Bisphenol A and its analogues in thyroid diseases: Evidence from dysfunction, autoimmunity, and cancer

Summary

Bisphenol A (BPA) and its analogues are widely used industrial chemicals in the production of polycarbonate plastics, epoxy resins, and related polymeric materials. Their extensive production and application have led to pervasive environmental contamination, enabling human exposure via ingestion, inhalation, and dermal absorption. As endocrine disruptors, BPA and its analogues (such as bisphenol S and bisphenol F) can influence thyroid homeostasis through interference with hormone synthesis, metabolism, and receptor signaling pathways. Recent studies suggest that exposure to bisphenols may contribute to thyroid dysfunction, autoimmune thyroid disease, and possibly thyroid carcinogenesis. Although some BPA alternatives appear to exert thyroid disrupting effects comparable to BPA, limited epidemiological evidence precludes a clear assessment of their relative safety. Given the ongoing rise in global bisphenol exposure, clarifying molecular mechanisms, defining susceptible subpopulations, and improving regulatory oversight are critical steps toward reducing thyroid-related health risks.

Graphical abstract

Health sciences; Medicine; Internal medicine; Endocrinology

Introduction

Thyroid diseases include a series of diseases affecting thyroid function, size and structure, mainly including thyroid dysfunction (hyperthyroidism, hypothyroidism, autoimmune thyroid diseases (AITD)), thyroid nodules, and thyroid cancer.^1,2 Epidemiological studies have shown that in recent decades, the prevalence of thyroid diseases has increased significantly in addition to hyperthyroidism.^3,4

Thyroid diseases develop through multifactorial regulation, underpinned by intricate pathophysiological mechanisms. Beyond common etiologies such as genetic susceptibility, environmental exposures, and chronic inflammation,^5,6,7 distinct thyroid disorders exhibit specific pathogenic pathways. Environmental and lifestyle factors, such as tobacco use, irregular iodine consumption, and psychological stress have been implicated in the pathogenesis of hyperthyroidism.⁸ Hypothyroidism is commonly linked to mutations in genes such as thyroid- hormone receptor (TSHR) and FOXE1, as well as factors like radioactive iodine therapy, pharmacological treatments, infections, or immunodeficiency.⁶ A hallmark of autoimmune thyroid disease is T cell-mediated infiltration, alongside dysregulated activation of feedback loops mediated by cytokines and chemokines.⁹ The pathogenesis of thyroid cancer involves mutations in key regulatory genes, including those in the ERK-MAPK and PI3K pathways, TERT promoter, TP53, and epigenetic alterations.⁷ The development of thyroid diseases is commonly accompanied by disturbances in hormonal homeostasis. Hypothyroidism is characterized by elevated thyroid-stimulating hormone (TSH) levels above the reference range, accompanied by reduced or normal free thyroxine (FT4) concentrations.¹⁰ Hyperthyroidism is characterized by suppressed serum TSH levels and elevated concentrations of thyroxine (T4), triiodothyronine (T3), or both. Subclinical hyperthyroidism is defined by low serum TSH levels in the presence of normal T4 and T3 concentrations.¹¹ AITD are characterized by the presence of specific autoantibodies, including thyroid peroxidase antibodies (TPOAb), thyroid-stimulating hormone receptor antibodies (TRAb), and thyroglobulin antibodies (TgAb), with some patients exhibiting hypo- or hyperthyroid manifestations.⁵ Elevated levels of TSH have been proposed as a potential hormonal marker in patients with thyroid cancer.¹² Additionally, an increased likelihood of elevated estrogen levels has been observed in both AITD and thyroid cancer, which may contribute to disease progression.¹³ The diagnosis of thyroid diseases primarily relies on serum biomarker assessment, supplemented by neck ultrasonography and fine-needle aspiration biopsy when indicated. Current therapeutic strategies for thyroid diseases mainly include pharmacological treatment, surgical intervention, and radioactive iodine therapy.^2,4 Presently, it is recognized that environmental exposures influence thyroid health, potentially inducing thyroid dysfunction and elevating the risk of thyroid cancer.^14,15,16 However, the mechanism of environmental factors affecting thyroid disease is still unclear.

Bisphenols (BPs) primarily comprise bisphenol A (BPA), bisphenol B (BPB), bisphenol C (BPC), bisphenol S (BPS), bisphenol F (BPF), and bisphenol AF (BPAF). This class of chemicals possesses endocrine-disrupting properties and is commonly used in the production of plastic containers, epoxy resins, food and beverage cans, water pipes, electronic equipment, thermal paper, kitchen appliances, toys, and dental sealants.¹⁷ The chemical structures of BPs resemble those of estrogens and thyroid hormones (Figure 1). Despite structural similarity in the bisphenol core, differences in substituents or bridging moieties among BPs lead to changes in physicochemical behavior and binding modes with target molecules, such as via hydrophobic forces or hydrogen bonds, ultimately affecting their disruptive potency and specificity.¹⁸BPs exert endocrine-disrupting effects through interactions with various targets, including the estrogen receptor (ER)and TH receptor (TR), consequently interfering with hormone synthesis, secretion, release, and transport.^19,20 Estrogenic activity of BPA analogs requires at least one 4-hydroxyl moiety, and a second phenyl group at the 2-position of the central propane structure is also critical.²¹ In addition, BPs induce oxidative stress, mitochondrial dysfunction, and epigenetic alterations,^22,23,24,25 which pose health risks to multiple organ systems, including the reproductive, endocrine, and nervous systems, as well as metabolic, immune, developmental, and oncogenic processes.²⁶ Of particular concern is that BPA has been shown to disrupt the hypothalamic pituitary thyroid (HPT) axis, affecting TH biosynthesis, release, plasma protein binding, metabolism, and signal transduction, leading to thyroid dysfunction.²⁷ Therefore, it is very important to clarify the specific mechanism of these compounds affecting thyroid diseases for improving disease prevention, diagnosis and treatment.

Figure 1.

Chemical structures of estrogen, thyroid hormones, and bisphenols

Structural similarities among endogenous estrogen (E2), thyroid hormones (T3 and T4), and major bisphenols (BPA, BPF, BPS, BPB, BPAF, and BPC) are shown, highlighting their shared phenolic frameworks that underlie their endocrine-disrupting potential. Abbreviation: BPA = bisphenol A, BPAF = bisphenol AF, BPB = bisphenol B, BPC = bisphenol C, BPS = bisphenol S, BPF = bisphenol F, T3 = triiodothyronine, T4 = thyroxine.

BPs

BPs such as BPA, BPS, and BPF have been widely detected across multiple environmental matrices on a global scale, including aquatic systems, sediments, sewage, and indoor dust. Human exposure to these substances occurs primarily through dietary intake, dermal contact, and inhalation, with biomonitoring data confirming widespread exposure across the general population. These compounds are capable of accumulating in the human body and may exert long term biological effects even after initial exposure. Among them, BPA exhibits pronounced bioaccumulation, whereas certain analogues, such as BPF, preferentially accumulate in specific tissues, including the liver, adipose tissue, and kidneys.^28,29

BPA

BPA (2,2-bis-(4-hydroxyphenyl)propane) is a widely used synthetic organic compound, which is the primary raw material for the production of polycarbonate plastics and epoxy resin. It is commonly found in products including food cans, dental sealants, and the inner coatings of plastic bottles.¹⁷ Human exposure to BPA occurs primarily through dietary routes (via food and food contact materials) and non-dietary pathways (airborne, dust, skin contact, soil, etc.). Dietary exposure constitutes the primary source. BPA can migrate from food-packaging materials or containers into food and drinking water, subsequently entering the human body.²⁷ Once ingested, BPA is primarily metabolized in the liver through glucuronidation, after which it enters the bloodstream and is excreted in urine. Due to its widespread use, BPA has been detected in blood, urine, breast milk, and other human tissues and body fluids.²⁶ It can influence fetal growth and development by crossing the placental barrier.³⁰ BPA exposure is linked to an increased risk of several hormone related cancers, including breast, prostate, and colorectal cancers.^31,32,33,34 In addition, BPA is associated with a variety of non-neoplastic diseases, including polycystic ovary syndrome, hepatic injury, colitis, renal impairment, and cardiotoxicity.^35,36,37,38 As the European Union has issued regulations prohibiting or restricting BPA on numerous occasions, a significant number of BPA analogs have emerged.

