Impact of endocrine disrupting chemical exposure on thyroid disruption and oxidative stress in early pregnancy

Ju Hee Kim; Nalae Moon; Su Ji Heo; Young Joo Lee; Jong Yun Hwang; Se Jin Lee; Jae Hi Im; Hosub Im

doi:10.5620/eaht.2025002

Environ Anal Health Toxicol > Volume 40:2025 > Article

Kim, Moon, Heo, Lee, Hwang, Lee, Im, and Im: Impact of endocrine disrupting chemical exposure on thyroid disruption and oxidative stress in early pregnancy

Original Article

Environ Anal Health Toxicol 2025; 40: e2025002.

Published online: January 22, 2025

DOI: https://doi.org/10.5620/eaht.2025002

Impact of endocrine disrupting chemical exposure on thyroid disruption and oxidative stress in early pregnancy

Ju Hee Kim^1,^*

, Nalae Moon¹

, Su Ji Heo¹

, Young Joo Lee²

, Jong Yun Hwang³

, Se Jin Lee³

, Jae Hi Im⁴, Hosub Im⁵

¹Department of Nursing, College of Nursing Science, Kyung Hee University, Seoul, Republic of Korea

²Department of Obstetrics and Gynecology, College of Medicine, Kyung Hee University, Seoul, Republic of Korea

³Department of Obstetrics and Gynecology, College of Medicine, Kangwon National University, Chuncheon, Republic of Korea

⁴Joeun Obstetrics and Gynecology Hospital, Namyangju, Republic of Korea

⁵Institute for Life & Environmental Technology, Smartive Corporation, Hanam, Republic of Korea

^*Correspondence: juheekim@khu.ac.kr

Received August 8, 2024 Accepted January 5, 2025

This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Non-persistent endocrine disrupting chemicals (EDCs) are associated with increased oxidative stress and disrupted thyroid-stimulating hormone (TSH) during pregnancy; however, the results of previous studies are inconsistent. This study assessed the concentrations of 15 non-persistent chemicals, TSH, and oxidative stress biomarkers in pregnant women during the first trimester in Korea. This study was a prospective cohort study, recruiting a total of 242 pregnant women from March 18, 2022 to March 17, 2023. Pregnant women who agreed to participate in the study provided blood and urine samples in the first and third trimesters of pregnancy. Concentrations of three bisphenols, four parabens, triclosan, benzophenone-3, two volatile organic compounds (VOCs), and four polycyclic aromatic hydrocarbons (PAHs) were analyzed in urine samples. TSH, malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) were measured as biomarkers of thyroid function and oxidative stress. The geometric mean concentration of the chemicals ranged from 0.07 to 45.20 μg/g creatinine, and were lower or similar to those in previous studies, except for ethyl paraben (EP). Spearman’s coefficients of correlation ranged from −0.26 to 0.51. A multiple linear regression model was constructed after adjusting for covariates (maternal age, pre-pregnancy body mass index, education level, income, residence area, parity, and maternal cotinine level). BPF (ß = −0.184, p = .020, 95 % CI = −0.223 to −0.020), 1-hydroxypyrene (1-OHP) (ß = −0.197, p = .046, 95 % CI = −0.915 to −0.009), and , 2-hydroxyfluorene (2-FLU) (ß = 0.199, p = .026, 95 % CI = 0.053 to 0.819) were significantly associated with TSH. trans, trans-muconic acid (t,t-MA) (ß = 0262, p = .001, 95 % CI = 0.050 to 0.181) showed a positive association with malondialdehyde (MDA) as a biomarker for oxidative stress. Therefore, pregnant women should minimize their exposure to EDCs, which impact oxidative stress and TSH in the early stages of pregnancy.

Keywords: Thyroid stimulating hormone, oxidative stress, endocrine disrupting chemicals, prenatal exposure

Introduction

Environmental pollutants, including phenols, polycyclic aromatic hydrocarbons (PAHs), and volatile organic compounds (VOCs), are estrogenic and anti-androgenic chemicals that are commonly present in personal care products, consumer goods, sunscreen, cosmetics, and dust; common exposure routes include ingestion, inhalation, and dermal contact [1-3]. Many recent in vitro and in vivo studies have reported an association between exposure to phenols, PAHs, and VOCs and oxidative stress during pregnancy [2,4-16]. In addition, many epidemiology studies have explored the associations between exposure to endocrine-disrupting chemicals (EDCs) and thyroid function during pregnancy [17-26]. Thyroid function is essential for the normal development, growth, and neurodevelopment of the fetus, and for metabolism during pregnancy [18,23]. In particular, since fetal thyroid hormones are not produced until 10 to 12 weeks of gestational age, the fetus is entirely dependent on thyroid hormones from the mother in the early stages of pregnancy [18,23,25,27]. Several animal studies have reported that low thyroid hormone levels during pregnancy cause structural and functional abnormalities in the fetal cerebral cortex and hippocampus [28-30]. Previous human epidemiologic studies have also reported that maternal thyroid hormone insufficiency during pregnancy is associated with adverse perinatal outcomes, including fetal cortical underdevelopment, intrauterine growth restriction, low birth weight, and preterm birth [20,31-36], as well as neonatal complications including impaired cognition, neurological development, behavioral disorders, and abnormal cortical morphology [32,37-39]. In this regard, many countries include the assessment of thyroid stimulating hormone (TSH) within standard antenatal screenings and neonatal checkups [40].

