introduction

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