BPF and BPS

BPF (4,4′-dihydroxydiphenylmethane) and BPS (bis-(4-hydroxyphenyl)sulphone) are presently the most prevalent substitutes for BPA.³⁹ BPF is usually used to manufacture rigid polycarbonate plastics for household appliances and vehicle parts, beverage can linings, dental sealants and protective coatings for floors, roads, and water tanks. BPS is primarily utilized in the production of polycarbonate and epoxy resin, thermal paper (including receipts), food containers, and various consumer products labeled as “BPA Free”.⁴⁰ Urinary concentrations and detection frequencies of BPS and BPF have been reported to be comparable to those of BPA.⁴¹ Studies indicate that BPS and BPF are widely present in the environment, and their concentrations in humans have shown a gradual upward trend over time.⁴² Both compounds exhibit hormone like activities similar to BPA, which can disrupt endocrine function and cause multiple system damage.⁴³ Exposure to BPS is linked to infertility, colon damage, depression, and colorectal cancer.^37,44,45,46 And BPF has been shown to contribute to obesity, infertility, breast cancer, lung injury, and various other diseases.^47,48,49,50

BPB and BPAF

BPB (2,2-bis-(4-hydroxyphenyl)butane) and BPAF (1,3-trifluoro-2,2-bis-(4-hydroxyphenyl)propane) have similar structure to BPA. The U.S. Food and Drug Administration (FDA) has approved BPB as an indirect food additive for food contact resins and polymer coatings.⁵¹ BPAF is widely employed as a cross-linking agent.⁵² BPB and BPAF have been detected in multiple environmental matrices, including food, municipal wastewater, surface water, and indoor dust. In some environmental and biological samples, their concentrations are significantly higher than those of BPA.⁵³ Furthermore, studies have demonstrated that BPB and BPAF exert stronger anti-estrogenic effects than BPA through activation of the G protein-coupled estrogen receptor (GPER) pathway.⁵⁴ GPER activation influences the TSH signaling pathway, which directly impacts thyroid function by modulating the synthesis and secretion of thyroid hormones. GPER activation also plays a role in the development of papillary thyroid carcinoma (PTC).⁵⁵The potential endocrine disrupting effects of BPB and BPAF elevate the risk of ovarian disease, uterine lesions, and breast cancer.^53,56,57

BPC

BPC (4-[2,2-dichloro-1-(4-hydroxyphenyl)ethenyl]phenol) is an industrial compound used in the synthesis of polycarbonate and other polyester polymers and commonly utilized in the production of water bottles, food packaging materials, textiles, and various other consumer products.⁵⁸ Recent studies have detected BPC in a range of environmental and biological matrices, including wastewater (up to 2560 ng/L), bottled drinking water (up to 9.1 ng/L), children’s urine (up to 186 ng/L), and maternal serum (16.6 ng/L), suggesting that human exposure to BPC may pose potential health risks.⁵⁹ In vitro and in vivo research further indicates that BPC exposure induces oxidative stress and lipid accumulation, leading to spinal deformities, genital abnormalities, and developmental defects in organs such as the heart, liver, and intestines.^58,59,60,61

BPs and the thyroid

BPs have been increasingly implicated in the occurrence and progression of thyroid diseases. Accumulating evidence indicates that BPs not only disrupt TH homeostasis and impair normal thyroid function, but may also contribute to the initiation and progression of thyroid cancer.^62,63,64 Accordingly, this review integrates epidemiological evidence from the past decade (Table 1) with mechanistic studies (Table 2) to systematically elucidate the molecular pathways through which different bisphenol analogues interfere with thyroid function and promote thyroid carcinogenesis. Importantly, BPA alternatives have not demonstrated improved safety profiles, and several analogues exhibit even stronger thyroid disrupting activities. In terms of estrogenic potency, bisphenol compounds follow the order BPC > BPAF > BPB > BPA > BPF > BPS.⁶⁵ Regarding TR binding, the affinity for the ligand-binding domain (LBD) of TRβ follows the order BPB > BPF ≥ BPS > BPAF ≥ BPA, whereas for TRα-LBD the order is BPB > BPS ≥ BPF > BPAF ≥ BPA. Most analogues, including BPA, BPB, BPS, and BPAF, display higher affinity for TRα-LBD than for TRβ-LBD, while BPF exhibits the opposite binding preference.¹⁸ Structural analyses further reveal that the strong interactions between BPB, BPF, and BPS and TR-LBD are predominantly mediated by hydrophobic forces, whereas electrostatic interactions significantly contribute to the binding of BPS and BPAF to TRα-LBD. In addition, van der Waals forces and hydrogen bonding play critical roles in the interaction of BPA and BPF with TRβ-LBD.¹⁸ Notably, the binding affinities of these bisphenol analogues to TR-LBD are generally higher than that of the endogenous ligand T3, suggesting their ability to competitively alter receptor conformation and signaling.¹⁸ Collectively, these structural and binding characteristics provide a mechanistic basis for the heterogeneous thyroid-disrupting effects observed among different bisphenol compounds.

Table 1.