Oxidative stress refers to an imbalance between antioxidant and pro-oxidant capacities. Excessive accumulation of reactive oxygen species (ROS) in the human body causes structural and functional changes in cells by damaging proteins, lipids, and DNA [41-43]. Throughout the gestational period, a large amount of ROS accumulates in the maternal body because she experiences physiological changes such as increased respiratory and cardiac output, concomitant with shifts in nutritional profile and metabolic dynamics [40,44,45]. In this regard, increased ROS production is known to cause pathologies, leading to adverse pregnancy outcomes such as preterm birth, recurrent spontaneous abortion, intrauterine growth restriction, preeclampsia, and gestational diabetes mellitus [1,46-51]. In light of the foregoing, it is imperative to investigate the potential impacts of EDCs on TSH levels and oxidative stress during pregnancy, with a specific emphasis on the early gestational phase, in consideration of their implications for maternal well-being and fetal health. However, despite its importance, studies confirming the association between EDCs, TSH, and oxidative stress in early pregnancy are limited, and the results are inconsistent. For example, several studies have reported significant associations between exposure to bisphenols, parabens, PAHs, and TSH levels during pregnancy [17,20,21]. However, a population-based prospective cohort study in Sweden and France reported no association between BPA and BPS levels with TSH levels [22,24].

To address these inconsistencies and provide a more comprehensive perspective, this study focused on 15 nonpersistent chemicals. These chemicals were selected based on their high potential for exposure among pregnant women, their established associations with oxidative stress and thyroid function in previous studies, and their frequent detection in biomonitoring studies. These chemicals are widely used in consumer products and personal care products (PCPs) and are considered important in studies on health effects related to pregnancy and childbirth [1-3]. Therefore, the purpose of this study was to assess the concentration of 15 non-persistent chemicals (three bisphenols, four parabens, triclosan (TCS), benzophenone-3 (BP-3), two VOCs, and four PAHs), TSH, and two biomarkers of oxidative stress (8-hydroxy-2- deoxyguanisine [8-OHdG], malondialdehyde [MDA]) in the 1st trimester of pregnancy, and to confirm the effect of these 15 non-persistent chemicals on maternal TSH and oxidative stress.

Materials and Methods

Study population and data collection

This study included pregnant women from the NoE-MoC (No Environmental Hazards for Mother-Child) cohort. The NoE-MoC Cohort study was established to investigate the effects of prenatal exposure to non-persistent EDCs on pregnancy outcomes, and newborn development from early pregnancy to postpartum. Healthy pregnant women who completed the first prenatal evaluation in the 1st trimester and with a singleton were recruited from five hospitals nationwide. Pregnant women with chronic diseases, such as thyroid function abnormalities, hypertension, or diabetes, were excluded. In total, 242 pregnant women were recruited from March 18, 2022, to March 17, 2023. After obtaining informed consent, pregnant women completed a questionnaire and provided blood and urine samples in the first trimester during routine checkups in the hospital. The questionnaire included sociodemographic, obstetric, and health information. A 20 ml sample of midstream urine was collected in a polypropylene tube and stored in a freezer at a temperature of −80 ℃ until analysis. This study was approved by the Ethics and Human Committee of Kyunghee University (KHSIRB-21-598(NA]) and Kangwon National University Hospital (KNUH-2022-02-001-001).

Laboratory analyses

All chemicals and standard materials were purchased from Sigma-Aldrich (St. Louis, MO, USA), Merck (Darmstadt, Germany), Burdick and Jackson (Muskegon, USA), Roche (Mannheim, Germany), or the National Institute of Standards and Technology (NIST, Gaithersburg, MD, USA).

Analyses of five environmental pollutant classes, including five phenols (BPA, BPF, BPS, TCS, BP-3), four parabens (MP, EP, BP, and PP), four PAHs (1-OHP, 2-NAP, 1-PHE, 2-FLU), and two VOCs (t, t-MA, BMA) of urine samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) as described in previous study with minor modifications [52]. Briefly, urine (0.5 mL) was placed in a tube and 10 μL of internal standard (ISTD) solution, 700 μL of phosphate buffer (pH 7.2), and 50 μL of -glucuronidase was added. For the enzymatic hydrolysis of the glucuronide conjugates, the mixture was incubated at 37 ºC for 16 h. The mixture was incubated for 10 min, centrifuged at 25,000 rpm at 4 ºC for 5 min, and the supernatant was transferred to a new glass tube. The remaining mixture was mixed again with 60 μL of 6N HCL and 5 mL of ethyl acetate and centrifuged again at 25,000 rpm at 4 ºC for 5 min to obtain the supernatants. The two supernatants were mixed and concentrated under nitrogen gas. Finally, 10 μL of the reconstituted sample containing 0.01 % acetic acid in water was injected into the LC-MS/MS system. A Thermo Scientific™ Vanquish™ ultrahigh-performance liquid chromatography (UHPLC) system (Thermo Finnigan, San Jose, CA, USA) with an ACE Excel 2 C18-AR column (150 × 2.1 mm inner diameter; Advanced Chromatography Technology, Scotland) was connected to a TSQ Altis triple quadrupole mass spectrometer (Thermo Finnigan) equipped with an electrospray ionization (ESI) source. The spray voltage was set to 4,500 V in the positive mode and 3,500 V in the negative mode. The temperature of the ion transfer tube was 320 ºC and that of the vaporizer was 340 ºC in both modes. The column temperature was maintained at 35 ºC. All experiments were performed in time-dependent reaction monitoring mode for simultaneous analysis. For quality control, we used calibration curves (r > 0.999), procedural blanks, duplicate samples, transport blanks, and matrix spike samples. The range of mean recoveries of all the target analytes was from 87% to 110 % for the matrix spiked samples (1 or 10 ng for each analyte, the same as the internal standards mentioned above, except for some analytes that showed extremely high concentrations). No target analyte was detected in any of the blanks. The limits of detection (LOD) ranged from 0.01 to 0.58 µ g/L (Table 2).