Epidemiological studies on BPs exposure and thyroid diseases

Participants	Country	Research type	BPs detection method	BPs concentration	Main Outcomes	Reference
N = 2340 adults	Thailand	cross-sectional analysis	ELISA	•serum BPA = median of 0.33 ng/mL	•BPA was negatively correlated with FT4 in males	Sriphrapradang et al.66
N = 106 thyroid nodules patients and 106 controls	Cyprus, Romania	case-control study	GC-MS/MS	•urinary BPA = medians of 2710 ng/L (controls), and 1751 ng/L (cases) •urinary BPF levels were comparable in cases and controls	•BPA was positively correlated with TSH •BPF was not significantly correlated with TSH	Andrianou et al.67
N = 718 students	China	cross-sectional analysis	UPLC-MS/MS	•urinary BPA = medians of 2.64 μg/g Cr (boys), and 2.35 μg/g Cr (girls)	•BPA was negatively correlated with multinodular thyroid disease	Wang et al.68
N = 2361 participants	Thailand	cross-sectional analysis	ELISA	•serum BPA = median of 0.32 ng/mL	•BPA was correlated with TPOAb positivity	Chailurkit et al.69
N = 116 preterm birth cases and 323 controls.	USA	case-control study	ID-LC-MS/MS	•urinary BPA = 1.33 μg/L(GM, 9.64 weeks) •urinary BPA = 1.04 μg/L (GM, 17.9 weeks) •urinary BPA = 1.22 μg/L (GM, 26 weeks) •urinary BPA = 1.12 μg/L (GM, 35.1 weeks)	•BPA was negatively correlated with TSH and positively correlated with FT4.	Aung et al.70
N = 6003 adults	Korea	cross-sectional analysis	UPLC-APCI-MS/MS	•urinary BPA = 1.126 μg/L(GM)	•BPA was negatively correlated with TSH	Park et al.71
N = 53 PTC patients, 60 NG patients, and 65 healthy volunteers	China	cross-sectional study	HPLC–MS/MS	•urinary BPA = 2.82 μg/g Cr (overall, GM), 4.68 μg/g Cr (PTC group, GM), 5.22 μg/g Cr (NG group, GM), and 1.06 μg/g Cr (healthy control group, GM)	•BPA and iodine were higher in the NG and PTC groups than in the control group	Zhou et al.72
N = 1560 adults	USA	cross-sectional analysis	GC-MS	•serum BPA = 2.19 ng/mL(GM, males), 2.00 ng/mL(GM, females)	•BPA was negatively correlated with TT4 in males and positively correlated with T3 in females	Przybyla et al.73
N = 602 pregnant women	Puerto Rico	prospective cohort study	ID-LC-MS/MS	•urinary BPA = 2.31 μg/L(GM, 16–20 weeks), 1.88 μg/L(GM, 24–28 weeks) •urinary BPS = 0.54 μg/L(GM, 16–20 weeks, 24–28 weeks) •urinary BPF = 0.35 μg/L(GM, 16–20 weeks), 0.31 μg/L(GM, 24–28 weeks)	•BPA was positively correlated with FT4 and T3 •BPS was negatively correlated with TSH •BPF was positively correlated with FT4	Aker et al.74
N = 1996 pregnant women	Swedish	prospective cohort study	LC-MS/MS	•urinary BPA = median of 1.51 ng/mL •urinary BPF = median of 0.15 ng/mL	•BPA was positively correlated with FT3 and negatively correlated with FT4/FT3 and TT4/TT3 ratios in early(mean 7 weeks) pregnancy •BPF was positively correlated with FT3	Derakhshan et al.75
N = 705 thyroid nodules patients and 711 controls	China	case-control study	HPLC-MS/MS	•urinary BPA = median of 1.35 μg/L (total), median of 1.25 μg/L (control), and median of 1.45 μg/L (case)	•BPA was positively correlated with the risk of thyroid nodules in patients with positive TgAb and TPOAb	Li et al.76
N = 386 mother-child pairs	China	prospective cohort study	GC-MS/MS	•urinary BPA = median of 1.75 μg/L (maternal), median of 1.29 μg/L (childhood)	•BPA was positively correlated with FT4 in cord serum	Guo et al.77
N = 5108 adults	Korea	cross-sectional analysis	UPLC-MS/MS	•urinary BPA = 1.48 μg/g Cr(GM)	•BPA was negatively correlated with T3 and T4 •BPA was not correlated with TSH	Kwon et al.78
N = 180 participants	Poland	cross-sectional study	HPLC-MS/MS	•urinary BPC = 0.016(0.048)ng/mL(mean(SD))	•BPC was positively correlated with TSH •BPC was negatively correlated with thyroid volume	Milczarek-Banach et al.79
N = 345 children	China	cross-sectional study	HPLC-MS/MS	•serum BPA = 1.6 ng/mL(GM) •serum BPF = 0.08 ng/mL(GM) •serum BPS = 0.04 ng/mL(GM)	•BPA was higher in hyperthyroid children than in euthyroid children •BPA was negatively correlated with TSH in euthyroid children and positively correlated with TSH in hyperthyroid children.	Guo et al.80
N = 574 children	Korea	prospective cohort study	HPLC-MS/MS	•urinary BPF = median of 0.05 μg/L (Total), median of 0.05 μg/L (Boys), median of 0.05 μg/L (Girls) •urinary BPS = median of 0.01 μg/L	•BPF was negatively correlated with FT4 in girls •BPS was not correlated with TH	Jang et al.81
N = 1267 mothers, 853 newborns, and 882 children	Netherlands	prospective cohort study	HPLC-ESI-MS/MS	•urinary BPA = 1.61 ng/mL (median, early pregnancy (<18 weeks)), 1.47 ng/mL (median, middle pregnancy (18–25 weeks)), 1.65 ng/mL (median, late pregnancy (>25 weeks)) •urinary BPS = 0.34 ng/mL (median, early pregnancy (<18 weeks)), 0.24 ng/mL (median, middle pregnancy (18–25 weeks))	•BPA(late pregnancy) was positively correlated with TSH in female newborns and FT4 in boys •BPS was positively correlated with maternal TT4 and was associated with a reduced association between maternal FT4 and TSH.	Derakhshan et al.82
N = 446 pregnant women	China	prospective cohort study	UHPLC-MS/MS	•serum BPF = 0.606 ng/mL(median) •serum BPB = 0.234 ng/mL(median) •serum BPS = 0.097 ng/mL(median)	•BPF was positively correlated with T4, FT4, and TSH in the first trimester, but was negatively correlated with TSH in the second trimester •BPS was negatively correlated with T3 in the first trimester •BPB was negatively correlated with T4 and FT4 in the first trimester	Huang et al.83
N = 162 pregnant women	China	cross-sectional study	UHPLC-MS/MS	•urinary BPA = 1.30 ng/mL(median) •urinary BPB = 0.10 ng/mL(median) •urinary BPC = 1.24 ng/mL(median) •urinary BPF = 0.13 ng/mL(median) •urinary BPS = 0.11 ng/mL(median) •urinary BPAF = 0.26 ng/mL(median)	•BPB and BPC were positively correlated with TT3 •BPS was negatively correlated with TT3 •BPF and BPB, BPC and BPAF showed synergistic effects on thyroid autoantibody positivity •BPs and iodine deficiency synergistically increased susceptibility to thyroid autoimmunity	Lu et al.84
N = 143 TC patients and 224 controls	China	case-control study	UHPLC	•urinary BPA = median of 1.25 μg/L(control), median of 1.04 μg/L(malignancy) •urinary BPS = median of 0.67 μg/L(control), median of 0.83 μg/L(malignancy)	•BPA and BPS were positively correlated with the risk of TC	Chen et al.85
N = 258 mother-child pairs	China	prospective cohort study	HPLC-MS/MS	•urinary BPA = 0.66 μg/L (median) •urinary BPS = 0.003 μg/L (median) •urinary BPAF = 0.024 μg/L (median)	•BPA was negatively correlated with TT4/FT4 in cord blood •BPS was negatively correlated with TSH in boys •BPAF was positively correlated with TT3/FT3 in cord blood;	Xi et al.86
N = 904 mother-newborn pairs	China	prospective cohort study	UHPLC	•SG-adjusted urinary BPA = 1.42 μg/L(median, first trimester), 1.29 μg/L(median, second trimester), 1.24 μg/L(median, third trimester) •SG-adjusted urinary BPS = 0.39 μg/L(median, first trimester), 0.37 μg/L(median, second trimester), 0.40 μg/L(median, third trimester)	•BPA and BPS(maternal) were positively correlated with neonatal TSH	Xiong et al.87
N = 177 adults	China	cross-sectional study	UPLC-MS/MS	•urinary BPF = median of 0.03 μg/g Cr	•BPF was negatively correlated with TT3, TT4, FT3, FT4, and positively correlated with TT3/TT4 ratio	Yue et al.88
N = 111 PTC patients and 111 healthy controls	China	case-control study	UPLC-MS/MS	•urinary BPA = 0.15 μg/L (GM,PTC patients), 0.36 μg/L (GM,healthy controls) •urinary BPS = 0.02 μg/L (GM,PTC patients), 0.07 μg/L (GM,healthy controls) •urinary BPF = 0.05 μg/L (GM,PTC patients), 0.02 μg/L (GM,healthy controls)	•BPF was positively correlated with PTC •BPA and BPS were negatively correlated with PTC	Zhang et al.89
N = euthyroid group (n = 60) and AITD group (n = 95)	China	cross-sectional study	ELISA	•urinary BPA = 1.13 μg/L Cr(median, euthyroid group), 1.73 μg/L Cr(median, AITD group)	•BPA was not correlated with AITD.	Yuan et al.90

Differences in exposure assessment methods, concentration units, statistical indicators, and outcome definitions across studies complicate direct comparisons of findings. In addition, substantial variation in sample size exists among studies, with large-scale and prospective investigations generally considered to provide more robust and reliable evidence. However, epidemiological data for certain bisphenol analogues, such as BPC, remain limited, and conclusions regarding their health effects should therefore be interpreted with caution.

Divergent and even contradictory findings have been reported regarding the associations between BPs and TSH and related indicators. These inconsistencies are mainly attributable to multiple factors, including iodine nutritional status, differences in exposure assessment methods, non-monotonic dose-response relationships, population heterogeneity, exposure time windows, sex-specific effects, variations in thyroid regulatory stages, and disease subtypes.

BPA = bisphenol A, BPB = bisphenol B, BPC = bisphenol C, BPS = bisphenol S, BPF = bisphenol F, BPAF = bisphenol AF, Cr = creatinine, GM = geometric mean, SD = standard deviation, TC = thyroid cancer, PTC = papillary thyroid carcinoma, NG = nodular goiter, TgAb = thyroglobulin antibody, TPOAb = thyroid peroxidase antibody, HT = Hashimoto’s thyroiditis, TH = thyroid hormone, AITD = autoimmune thyroid diseases, FT3 = free triiodothyronine, FT4 = free thyroxine, TSH = thyroid stimulating hormone, TT3 = total triiodothyronine TT4 = total thyroxine, T3 = triiodothyronine, T4 = thyroxine, ELISA = enzyme-linked immunosorbent assay, GC-MS = gas chromatography–mass spectrometry, GC-MS/MS = gas chromatography-tandem mass spectrometry, UPLC-MS/MS = ultra performance liquid chromatography-tandem mass spectrometry, ID-LC-MS/MS = isotope dilution liquid chromatography–tandem mass spectrometry, APCI = atmospheric pressure chemical ionization, HPLC-MS/MS = high-performance liquid chromatography-tandem mass spectrometry, LC-MS/MS = liquid chromatography-tandem mass spectrometry, HPLC-ESI-MS/MS = high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry, UHPLC-MS/MS = ultra high-performance liquid chromatography-tandem mass spectrometry.

Table 2.

Animal model studies on BP exposure and thyroid diseases

Exposed model	BPs	Dose	Experimental Cycle	Main Results	Reference
Zebrafish larvae	BPAF	•0, 5, 50, and 500 μg/L/day	168 h	•decreased TT3, TT4, FT3, and FT4 contents •increase the expression of TSHβ, DIO1, DIO2, Tg, and TTR(50 μg/L BPAF) •reduce the expression of NIS and TTR(50 μg/L and 500 μg/L BPAF) •reduce the expression of TRα and TRβ	Tang et al.91
Pregnant Wistar rats and their fetuses	BPA	•20 and 40 μg/kg BW/day	GD 1 to GD 20	•deceased T4 and T3 levels in serum •increased TSH levels in serum •maternal BPA induced fetal thyroid dysgenesis and thyroid-adipokine dysfunction.	Ahmed92
Zebrafish larvae	BPF	•0.2, 2, 20, and 200 μg/L/day	6 days	•decreased T4 contents •increased T3 contents •increase the expression of NIS, DIO2, and Tg •reduce the expression of TTR	Huang et al.93
Zebrafish larvae	BPS	•0, 1, 3, 10, and 30 μg/L/day	2 hpf to 168 hpf	•decreased T4 and T3 levels •increase the expression of Tg, Pax8, NIS, DIO1, DIO2, and UGT1ab (10 μg/L and 30 μg/L BPS) •reduce the expression of TTR	Zhang et al.94
Female F344 rats	BPA	•2800 mg DHPN/kg/day (pretreatment, DA group), •250 or 1000 μg BPA/kg/day, •1000 μg KI/L/day	1 week(DHPN), 64 weeks(BPA and KI)	•the highest incidence of TC was 50% (BPA250 + KI DA groups) •thyroid hyperplasia lesions reached 100% incidence (BPA1000 + KI DA groups)	Zhang et al.95
Adult zebrafish	BPA, BPS	•0, 50 or 100 μg/L/day	72 h	•increase the expression of NIS and reduce the expression of TPO(BPA) •increase the expression of NIS, Tg, and TPO(BPS)	Berto-Júnior et al.96
Wistar female rats and rat thyroid cells (PCCL3)	BPA	•40 mg BPA/kg BW/day •PCCL3 with 10−9 mol/L BPA	15 days(rats), 24 h(PCCL3)	•reduce iodide uptake and TPO activity •increased thyroid calcium-dependent H2O2 •reduce the expression of NIS •increase the expression of DUOX2	Da Silva et al.97
Zebrafish and the offspring	BPS	•1, 10, and 100 μg/L/day	2 hpf to 120 dpf	•decreased T4 and increased T3 •induced thyroid endocrine disruption	Wei et al.98
Male Wistar rats	BPA	•40 mg/kg BW/day	15 days	•inhibit liver DIO1 but not brown adipose tissue DIO2 activity	Da Silva et al.99
Zebrafish larval	BPA, BPF BPS	•0.08, 0.4, 2, and 10 mg BPA/L/day •0.08, 0.4, 2, and 10 mg BPF/L/day •0.4, 2, 10, and 50 mg BPS/L/day	<4 hpf to 120 hpf	•increased T3 and/or T4; •increase the expression of Tg, Hhex, TPO, TTR, and UGT1ab	Lee et al.100
Male Albino rats	BPA	•200 mg/kg BW/day	35 days	•reduce iodide uptake, GSH, and SOD activity •increase MDA contents, MPO activity •decreased serum T3 and T4 •increased serum TSH •reduce the expression of NIS, TPO, and TSHR	Mohammed et al.101
Zebrafish larvae	BPB	•0, 1, 10, 100, and 1000 μg/L/day	2 hpf to 144 hpf	•decreased T4 and increased T3 •increase the expression of Tg, TRHR, DIO1, DIO2, TRα, and TRβ •reduce the expression of TSH, TTR, and TRH	Yang et al.102
Zebrafish	BPAF	•12.5 and 125 μg/L/day	6 hpf to 7 dpf	•decreased THs, TR, and DIO •increase expressions of TTR	Chen et al.103
Female SD rats, Human thyroid cancer cell(BCPAP) and human thyroid follicular epithelial cell(Nthy-ori3–1)	BPA	•20 mg/kg BW/day(rats) •10−8 to 10−4 mol/L(BCPAP) •10−6–10−7 mol/L(Nthy-ori3-1)	30 weeks(rats), 24–48 h (BCPAP, Nthy-ori3-1)	•enhance thyroid tumor susceptibility via an HDAC6/PTEN/c-MYC pathway(rats) •stimulate HDAC6-dependent proliferation by inhibiting PTEN (via H3K9ac) and activating AKT and c-MYC(BCPAP) •induce proliferation through an HDAC6-independent mechanism involving ERK pathway activation(Nthy-ori3-1)	Zhang et al.104
Male C57BL/6 mice	BPA BPS	•0.002, 0.02, 2, and 20 mg/kg BW/day(respectively)	5 weeks	•increased serum TSH levels(20 mg/kg BW/d BPS) •reduce the expression of TSHR, TRβ, TPO, Tg, and NIS •increase the expression of TRHR and TSH	Hu et al.105
Male Wistar albino rats	BPS	•20, 100, and 500 mg/kg BW/day	28 days	•elevate the TFC proliferation index •increased the antioxidant enzyme activities such as CAT, SOD, GST, GPx •decreased content of GSH •decreased serum FT3	Bostancı et al.106

BPA = bisphenol A, BPB = bisphenol B, BPS = bisphenol S, BPF = bisphenol F, BPAF = bisphenol AF,GD = gestation day, hpf = hour postfertilization, KI = potassium iodine, DHPN = N-Bis (2-hydroxypropyl) nitrosamine, dpf = days post-fertilization, BW = body weight, CAT = catalase, SOD = superoxide dismutase, GST = glutathione-S-transferase, GPx = glutathione peroxidase, GSH = reduced glutathione, MDA =, MPO =, TC = thyroid cancer, FT3 = free triiodothyronine, FT4 = free thyroxine, TSH = thyroid stimulating hormone, TH = thyroid hormone, TT3 = total triiodothyronine, TT4 = total thyroxine, T3 = triiodothyronine, T4 = thyroxine, DIO = deiodinase, TTR = thyroxine-binding preprotein, NIS = sodium/iodide symporter, TR = thyroid hormone receptor, TSHR = thyroid stimulating hormone receptor, TRHR = thyroid-releasing hormone receptor, Tg = thyroglobulin, DUOX = dioxygenase, TPO = thyroid peroxidase, UGT = uridine diphosphate glucuronosyltransferase, Pax8 = paired box gene 8, TFC = thyroid follicular cell, Hhex = homeobox transcription factor.

BPs and thyroid disease

BPs and thyroid dysfunction

Thyroid dysfunction, as one of the most prevalent endocrine abnormalities, has become a significant public health concern. This condition primarily encompasses clinical and subclinical hyperthyroidism and hypothyroidism¹⁰⁷ and is associated with dysregulation of the HPT axis.