TSH levels were measured using electrochemiluminescence assays (Roche Diagnostics GmbH, Cobas e601 analyzer, Germany). MDA and 8-OHdG levels were determined using OxiSelect (TBARS Assay Kit, San Diego, CA, USA) and a competitive enzyme-linked immunosorbent assay kit (JaICA New 8-OHdG Check ELISA Kit; Shizuoka, Japan), respectively.

Statistical analyses

Socioeconomic and obstetrical variables of subjects were described as the mean ± standard deviation (SD), or numbers and percentages or medians (min-max). The urinary concentration of the analytes was natural log-transformed because they had a right-skewed distribution. Concentrations below the LOD were substituted for the value divided by the square root of 2 [53] with creatinine-adjusted values. The Spearman correlation coefficient was used to identify correlations between the analytes. Multiple linear regression was used to confirm the association between each analyte (bisphenols, parabens, TCS, BP-3 PAHs, and VOCs), TSH, and oxidative stress biomarkers after adjusting for maternal age, prepregnancy body mass index (BMI), education, income, residential area, parity, and maternal cotinine level in urine. Before multiple linear regression analysis, multicollinearity was evaluated using variance inflation factor analysis; no chemicals showed multicollinearity. Statistical significance was set at a p = .05 and the 95 % confidence interval was calculated. All data were analyzed using R 4.1.0 (R Development Core Team, Vienna, Austria) and SAS (version 9.4; SAS Institute Inc., Cary, NC, USA).

Results

General characteristics of participants

Table 1 represents the socio-economic status of the participants. The average age of mothers was 33.8 years old, ranging from 21 to 42 years old. The mean pre-pregnancy BMI was 23.2 kg/m² and > 80 % of mothers graduated from college. Among the mothers, 51.2 % earned < 5,000,000 $/month, ~65 % were employed, and 64 % lived in a metropolitan area. In terms of parity, 57.4 % of mothers were primipara and 42.6 % were multipara women. The level of cotinine in mothers’ urine was used as a covariate in the multivariate analysis and the average level was 25.4 μg/g creatinine.

Urinary concentrations of chemicals, TSH, and oxidative stress

Table 2 and Table 3 show the urinary concentration of 15 non-persistent EDCs, TSH levels, and oxidative stress in urine samples in this study and previous studies. MP, BP, and 2-NAP were detected in all urine samples, while BPF and PP were found in < 50% of samples. The geometric mean (GM) concentration of chemicals ranged from 0.07 to 45.20 μg/g for creatinine. MP, EP, and BMA showed extremely high maximum values with high detection rates of > 99 % (1,390, 2,900, and 10,100 μg/g creatinine respectively). Figure 1 shows the coefficients of correlation between bisphenols, parabens, PAHs, and VOCs. MP and PP were most positively correlated (r = 0.51), followed by BPA and 1-OHP (r = 0.37); 1-OHP was positively correlated with 2-NAP (r = 0.21), 1-PHE (r = 0.27), and t, t-MA (r = 0.24), and BPA was positively correlated with 1-PHE (r = 0.29), t, t-MA (r = 0.26), and BP (r = −0.26).

Association between EDCs, TSH, and oxidative stress

The associations of TSH and oxidative stress biomarker levels with creatinine-adjusted urinary metabolites of 15 non-persistent EDCs were evaluated using multivariate linear regression analysis (Table 4, Figure 2). Table 4 shows the fully adjusted model with covariates, including maternal age, pre-pregnancy BMI, education level, income, residence area, parity, and maternal cotinine level. In the regression model, BPF (ß = −0.184, p = .020, 95 % CI = −0.223 to −0.020), 1-OHP (ß = −0.197, p = .046, 95 % CI = −0.915 to −0.009), and 2-FLU (ß = 0.199, p = .026, 95 % CI = 0.053 to 0.819) were significantly associated with TSH levels. MDA showed a positive association with t, t-MA (ß = 0262, p = .001, 95 % CI = 0.050 to 0.181). However, 8- OHdG showed no significant association with the 15 non-persistent EDCs at a significance of p < .05. The estimates of coefficients and 95 % confidence intervals are shown as forest plots in Figure 2.