The HPT axis is a key endocrine pathway regulating metabolism, thermogenesis, growth, development, and central nervous system maturation, primarily through TH signaling. Regulation of the HPT axis commences with the hypothalamus secreting thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to synthesize and release TSH. TSH subsequently acts upon the thyroid gland, promoting the synthesis and secretion of T3 and T4. Circulating T3 and T4 then exert negative feedback inhibition on the release of hypothalamic TRH and pituitary TSH, thereby maintaining endocrine homeostasis.¹⁰⁸ Thyroxine-binding globulin (TBG) is the primary plasma-bound TH-binding and carrier protein. The majority (70%) of circulating T4 and T3 exhibit high-affinity binding to TBG, while a minor fraction binds with low affinity to thyroxine-binding preprotein (TTR) (10%–15%) and human serum albumin (10%–15%).¹⁰⁹ Thyroid follicular cells synthesize the glycoprotein Tg and capture iodide required for TH biosynthesis via the sodium/iodide symporter (NIS). Tg provides tyrosine residues, which are iodinated by thyroid peroxidase (TPO) to form iodotyrosine, a reaction dependent on H₂O₂ produced by dioxygenase (DUOX, NADPH oxidase). Thyroid transcription factor 1 (NKX2.1) and paired box gene 8 (Pax8) synergistically activate the transcription of Tg, NIS, and TPO.¹¹⁰ Furthermore, the regulation of TH activity relies on deiodinases in peripheral tissues. Although T4 possesses certain physiological functions, it is primarily regarded as a prohormone. Its active form, T3, is mainly generated by the catalytic removal of an iodine atom from the outer ring of T4 via deiodinase (DIO). This process serves as a crucial mechanism for regulating local TH levels.¹¹¹ Increasing evidence indicates that bisphenol compounds may interfere with regulatory processes, potentially resulting in thyroid dysfunction.

BPA and thyroid dysfunction

Epidemiological studies have extensively explored the association between BPA and thyroid dysfunction. Although substantial evidence exists, the outcomes remain complex and often inconsistent. Most cross-sectional studies have reported statistically significant associations between BPA exposure and TH levels.¹¹² Data from the 2007–2008 National Health and Nutrition Examination Survey in the United States indicated that urinary BPA concentrations were negatively correlated with total thyroxine (TT4) levels.⁷³ In the Korean National Environmental Health Survey conducted from 2012 to 2014, urinary BPA concentrations were negatively associated with TSH levels.⁷⁸ Similarly, the 2009 National Health Examination Survey in Thailand reported that serum BPA concentrations in men were negatively correlated with FT4 levels.⁶⁶ Smaller studies also indicated an association between BPA and TSH.^67,70,113 In adult males and females, urinary BPA levels were negatively correlated with TSH.⁷¹ Among pregnant women, urinary BPA levels were positively correlated with FT4 and T3,⁷⁴ whereas they were negatively correlated with TSH.⁷⁰ Additionally, another study found that elevated urinary BPA levels were associated with reduced TT4 levels, and BPA exposure exhibited a time-dependent effect. At the start of pregnancy (7 weeks), they observed a positive correlation between BPA and free triiodothyronine (FT3), which disappeared by 12 weeks of gestation.⁷⁵ Serum bisphenol A concentrations were greater in hyperthyroidism than in healthy children. Furthermore, BPA levels were positively associated with TSH levels in hyperthyroid children but negatively associated with TSH levels in healthy children.⁸⁰ These results suggest that the effects of BPA on thyroid function may be modulated by factors such as age, gender, and pregnancy status. Given thyroid hormones’ critical role in fetal neurodevelopment, maternal BPA exposure carries greater clinical significance than general population exposure.

There is also an association between maternal BPA exposure during pregnancy and offspring thyroid function. Maternal exposure to BPA was positively correlated with neonatal TSH levels.⁸⁷ In contrast, gestational BPA exposure was associated with reduced TT4 and FT3 in umbilical cord blood,⁸⁶ Maternal urinary BPA levels were linked to increased FT4 levels in umbilical cord serum, and no association between BPA and TSH,⁷⁷ another study found that this association varied by gestational timing and sex, with higher maternal urinary BPA levels in late pregnancy linked to higher TSH in female neonates and higher FT4 in male children during childhood. However, no association was observed between BPA exposure in the first or second trimester and cord blood or childhood TSH and FT4 levels.⁸² Nevertheless, some studies failed to detect a significant association between BPA exposure and neonatal umbilical cord TH levels,¹¹⁴ and considerable heterogeneity in the direction and magnitude of this association across populations was observed.

To supplement the limitations of human epidemiological studies, several animal experiments have been conducted. Research has found that BPA exposure in adult rats (40 mg/kg, 15 days, and gavage) increases T4 levels.⁹⁹ Neonatal exposure to BPA (2.5–6.2 mg/kg, subcutaneous injection for 10 days) reduced adult T4 levels and increased TSH levels.¹¹⁵ Another study found no baseline alterations in T4 or TSH stimulation in offspring of mothers exposed to BPA during gestation and lactation.¹¹⁶ Maternal rat exposure to BPA alters offspring TH levels. Oral administration of BPA (20 or 40 μg/kg body weight) to pregnant rats from gestational days (GD) 1–20 resulted in lower serum T4 and T3 levels in both maternal rats and fetuses compared to controls, and TSH levels were elevated compared with controls at GD20.⁹² In the zebrafish model, larvae exposed to BPA (0.08–10 mg/L) resulted in elevated T3 levels.¹⁰⁰ These findings indicate that BPA may disrupt thyroid function, with specific effects varying by exposure route, dose, duration, and developmental stage (Table 2).

The process by which BPA impairs thyroid function is complex, involving several steps from hormone synthesis to the ultimate effect (Figure 2). BPA modulates the expression of genes involved in TH production. In zebrafish and rat models, BPA reduces NIS expression in thyroid cell lines (FRTL-5 and PCCL3), and impairs iodide uptake and TPO activity.^96,117 These effects may be associated with BPA induced upregulation of DUOX2. DUOX2 is an enzyme involved in calcium-dependent hydrogen peroxide (H₂O₂) generation in the thyroid gland, suggesting that BPA enhances thyroidal oxidative stress. However, when cells were co-treated with BPA and the antioxidant N-acetylcysteine (NAC), suppression of NIS and TPO expression was not observed,⁹⁷ suggesting that oxidative stress plays a critical role in downregulating NIS and TPO. BPA also suppresses the expression of TSHβ, TR, and DIO2 in pituitary GH3 cells, thereby disrupting central regulatory pathways.¹¹⁸ It may also impede TH absorption by suppressing the monocarboxylate transporter 8 (MCT8) in the brain,¹¹⁹ thereby impairing normal feedback regulation of the HPT axis.

Figure 2.

BPA interferes with thyroid function via various mechanisms

BPA inhibits the expression of TSHβ, TR, MCT8, and DIO2 in pituitary GH3 cells. Additionally, BPA upregulates DUOX2 synthesis in thyroid cells, leading to increased H2O2 production, which subsequently inhibits the activity of NIS and TPO. BPA also demonstrates differential effects on thyroid hormone metabolism in rats and zebrafish. Furthermore, BPA inhibits the T3/T4-induced β3-integrin/c-Src/MAPK pathway, which impedes TRβ1 phosphorylation and its release from co-repressors. (By Figdraw). Abbreviation: BPA = bisphenol A, TPO = thyroid peroxidase, DUOX = dioxygenase, NIS = sodium/iodide symporter, DIO = deiodinase, UGT = uridine diphosphate glucuronosyltransferase, MCT = monocarboxylate transporter, TSH = thyroid-stimulating hormone, TR = thyroid hormone receptor, SMRT = silencing mediator for retinoid and thyroid hormone receptors, N-CoR = nuclear receptor co-repressor, MAPK = mitogen-activated protein kinase, c-Src = c-steroid receptor coactivator, T3 = triiodothyronine, T4 = thyroxine.

Regarding the transport of thyroid hormones in the circulatory system, these hormones are bound to proteins, including TBG and TTR. Nonetheless, BPA demonstrates a limited affinity for the TH transport proteins TTR and TBG. At concentrations pertinent to the human environment, it may be inadequate to disrupt hormone transport.¹²⁰ BPA metabolically reduces DIO1 activity in rat liver, impacting the peripheral conversion of T4 to T3, while simultaneously inducing DIO1 and uridine diphosphate glucuronosyltransferase (UGT1ab) gene expression in zebrafish.^99,100 In zebrafish, UGTs catalyze the glucuronidation of T4 and T3, enhancing water solubility and promoting their efflux.¹²¹

In disrupting TH signaling pathways, BPA acts as an antagonist for TRα1 and TRβ1 due to its structural similarity to T3. It recruits the corepressor (NCoR) to TRs and increases the activity of the TSHα subunit promoter in gene reporter assays, thereby inhibiting T3-mediated gene transcription.¹²² Beyond disrupting typical TH actions, BPA inhibits TH receptor transcription via non-genomic mechanisms. In immunoprecipitation assays, BPA was shown to abrogate T3-or T4-induced activation of the β3-integrin pathway. BPA’s inhibition of β3-integrin/c-Src/MAPK signaling also impacts TH’s typical actions, as this pathway leads to TRβ1 phosphorylation and dissociation from nuclear receptor co-repressor (N-CoR) and silencing mediator for retinoid and TH receptors (SMRT), both of which are impaired by BPA.¹²³ It is thought that BPA’s TR antagonism may represent its primary mechanism for disrupting thyroid function.

BPA analogues and thyroid dysfunction

With restrictions on BPA use in certain products, exposure to its substitutes (such as BPF, BPS, and BPC) has become increasingly prevalent. Nonetheless, the epidemiological evidence concerning the thyrotoxicity of these analogues is still in its early stages, and the conclusions drawn from research are inconsistent.¹²⁴ Current epidemiological studies indicate that BPA analogues may be associated with changes in TH levels, although the results are inconsistent and complex. In population studies, an analysis investigating the relationships between urinary mixtures of various endocrine disruptors and thyroid hormones revealed that higher levels of BPF were associated with lower total triiodothyronine (TT3), TT4, FT3, and FT4 levels, as well as an increased TT3/TT4 ratio.⁸⁸ Research on women of reproductive age found a negative correlation between urinary BPC levels and thyroid volume, and a positive correlation with TSH. This suggests that exposure to BPC may lead to hypothyroidism, which could have detrimental effects on pregnancy and offspring.⁷⁹

Research among pregnant women reveals more intricate findings. Studies indicate that elevated BPF levels correlate with higher FT4. At the same time, BPS is associated with reduced TSH, with this association being stronger during weeks 16–20 of gestation,⁷⁴ another study found elevated BPF levels correlated with higher FT3, but BPS showed no significant association with serum TH levels,⁷⁵ regarding the overall effects of exposure during pregnancy, studies indicate that BPS may reduce maternal T3 levels, BPB may decrease T4 and FT4 levels in early pregnancy, while BPF may increase T4 and FT4 levels in mid-pregnancy. It also exerts phasic effects on TSH, elevating TSH in early pregnancy and reducing it in mid-pregnancy.⁸³ Furthermore, exposure to BPB or BPC increases TT3 levels, whereas exposure to BPS reduces TT3 levels. Notably, TH levels in male fetuses appear more sensitive to bisphenols, with BPB and BPS associations with FT3 being significant only in male fetuses.⁸⁴ In another prospective birth cohort, elevated BPS concentrations correlated with higher maternal TT4 but showed no association with TSH or FT4.⁸² Regarding the impact of prenatal exposure on neonates, studies have shown that prenatal exposure to BPs (such as BPF, BPS, and BPAF) can affect TH homeostasis in cord blood. Specifically, BPS exposure is associated with lower TSH in boys, whereas BPAF exposure is associated with higher TT3 and FT3.⁸⁶ However, other studies have found a positive correlation between maternal BPA and BPS exposure and neonatal TSH levels, which is more pronounced in female infants.⁸⁷ Studies in children have shown that urinary BPS concentration is not significantly associated with any TH levels. In contrast, higher urinary BPF concentration is only associated with lower FT4 levels in girls.⁸¹ A case-control study also found that children with hypothyroidism had higher urinary BPS levels than healthy children.¹²⁵

Research using animals has elucidated the thyroid toxicity associated with BPA analogs. Research utilizing zebrafish models has demonstrated that certain analogs can induce thyroid dysfunction. Exposure to BPAF (at doses over 12.5 μg/L) resulted in substantial reductions in TT4, TT3, FT4, and FT3 levels, and elevated TSH levels.^91,103 Exposure to BPF resulted in reduced T4 levels, elevated T3 levels, and a concentration-dependent rise in TSH levels.⁹³ A subsequent study found that BPS exposure led to markedly reduced whole-body T4 and T3 levels, suggesting that BPS may induce hypothyroidism in zebrafish larvae.⁹⁴ It is important that as BPF and BPS exposure levels escalated by one to three orders of magnitude and the length of exposure extended, T3 and/or T4 levels in the larvae markedly rose, indicating a complicated dose-response relationship.¹⁰⁰ Zebrafish larvae exposed to BPB demonstrated thyroid dysfunction, indicated by significantly elevated T3 levels and T3/T4 ratios, alongside reduced T4 levels; nevertheless, T4 levels increased at a high exposure dose of 1000 μg/L.¹⁰² Moreover, parental exposure of zebrafish to BPS resulted in thyroid endocrine disturbance in the progeny, evidenced by reduced plasma T4 levels in F0 generation females, elevated T3 levels in both sexes, and postponed embryonic development and hatching.⁹⁸ In animal models, findings were similarly consistent with the thyroid-disrupting effects of BPA analogs: rats exposed continuously to 20 mg/kg/d of BPS for 5 weeks showed markedly elevated serum TSH levels.¹⁰⁵ Conversely, rats exposed to BPS (20, 100, and 500 mg/kg/d, gavage for 28 days) exhibited significantly decreased serum FT3 levels, with no significant changes in FT4 and TSH levels.¹⁰⁶ These epidemiological and experimental studies collectively indicate that BPA analogs are not safe alternatives, and their impact on thyroid hormones may be even more substantial than that of BPA.

BPA analogs (such as BPAF, BPF, BPS, and BPB) interfere with thyroid function through mechanisms similar to, and as complex as, BPA, involving multiple processes, including hormone synthesis, regulation, metabolism, and signaling (Figure 3). In zebrafish models, regarding TH synthesis, BPAF, BPB, BPF, and BPS all upregulate Tg transcription; BPF and BPS also upregulate the transcription of TPO, homeobox transcription factor (Hhex), and NIS, whereas BPAF leads to downregulated NIS expression. BPS also specifically induces the expression of Pax8, TSHR, and NKX2.1.^{91,93,94,100,102} At the level of central regulation, both BPAF and BPS stimulate the pituitary, leading to increased TSHβ mRNA levels; BPS can further promote upregulation of hypothalamic corticotropin releasing hormone (CRH) gene transcription. However, BPB has the opposite effect, leading to downregulation of TSHβ and hypothalamic TRH expression.^94,100,102 During hormone metabolism, BPAF, BPF, and BPS all upregulate the transcription of deiodinase genes (DIO1 and/or DIO2) and UGT1ab. This pattern promotes the conversion of T4 to T3 and accelerates the metabolism and excretion of T4.^91,93,94 But we observed that the effect of BPAF on deiodinase levels might be influenced by exposure level, as at 12.5 μg/L, DIO1 and DIO2 were inhibited.¹⁰³ During hormone transport, BPB, BPS, BPAF, and BPF all upregulate TTR gene expression, but at higher exposure concentrations, BPS and BPF can also downregulate its expression.^{91,93,94,100,102} Regarding interference with TH signaling, different analogs have varying effects: BPF increases TRα transcription, BPB upregulates both TRα and TRβ expression, whereas BPAF downregulates TRα and TRβ gene expression. No significant changes in TH receptor expression were observed after BPS treatment.^91,93,94,102 In mouse and rat models, BPS downregulated the expression of TSHR, NIS, Tg, and TPO, which might be related to the increased activity of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione-S-transferase (GST) in thyroid tissue after BPS exposure, disrupting the oxidant/antioxidant balance.^105,106 These findings indicate that the mechanisms of action of BPA analogs differ across species, and current research in mammalian models remains relatively limited, warranting further in-depth exploration.