Discussion

In this study, all chemicals except BPF and PP were detected at > 70 %, and all oxidative stress biomarkers were detected at > 98 %. The observed differences in detection rates may be attributed to the characteristics of the chemicals or the consumption patterns of Korean pregnant women. This study compared the urinary chemical concentrations of pregnant women in Korea and other countries and found several similarities and differences. First, for bisphenols (BPA, BPS, BPF), relatively consistent concentrations were observed across countries. This may result from increasing global awareness of the endocrine disrupting properties of bisphenols, leading to strict regulatory measures in many countries. For instance, BPA is currently regulated in major countries, including Korea, China, the United States, and EU, where its production and use are restricted [54]. In contrast, notable differences were observed for parabens. Specifically, the concentrations of EP in Korean pregnant women were significantly higher than those reported in other countries. This finding is consistent with previous studies, which reported that the EP levels in the Korean population were up to 10 times higher than those in other countries [55,56]. These results may be partially due to the unique Korean dietary patterns, which include high consumption of traditional fermented condiments such as soybean paste and red pepper paste [57]. These foods may contain EP, which is added as a preservative during manufacturing or storage [56]. Such dietary patterns can affect the concentration levels of specific chemicals in the human body. The concentrations of PP were reported to be lower in Korea compared to other countries. This may be due to regulations from the Korean Ministry of Food and Drug Safety, which prohibited the use of PP as a food additive since 2008 [55]. A cross-country comparison found that PP concentrations were highest in the United States, possibly reflecting its extensive use in PCPs manufactured in the region. According to previous study, PCP products manufactured in the United States exhibited the highest levels of MP and PP [57]. These international comparisons highlight the importance of considering cultural contexts when interpreting exposure levels to non-persistent chemicals. Differences in biomonitoring results for specific chemicals across regions may reflect variations in regulatory policies and manufacturing practices [55]. However, data on VOCs were insufficient, limiting the feasibility of direct comparisons with findings from other studies. For PAHs, the geometric mean of urinary concentrations in Korean pregnant women ranged from 0.06 to 2.39 μg/g creatinine, which were similar to those reported in Chinese studies (0.11 to 1.91 μg/g creatinine). However, direct comparisons were difficult due to differences in units and the limited number of available studies. Our study provides a comprehensive assessment of multiple EDCs, including bisphenols, parabens, PAHs, and VOCs, within a single cohort of pregnant women. This integrated approach not only allows for the assessment of individual chemical exposures, but also highlights the interactive effects of these chemicals during pregnancy. This study highlights the need for comprehensive biomonitoring efforts to understand the health effects of EDC exposure in vulnerable groups such as pregnant women.

The results of this study confirmed that only BPF and some PAHs (1-OHP and 2-FLU) were significantly associated with TSH. Additionally, only t,t-MA, a type of VOCs, was significantly associated with an increase in MDA as a biomarker for oxidative stress. We found a significant association between high concentrations of BPF and some PAHs (1- OHP and 2-FLU) with TSH levels, which is consistent with previous studies (Supplement Table 1) [21,23]. The urinary concentrations of BPA and BPS were not significantly associated with TSH levels, consistent with previous studies [18,22-25]. However, one cohort study in Puerto Rico reported that an increase in BPS concentration significantly reduced TSH levels by 12% [17]. Thyroid hormone is synthesized in the thyroid gland by TSH produced from the hypothalamus-pituitary gland-thyroid (HPT) axis, and the synthesized thyroid hormone binds to proteins, circulates in the blood, and acts on target organs [58]. The structure of bisphenols (BPA, BPF, and BPS) is similar to that of T3 and can act as antagonists by binding to the thyroid hormone receptor (TR) beta isoform (TRß) or directly affecting the thyroid gland [59,60]. Furthermore, EDCs such as bisphenols and PAHs may indirectly interfere with thyroid function by interfering with endocrine signaling and causing oxidative stress via overproduction of ROS [21]. Overproduction of ROS can impair thyroid hormone biosynthesis and increase TSH levels by interfering with the activity of thyroid peroxidase (TPO), a key enzyme in T3 and T4 synthesis [61]. These findings highlight the role of ROS as a mediator between EDC exposure and thyroid dysfunction. Some animal studies have reported that BPF exposure in zebrafish altered T3, T4, and TSH levels and altered expression of genes including thyroglobulin (Tg), Ttr, and Ugt1ab. BPA exposure alters the weight of the thyroid gland and changes its histology [62-64]. PAHs are found in polluted air generated during forest fires or when grilling meat. Studies examining the relationship between PAH and thyroid hormones are limited, except for a few epidemiological reports [65,66]. In this study, 1-OHP, a metabolite of pyrene, was found to be significantly associated with TSH, and the levels were in accordance with the National Environmental Basic Survey conducted on Korean citizens. In this survey, PAH exposure was positively associated with total T3 in men [67]. While this study found significant associations between specific EDCs and thyroid function or oxidative stress biomarkers, it is important to consider the potential influence of confounding factors that may have contributed to these results. Socioeconomic factors such as maternal age, pre-pregnancy BMI, education level, income, and residence area could have contributed to variability in the observed associations [2,6,19]. For example, pre-pregnancy BMI is a potential confounding factor that may affect thyroid function and oxidative stress levels. Higher BMI is associated with an increased risk of hypothyroidism and elevated oxidative stress, which may influence the observed relationships [68,69]. Considering these factors is important to accurately interpreting the findings.

Little is known about the underlying mechanism which can only be speculated based on its association with thyroxine-binding globulin (TBG), thyroid autoantibodies in the blood, peripheral deiodinase activity, and indicators of thyroid secretory capacity. Several animal experimental studies have reported that exposure to pyrene in rockfish affected the development of the thyroid gland, and exposure to benzopyrene/naphthoflavone in rats and fish lowered the levels of the thyroid hormone [70-72]. These differences between animal experiments and the results of epidemiological studies can be explained by differences in species, PAH exposure dose, and study design. Although no significance was found between the concentrations of parabens (MP, EP, BP, and PP) and TSH levels in the current study, two previous cohort studies reported a significant association between PP concentrations and TSH levels [17,20]. The inconsistencies between EDC and TSH levels in this study and previous studies are likely because our research subjects were pregnant women, who are known to undergo significant physiological and metabolic changes. Therefore, more research is needed to understand this phenomenon.