Figure 3.

Effects of BPA analogs on thyroid function in zebrafish and rodents

This diagram illustrates how different BPA analogs (BPB, BPAF, BPF, and BPS) affect thyroid function in zebrafish and rodents. It shows the impact on hormone synthesis, regulation, metabolism, and signal transmission, with common effects including upregulation of Tg, TSH, TTR, and TRs. These analogs influence various thyroid pathways in both species, highlighting their potential as endocrine disruptors. (By Figdraw). Red upward arrows (↑) represent upregulation, and red downward arrows (↓) represent downregulation. Abbreviation: BPB = bisphenol B, BPAF = bisphenol AF, BPF = bisphenol F, BPS = bisphenol S, Tg = thyroglobulin, TSH = thyroid-stimulating hormone, TPO = thyroid peroxidase, TRH = thyrotropin-releasing hormone, TTR = thyroxine-binding preprotein, TR = thyroid hormone receptor, NIS = sodium/iodide symporter, UGT = uridine diphosphate glucuronosyltransferase, Hhex = homeobox transcription factor, Pax = paired box gene, NKX = thyroid transcription factor, CRH = corticotropin releasing hormone, DIO = deiodinase, TSHR = thyroid-stimulating hormone receptor.

Collectively, these findings indicate that BPA and its analogues disrupt thyroid function not only through direct hormonal interference, but also via multiple indirect mechanisms, including oxidative stress, alterations in gene transcription, epigenetic regulation, and dysregulation of central and peripheral thyroid axes.

BPs and AITD

Thyroid autoimmunity is a T cell-mediated organ-specific autoimmune disease characterized by the presence of TPOAb and/or TgAb, often leading to AITD.¹²⁶ Hashimoto’s thyroiditis (HT) is one of the most common AITD, typically characterized by elevated levels of TPOAb and TgAb. It has become the leading cause of hypothyroidism in iodine-sufficient regions worldwide.¹²⁷

BPA and AITD

Beyond directly affecting TH levels, whether BPA exposure is involved in the pathogenesis of AITD has been a research hotspot in recent years. Some epidemiological studies provide supportive evidence: one study found that BPA exposure was independently associated with an increased serum TPOAb positivity rate.⁶⁹ Among TPOAb- or TgAb-positive individuals, BPA was also positively correlated with the risk of thyroid nodules.⁷⁶ Furthermore, a negative correlation between BPA and FT4 levels was observed in children with HT.¹²⁸ However, findings in this field are inconsistent, as several other studies found no significant association between BPA and AITD risk or thyroid antibody positivity.⁹⁰ Therefore, the causal relationship between BPA and autoimmune thyroid disease remains unconfirmed. Current animal studies indicate that BPA exposure can inhibit deiodinase and TPO activity,^96,117 alter TH levels, and potentially affect autoimmunity by mimicking estrogenic activity.¹²⁹ Still, there is a lack of animal experiments directly linking BPA to TPOAb and TgAb. BPA can exert estrogen-like effects by binding to ERs, influencing T cell proliferation, the differentiation and function of regulatory T cells (Treg), and Th1/Th2 polarization, thereby enhancing immune responses.^130,131,132 At the signaling pathway level, BPA can activate pathways such as ERK1/2, p38 MAPK, and NF-κB, promote the release of inflammatory factors (e.g., TNF-α, IL-6), and affect cytokines like IL-17 and IL-21 derived from Th17 cells, further exacerbating autoimmune responses. Animal experiments show that prenatal and adult exposure to BPA can reduce the proportion of CD4⁺CD25⁺ Treg cells in mice, disrupt immune tolerance, and trigger uncontrolled autoimmune reactions.¹³³ Another study found that BPA, under a naive immune state, could reduce the secretion of IL-2, IL-4, and IFN-γ while increasing the production of IgA and IgG2a, interfering with antigen-specific immune responses.¹³⁴ A network toxicology analysis further suggested that BPA might upregulate genes related to inflammation and proliferative responses (such as PTGS2, BCL2L1, SRC, EGFR) while downregulating CCND1, which is involved in cell cycle progression, leading to impaired immune cell renewal and thereby exacerbating thyroid autoimmunity.¹³⁵ However, epidemiological inconsistencies and the lack of direct mechanistic experiments in thyroid tissue warrant cautious interpretation.

BPA analogs and AITD

Compared to BPA, epidemiological evidence on the association between BPA analogs and AITD is extremely limited. A few studies provide preliminary clues: one report indicated that analogs, such as BPF, BPB, BPC, and BPAF may have a synergistic effect on thyroid antibody positivity rates when combined.⁸⁴ The same study also found that even at low levels of BP exposure, iodine-deficient pregnant women remained susceptible to thyroid autoimmunity.⁸⁴ Furthermore, an in vitro experiment demonstrated that BPB and BPS could significantly inhibit the proliferation of human lymphocytes; BPS treatment increased levels of IL-6, IL-8, and TNF-α, while BPB increased IL-6 and decreased IFN-α2B.¹³⁶ In animal studies, no direct evidence currently links BPA analogs to AITD, but existing research suggests these substances can affect immune system function. Research involving zebrafish demonstrated that BPS and BPF can induce the expression of erα and NF-κB. Furthermore, these alterations in immune-related gene expression were inhibited by estrogen receptor and NF-κB antagonists.¹³⁷ BPAF inhibits the differentiation of U937-derived human macrophages, as evidenced by elevated levels of IFN-γ, IL-1RA, IL-8, and MIP-1β, alongside reduced IL-10.¹³⁸ Activation of the NF-κB pathway can promote oxidative stress in macrophages.¹³⁹ A separate study indicated that BPB and BPF may inhibit spi1 expression during early development, thereby restricting the differentiation of hemangioblasts into myeloid progenitors and decreasing the numbers of neutrophils and macrophages.¹⁴⁰ Current research on the mechanisms linking BPs, especially their analogs, to AITD remains underdeveloped, lacks clear consensus, and warrants further comprehensive investigation.

BPs and thyroid nodules and thyroid cancer

Thyroid nodules are common endocrine disorders, with a prevalence exceeding 67% in the general population, and occur more frequently in women, especially among the elderly and obese populations. Most patients have no obvious clinical symptoms, while some may experience dyspnea, hoarseness, or dysphagia due to nodule compression. The vast majority of thyroid nodules are benign, including nodular goiter, thyroid adenoma, and some inflammatory lesions, but they still carry a particular risk of malignancy; malignant lesions are primarily thyroid cancer, with common pathological types including papillary carcinoma, follicular carcinoma, medullary carcinoma, and anaplastic carcinoma.^141,142,143 Among these, differentiated thyroid cancer (DTC) encompasses PTC, follicular thyroid carcinoma (FTC), and Hürthle cell thyroid carcinoma (HCTC), with PTC being the most common, accounting for approximately 80% of all cases. The exact etiology of thyroid nodules and thyroid cancer is not yet fully understood, with known related factors including genetic background, environmental exposure, lifestyle, and various other factors.¹⁴⁴

BPA and thyroid nodules and thyroid cancer

Case-control studies have shown that urinary BPA concentrations in patients with thyroid cancer or thyroid nodules are significantly higher than those in healthy control groups.^72,85 An extensive case-control study involving 1416 Chinese women further found that urinary BPA concentration was positively associated with an increased risk of thyroid nodules only in individuals positive for thyroid autoantibodies.⁷⁶ However, another study of 718 Chinese children reported a negative correlation between urinary BPA concentration and the risk of multinodular thyroid disease.⁶⁸ Notably, under overweight or obese conditions, BPA exposure may further increase the risk of thyroid nodules being malignant (Figure 4).¹⁴⁵

Figure 4.