In this study, only t,t-MA (a VOC) was significantly associated with an increase in MDA as a biomarker for oxidative stress. This result is consistent with those of previous studies [2,73,74]. VOCs are common environmental pollutants emitted from natural and anthropogenic sources, including consumer products such as furniture aerosol sprays and paints [2]. As potential mechanisms by which EDCs such as VOCs induce oxidative stress, the accumulation of ROS such as phenoxyl radicals, superoxide anions, and hydrogen peroxide in the body, results in damage to nucleic acids and proteins in cell membranes, lipid peroxidation, and mitochondrial DNA damage [75-77]. In this study, t,t-MA, a VOC, was significantly associated with MDA, an indicator of oxidative stress and a metabolite of benzene and sorbic acid. Solvic acid is a commonly used food preservative that increases lipid peroxidation and downregulates hepatic lipid metabolism [73,78,79]. Benzene is a group 1 carcinogen and is strongly associated with lipid peroxidation, as evidenced in animal experiments [73,80]. In the current study, bisphenols (BPA, BPF, BPS), TCS, and BP-3 were not associated with oxidative stress, which is supported by several previous studies [3,14]. However, previous studies that investigated high concentrations of BPA [3,6,11,15], phenols (BP-3, TCS,) some parabens [7,10,16], and VOCs [2] showed significant associations with increased 8OHdG. In the current study, parabens were not associated with oxidative stress, which is consistent with the results of previous study [3]. However, a cohort study in China reported that increased MP, EP, and PP increased 8OHdG levels by 18.6 %, 9.85 %, and 12.1%, respectively, and a cohort study in the US reported that high MP and PP concentrations were associated with increased 8OHdG levels in a repeated-measures model [7,81]. Previous study reported that the concentration of EP was significantly related to the 8OHdG and MDA levels.10 In the current study, there was no significant association between PAHs and oxidative stress, but many previous studies reported that high PAH (1- OHP, 2-NAP, 2-FLU) concentrations were associated with increased oxidative stress [8,12,13].

This study was conducted to determine the concentration of 15 non-persistent chemicals in early pregnancy (1st trimester) urine samples in Korea and to establish the relationship between these chemicals and TSH and oxidative stress. The first trimester of pregnancy is a time of significant physiological change in the mother. Moreover, during this period, the fetus cannot produce thyroid hormones. Thyroid function homeostasis can be disrupted by EDCs such as bisphenols, parabens, PAHs, and VOCs and EDCs block synthesis of thyroid hormones by interfering with the sodium-iodine symporter or enzyme thyroperoxidase, or by binding to thyroid hormone receptors [24]. Therefore, if a pregnant woman is exposed to EDCs in the early stages of pregnancy, it affects the mother and the thyroid function of the fetus, thereby affecting the growth and development of the fetus, so evaluation in the early stages of pregnancy is important. This study collected and analyzed first-trimester urine from pregnant women. Considering the association of increased oxidative stress during pregnancy with various health outcomes, follow-up studies need to conduct repeat studies with various population groups and study designs during this period.

Strengths and limitations

There were some limitations to this study. First, the 15 chemicals chosen for analysis are non-persistent EDCs with short half-lives of 6–29 hours [2,27,74,82,83]. Thus, single-spot urine samples are limited in accurately assessing exposure in the 1st trimester. In future studies, it will be necessary to measure EDC exposure during the entire pregnancy period or variability through continuous measurement of urine. Second, there was a strong correlation between some chemicals in this study. For example, the r value for BPA and 2-FLU was 0.81; the r value for 1-OHP and 2-FLU was 0.62. Whether the chemical alone affected thyroid function or oxidative stress, or whether it was a result of a mixed effect, remains unclear. In future research, it is necessary to confirm the mixing effect of these chemicals through statistical methods such as Bayesian Kernel Machine Regression [84]. Third, this study measured the relationship between EDCs, TSH, and oxidative stress levels measured once during a short period in the first trimester of pregnancy. Although it was assessed at the cellular level, linking exposure to EDCs and human health from data collected over a short period may not be appropriate in reality. Therefore, repeated exposure studies are needed in future research. Lastly, while this study utilized MDA and 8-OHdG as independent biomarkers for oxidative stress, their relationship was not analyzed. MDA reflects lipid peroxidation, whereas 8-OHdG indicates oxidative DNA damage. Investigating the correlation between these two biomarkers could provide deeper insights into how oxidative stress affects various systems and tissues throughout the body. Despite these limitations, this study confirmed that EDC exposure during early stages of pregnancy can affect thyroid function and oxidative stress, emphasizing the need for further research on this critical developmental period.

Conclusions

The purpose of this study was to examine exposure to various EDCs including bisphenols, parabens, TCS, BP-3, VOCs, and PAHs in early pregnancy, and to investigate the relationship between these chemicals, TSH levels, and oxidative stress biomarkers (MDA and 8OHdG). In our study, BPF and some PAHs (1-OHP and 2-FLU) were significantly associated with TSH level, and exposure to t,t-tMA (a VOC) increased the MDA level. Early pregnancy is a time of significant physiological change in the mother; moreover, during the 1st trimester, the fetus cannot produce thyroid hormones on its own. Therefore, pregnant women should minimize their exposure to EDCs, which can affect oxidative stress and TSH, especially in the early stages of pregnancy.

Notes

Acknowledgement

This study was supported by the National Research Foundation of Korea (NRF) and funded by the Korean Government (Ministry of Science, ICT) [grant number NRF-2021R1A2C4001788]. We thank the women who participated in this study, as well as the following hospitals that participated in data collection: Kyung Hee University Medical Center, Kangwon National University Hospital, Joeun Obstetrics and Gynecology Hospital, Houm Obstetrics and Gynecology Clinic & Birthing Center, and Lin Women's Hospital.

Conflict of interest

The authors declare no competing interests, including financial interests or personal relationships, that could influence the work reported in this paper.

CRediT author statement

JHK designed, administered, and supervised this study, and was responsible for investigation, data curation, and formal analysis. NLM and SJH conducted sampling and statistical analysis. YJL, JYH, SJL, JHI provided resources for this study. HSI provided resources for this study and was responsible for the formal analysis. All authors participated in Writing-Original Draft, Writing-Review & Editing.

Supplementary Material

The results of a literature review on the association between chemicals and TSH are provided.

This material is available online at www.eaht.org.

eaht-40-1-e2025002-Supplementary.pdf

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Figure 1.

Coefficients of correlation between bisphenols, parabens, phenols, polycyclic aromatic hydrocarbons, and volatile organic compounds in 1st trimester Korean mothers’ urine samples. Darker colors denote larger absolute values of Spearman’s correlation coefficients. BPA, bisphenol A; BPF, bisphenol F; BPS, bisphenol S; MP, methylparaben; EP, ethylparaben; BP, butylparaben; PP, propylparaben; TCS, triclosan; BP-3, Benzophenon-3; t,t-MA, trans, trans-muconic acid; BMA, benzylmercapturic acid; 1-OHP, 1-hydroxypyrene; 2-NAP, 2-hydroxynaphthalene; 1-PHE, 1-hydroxyphenanthrene; 2-FLU, 2-hydroxyfluorene.

Figure 2.

Forest plots of multiple linear regression coefficients and 95 % confidence interval between 15 chemicals, TSH, and oxidative stress biomarkers. All results are adjusted with covariates (maternal age, pre-pregnancy BMI, education, income, residence area, parity, and maternal cotinine level in urine). Red boxes and lines represent statistically significant results (p < 0.05). BMI, body mass index; BPA, bisphenol A; BPF, bisphenol F; BPS, bisphenol S; MP, methylparaben; EP, ethylparaben; BP, butylparaben; PP, propylparaben; TCS, triclosan; BP-3, Benzophenon-3; t,t-MA, trans, trans-muconic acid; BMA, benzylmercapturic acid; 1-OHP, 1-hydroxypyrene; 2-NAP, 2-hydroxynaphthalene; 1-PHE, 1-hydroxyphenanthrene; 2-FLU, 2-hydroxyfluoren, TSH, thyroid stimulating hormone, 8-OHdG, 8-hydroxy-2-deoxyguanisine, MDA, malondialdehyde.

Table 1.

Socioeconomic characteristics of participants (n = 242).

Variables	Categories	n/ M	% /SD	Median	Min	Max
Age (years)		33.8	4.0	34.0	21.0	42.0
Pre-pregnancy BMI (kg/m²)		23.2	4.2	22.5	14.8	40.2
Education	< college	44	18.2	-	-	-
	≥ college	198	81.8	-	-	-
Household income ($/month)	≤ 5,000	124	51.2	-	-	-
	> 5,000	118	48.8	-	-	-
Employment status	Yes	157	64.9	-	-	-
	No	85	35.1	-	-	-
Residence area	Metropolitan	155	64.0	-	-	-
Non-Metropolitan		87	36.0	-	-	-
Parity	Primipara	139	57.4	-	-	-
	Multipara	103	42.6	-	-	-
Cotinine level (µg/g creatinine)		25.4	17.1	14.23	0.04	1718.6

M, mean; SD, standard deviation; Min, minimum; Max, maximum; BMI, body mass index.

Table 2.

Urinary concentration of chemicals, oxidative stress, and TSH (n= 242).

Analytes	DF (%)	LOD (μg/L)	Min	Max	GM	25th	50th	75th	95th
Creatinine adjusted (µg/g creatinine)
BPA	78.5	0.12	< LOD	22.7	0.64	0.36	0.61	1.06	2.83
BPF	42.1	0.08	< LOD	19.9	0.47	0.09	0.26	2.48	11.7
BPS	98.8	0.01	0.02	22.1	0.30	0.13	0.25	0.63	2.68
MP	100	0.15	0.59	1390	6.70	2.77	4.82	9.07	175
EP	99.6	0.14	0.16	2900	32.80	10.2	40.30	126	632
BP	100	0.07	0.22	23.8	0.78	0.48	0.70	1.09	3.74
PP	31	0.21	< LOD	250	1.99	0.34	0.93	12.7	95.4
TCS	71.5	0.04	< LOD	3.11	0.28	0.13	0.27	0.63	1.77
BP-3	71.5	0.10	< LOD	341	0.43	0.14	0.30	0.93	8.38
t,t-MA	99.6	0.58	4.00	554	45.20	21.40	44.80	92.0	244
BMA	99.6	0.04	0.12	10100	2.87	1.49	2.49	4.67	17.40
1-OHP	85.5	0.03	< LOD	4.08	0.14	0.07	0.13	0.23	0.73
2-NAP	100	0.05	0.26	84.1	2.39	1.24	2.07	3.96	14.8
1-PHE	77.3	0.02	< LOD	37.0	0.07	0.04	0.06	0.09	0.38
2-FLU	95	0.01	0.02	9.10	0.13	0.08	0.14	0.22	0.43
Unadjusted (µg/L)
BPA	78.5	0.12	0.12	15.3	0.64	0.39	0.70	1.43	4.84
BPF	42.1	0.08	0.08	36.1	0.47	0.13	0.24	3.53	15.2
BPS	98.8	0.01	0.02	40.5	0.30	0.12	0.30	0.66	2.48
MP	100	0.15	0.36	1290	6.70	3.02	5.23	11.7	210
EP	99.6	0.14	0.14	0.19	32.80	10.8	42.4	133	723
BP	100	0.07	0.76	32.3	0.78	0.76	0.77	0.78	0.84
PP	31	0.21	0.21	535	1.99	0.34	1.32	10.9	115
TCS	71.5	0.04	0.04	8.14	0.28	0.13	0.31	0.67	2.24
BP-3	71.5	0.10	0.10	242	0.43	0.18	0.38	1.04	8.10
t,t-MA	99.6	0.58	1.66	943	47.3	21.2	53.9	108	329
BMA	99.6	0.04	0.10	12300	3.01	1.38	2.77	6.17	26.4
1-OHP	85.5	0.03	0.04	5.00	0.16	0.08	0.14	0.26	0.83
2-NAP	100	0.05	0.14	89.2	2.48	1.10	2.27	4.89	24.8
1-PHE	77.3	0.02	0.02	71.9	0.09	0.04	0.07	0.12	0.52
2-FLU	95	0.01	0.02	6.13	0.14	0.07	0.14	0.25	0.62
Biomarker			Min	Max	GM	25th	50th	75th	95th
TSH (uIU/mL)			0.008	7.38	1.10	0.80	1.37	2.09	2.72
MDA (µg/g creatinine)			0	1165	345.62	280.10	344.58	446.60	641.78
8-OHdG (µg/g creatinine)			0	32	10.46	8.50	10.53	12.75	17.98

DF, detection frequency; LOD, limit of detection; GM, geometric mean; DF, detection frequency; Min, minimum; Max, maximum; BPA, Bisphenol A; BPF, Bisphenol F; BPS, Bisphenol S; MP, Methylparaben; EP, Ethylparaben; BP, Butylparaben; PP, Propylparaben; TCS, Triclosan; BP-3, Benzophenon-3; t,t-MA, trans, trans-muconic acid; BMA, benzylmercapturic acid; 1-OHP, 1-hydroxypyrene; 2-NAP, 2-hydroxynaphthalene; 1-PHE, 1-hydroxyphenanthrene; 2-FLU, 2-hydroxyfluorene; TSH, hyroid stimulating hormone, 8-OHdG, 8-hydroxy-2-deoxyguanisine, MDA, malondialdehyde.

Table 3.

Geometric mean/median concentration of 15 chemicals, TSH, and oxidative stress in this and previous studies.

Reference	Sample size (n)	Country	Concentrations
			Bisphenols			Parabens TCS				TCS	BP-3	VOCs		PAHs				TSH (uIU/mL)	Oxidative stress biomarker		Units
			BPA	BPF	BPS	MP	EP	BP	PP	TCS	BP-3	t,t-MA	BMA	1-OHP	2-NAP	1-PHE	2-FLU	TSH (uIU/mL)	8-OHdG	MDA	Units
This study (2023)	242	Korea	0.64	0.47	0.30	6.70	32.80	0.78	1.99	0.28	0.43	45.2	2.87	0.14	2.39	0.06	0.12	1.10	10.40	357	µg/g creatinine
Huang et al. (2018)	209	China	2.24	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	4.91	-	µg/g creatinine
Liang et al. (2020)	111	China	1.41^*		< LOD	-	-	-	-	-	-	-	-	-	-	-	-	-	0.02^*	-	µg/g creatinine
Wu et al. (2023)	358	China	0.87	0.06	0.07	-	-	-	-	-	-	-	-	-	-	-	-	-	8.80	-	µg/g creatinine
Zhao et al. (2017)	209	China	-	-	-	-	-	-	-	-	0.9	-	-	-	-	-	-	-	-	-	ng/ml
Lan et al. (2022)	2,583	China	-	-	-	20.50^*	1.66^*	1.58^*	-	-	-	-	-	-	-	-	-	-	-	-	ng/ml
Watkins et al. (2015)	238	Puerto Rico	2.86	-	-	149	-	1.03	33.30	27.30	58	-	-	-	-	-	-	-	-	-	ng/ml
Ferguson et al. (2019)	1,675	US	-	-	< LOD	185^*	2.13^*	0.84^*	45.10^*	10.60^*	42.30^*	-	-	-	-	-	-	-	121^*	-	ng/ml
Kang et al. (2013)	46	Korea	-	-	-	169.9^*	44.6^*	< LOD	8.6^*	-	-	-	-	-	-	-	-	-	-	-	µg/L
Peng et al. (2020)	77	China	-	-	-	-	-	-	-	-	-	-	-	0.51^*	-	-	-	-	2.66^*	-	ng/ml
Ferguson et al. (2017)	200	US	-	-	-	-	-	-	-	-	-	-	-	-	2477	205	135	-	-	-	pg/ml
Lou et al. (2019)	188	China	-	-	-	-	-	-	-	-	-	-	-	0.11-0.14	1.15-1.91	-	0.13-0.16	-	13.8-16.7	-	µg/g creatinine
Aker et al.(2019)	439	US	2.31	0.35	0.54	152.43	3.73	1.21	33.90	16.82	52.62	-	-	-	-	-	-	0.77	-	-	µg/L
Berger et al. (2018)	452	US	-	-	- 0.09	126.5	-	0.4	30.9	17.5	21	-	-	-	-	-	-	-	-	-	ng/ml
Huang et al. (2022)	446	China	1.90	0.45	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	ng/ml
Sarzo et al. (2022)	387	Spain	2.63^*	-	-	65.30^*	5.05^*	0.68^*	15.40^*	19.30^*	3.66^*	-	-	-	-	-	-	1.23^*	-	-	ng/mg
Skarha et al. (2019)	317	US	-	-	-	-	-	-	-	7.8	-	-	-	-	-	-	-	1.9^*	-	-	µg/L
Nakiwala et al. (2022)	437	France	2.08^*		< LOD	12^*	0.71^*	< LOD	0.45^*	0.91^*	1.20^*	-	-	-	-	-	-	-	-	-	µg/L
Derakhshan et al. (2019)	1,996	Sweden	1.51^*	0.15^*	0.08^*	-	-	-	-	-	-	-	-	-	-	-	-	1.31^*	-	-	ng/ml
Cathey et al. (2020)	659	Puerto Rico	-	-	-	-	-	-	-	-	-	-	-	6768	113	105	-	1.41	-	-	-

^* Median value

Table 4.

Multiple linear regression between 15 chemicals, TSH, and oxidative stress.

Chemicals	TSH					MDA					8-OHdG
Chemicals	B	β	p-value	Lower 95% CI	Upper 95% CI	B	β	p-value	Lower 95% CI	Upper 95% CI	B	β	p-value	Lower 95% CI	Upper 95% CI
BPA	0.077	0.072	0.441	−0.120	0.273	−0.018	−0.018	0.850	−0.209	0.172	−0.033	−0.033	0.734	−0.224	0.158
BPF	−0.122	−0.184	0.020	−0.223	−0.020	−0.073	−0.114	0.148	−0.172	0.026	0.047	0.077	0.353	−0.052	0.146
BPS	−0.002	−0.002	0.974	−0.152	0.147	−0.054	−0.055	0.461	−0.199	0.091	−0.001	−0.001	0.987	−0.148	0.145
TCS	−0.022	−0.015	0.839	−0.238	0.194	−0.008	−0.006	0.941	−0.218	0.202	0.003	0.002	0.977	−0.207	0.213
BP-3	−0.043	−0.082	0.259	−0.119	0.032	−0.011	−0.021	0.772	−0.084	0.062	−0.024	−0.049	0.521	−0.098	0.050
MP	−0.013	−0.038	0.707	−0.080	0.054	0.063	0.193	0.058	−0.002	0.128	−0.031	−0.098	0.356	−0.097	0.035
EP	0.026	0.095	0.199	−0.014	0.066	−0.001	−0.005	0.947	−0.040	0.038	−0.036	−0.138	0.075	−0.075	0.004
PP	0.064	0.152	0.121	−0.017	0.145	−0.030	−0.073	0.459	−0.108	0.049	0.010	0.023	0.820	−0.073	0.092
BP	−0.125	−0.114	0.148	−0.294	0.045	−0.025	−0.023	0.772	−0.191	0.142	−0.138	−0.130	0.117	−0.311	0.035
1-OHP	−0.462	−0.197	0.046	−0.915	−0.009	−0.132	−0.058	0.555	−0.571	0.308	0.421	0.194	0.064	−0.024	0.865
2-NAP	0.078	0.130	0.090	−0.012	0.169	0.006	0.011	0.890	−0.082	0.094	−0.019	−0.034	0.673	−0.109	0.070
1-PHE	0.087	0.065	0.417	−0.124	0.298	0.175	0.135	0.093	−0.029	0.380	−0.035	−0.029	0.733	−0.241	0.170
2-FLU	0.436	0.199	0.026	0.053	0.819	0.196	0.093	0.298	−0.175	0.568	−0.074	−0.037	0.698	−0.452	0.303
t, t-MA	0.010	0.022	0.768	−0.056	0.076	0.116	0.262	0.001	0.050	0.181	0.052	0.127	0.113	−0.012	0.117
BMA	−0.048	−0.098	0.180	−0.119	0.022	−0.010	−0.020	0.780	−0.078	0.059	−0.011	−0.025	0.749	−0.080	0.058

Association between 15 non-persistent environmental chemicals (bisphenols, parabens, PAHs, and other chemicals) and TSH, MDA, and 8-OHdG levels in Korean mothers’ 1st trimester urine using a multiple linear regression model. Multiple linear regression results are adjusted for maternal age, pre-pregnancy body mass index, education, income, residence area, parity, maternal cotinine level in urine. B, unstandardized coefficients; SE, standard error; ß, standardized error; CI, confidence interval; BPA, bisphenol A; BPF, bisphenol F; BPS, bisphenol S; MP, methylparaben; EP, ethylparaben; BP, butylparaben; PP, propylparaben; TCS, triclosan; BP-3, Benzophenon-3; t,t-MA, trans, trans-muconic acid; BMA, benzylmercapturic acid; 1-OHP, 1-hydroxypyrene; 2-NAP, 2-hydroxynaphthalene; 1-PHE, 1-hydroxyphennthrene; 2-FLU, 2-hydroxyfluorene. 8-OHdG, 8-hydroxy-2-deoxyguanisine, MDA, malondialdehyde. Bold values are statistically significant (p < 0.05).