BPA and its analogs to thyroid nodules and thyroid cancer

Epidemiological studies show that obesity and thyroid autoantibodies increase the risk of thyroid nodules and thyroid cancer, while childhood exposure does not. BPA exposure promotes thyroid cancer progression through mechanisms such as HDAC6 activation, PTEN suppression, and ERK-Cox2 signaling. It also enhances EMT in conjunction with the BRAF V600E mutation. For BPA analogs (BPS, BPAF, and BPF), studies show mixed associations with thyroid cancer risk, with some showing elevated risks, while others present contradictory results in PTC tissues. Transcriptomic analyses suggest that BPA analogs activate pathways like necroptosis, adipocytokine signaling, and C-type lectin receptor signaling in early stages of cancer development. (By Figdraw). Abbreviation: BPA = bisphenol A, BPAF = bisphenol AF, BPF = bisphenol F, BPS = bisphenol S, Tg = thyroglobulin, PTC = papillary thyroid cancer, EMT = epithelial-mesenchymal transition, HDAC6 = histone deacetylase 6, PTEN = phosphatase and tensin homolog,ROX = reactive oxygen species, AKT = serine/threonine kinase, c-MYC = c-myc proto-oncogene protein, mERα = membrane estrogen receptor alpha, GPR30 = G protein-coupled receptor 30, PI3K = phosphoinositide 3-kinase, mTOR = mechanistic target of rapamycin, NOX4 = NADPH oxidase 4, ERK = extracellular signal-regulated kinase, Cox2 = cyclooxygenase-2.

Animal studies provide partial mechanistic support for BPA’s tumor-promoting effects. Research has indicated that exposure to environmentally relevant doses of BPA can promote thyroid carcinogenesis in immortalized rat follicular cells.¹⁴⁶ However, in F344 rats, low-dose BPA increased susceptibility to thyroid cancer induced by excess iodine and N-Bis(2-hydroxypropyl)nitrosamine. In contrast, BPA or potassium iodide alone did not significantly increase thyroid cancer incidence.⁹⁵ BPA primarily functions at the molecular level by promoting histone deacetylase 6 (HDAC6) expression, suppressing the tumor suppressor gene PTEN, activating the downstream AKT signaling pathway, and upregulating c-MYC expression, thereby enhancing susceptibility to thyroid cancers.¹⁰⁴ Moreover, BPA can attach to estrogen membrane receptors (mERα and GPR30), activate the PI3K/AKT/mTOR signaling pathway, and thus enhance the proliferation of thyroid cancer cells [134]. BPA can increase reactive oxygen species (ROS) production and promote cell proliferation by activating the NOX4/MAPK and NOX4/PI3K/AKT pathways.^147,148 At human exposure levels, BPA can synergize with the BRAF V600E mutation to facilitate epithelial-mesenchymal transition (EMT) in thyroid cells by activating the ERK-Cox2 signaling pathway, thereby enhancing the migratory and invasive potential of PTC.¹⁴⁹ Employing a three-dimensional PTC spheroid model, a subsequent investigation revealed that BPA diminished E-cadherin expression, elevated vimentin expression, and decreased Tg secretion in PTC cells. These findings suggest that BPA may augment tumor invasiveness and impede cellular differentiation by facilitating the EMT process.¹⁵⁰ Overall, existing research regarding the influence of BPA on thyroid cancer remains comparatively limited and necessitates immediate, comprehensive investigation.

BPA analogs and thyroid nodules and thyroid cancer

Research regarding the relationship between BPA analogs and thyroid nodules as well as thyroid cancer is limited, hindering the ability to establish definitive conclusions regarding their associated risks. Current epidemiological evidence reveals a multifaceted and at times contradictory landscape. Research indicates a positive association between exposure to BPS and BPAF and an elevated risk of thyroid cancer.^85,151 Conversely, another study reported lower BPS levels alongside elevated BPF levels in PTC tissues.⁸⁹ Studies have indicated no significant association between BPF and thyroid nodules.⁶⁷ The observed inconsistencies indicate that this field remains in its initial exploratory phase. Transcriptomic analysis indicates that exposure to BPF and BPS activates signaling pathways linked to cancer risk in zebrafish, implying potential carcinogenicity.¹⁵² In vitro transcription analysis demonstrated that BPA substitutes, including BPAF, can activate ERα via mechanisms akin to those of BPA, with BPAF exhibiting greater activation potency than BPA.¹⁵³ Nonetheless, the precise molecular mechanisms by which BP analogs initiate and promote thyroid cancer progression remain largely unexamined and warrant systematic clarification in forthcoming studies.

Public health prevention and control in populations

Reduction and blocking of exposure

From the perspective of public health, reducing the production and use of BPA and its analogues is the fundamental measure to prevent and deal with thyroid toxicity. At present, many countries have formulated relevant regulations on the use of BPA in food contact materials and children’s products. In 2011, the European Union banned the use of BPA in baby bottles. In 2015, France extended the ban to all food packaging. China and Japan have classified BPA as a regulated micropollutant in drinking water for compliance objectives.¹⁵⁴ In 2023, the European Food Safety Authority (EFSA) substantially lowered the tolerable daily intake (TDI) for BPA to 0.2 ng/kg body weight per day. Subsequently, in December 2024, the European Commission banned the use of BPA in food contact materials, including metal can coatings, reusable plastic beverage bottles, water coolers, and other kitchen utensils.¹⁵⁵The implementation of relevant laws and regulations has promoted the widespread adoption of alternatives such as BPS and BPF, but their toxicological properties remain incompletely understood, and systematic safety assessment is urgently needed.¹⁵⁶ At present, the main challenge faced is “regrettable substitution,” in which BPA regulation may prompt companies to adopt inadequately tested alternatives, with some studies suggesting their health risks could exceed those of BPA.⁴¹ Therefore, it is urgent to conduct regional or global environmental monitoring to establish baseline concentrations of these emerging chemicals, track their temporal and spatial distributions, and systematically assess the correlation between exposure levels and public health outcomes.²⁹ At the same time, encouraging the industry to develop and promote truly safe alternative materials is the key way to control pollutant exposure at the source.¹⁵⁷

Reducing environmental emissions and personal exposure

Interrupting exposure channels is a crucial tool for population protection when complete exposure removal is not practicable. In terms of environmental stewardship, it is essential to enhance the regulation of plastic waste recycling and industrial effluent treatment to reduce the release of Bisphenol A into the environment. Personal health education and behavioral interventions are essential. Research indicates that substituting food containers, kitchen utensils, personal care items, and cleaning supplies can markedly decrease urine bisphenol excretion over a 4-week period.¹⁵⁸ Nevertheless, the majority of healthcare workers remain inadequately informed about the origins of bisphenol exposure, its associated health hazards, and prevention strategies. An immediate necessity exists to elevate environmental health literacy within healthcare institutions via comprehensive educational initiatives and policy reforms.¹⁵⁹

Implementing precise public health protection

Protecting vulnerable populations is a core principle of public health intervention. The existing evidence clearly indicates that pregnant women, children,^75,80 patients with thyroid diseases (especially AITD),¹²⁸ and specific occupational groups, such as epoxy resin production practitioners¹⁶⁰ are more sensitive to the thyroid toxicity of BPA. Accordingly, public health systems should implement tiered protection strategies for these groups, including strengthened risk communication, routine clinical follow-up for patients, and occupation-specific exposure limits supported by appropriate personal protective equipment and health surveillance.¹⁶¹ Monitoring strategies should be tailored by population: for pregnant women and newborns, assess TSH, FT4, and FT3 with longitudinal follow-up; for children and adolescents, evaluate TSH/FT4/FT3 alongside growth- and development-related indicators; for autoimmune thyroid disease, monitor TPOAb, TgAb, TRAb, and thyroid hormones; and for occupationally exposed individuals, conduct repeated urinary bisphenol measurements (creatinine- or specific gravity-adjusted) in conjunction with periodic thyroid function tests and ultrasound examinations.

Current strengths, limitations, and future directions

This review synthesizes the current literature on the relationship between BPA and its analogues with various thyroid diseases, such as thyroid dysfunction, autoimmune thyroid disease, thyroid cancer, and nodules. Epidemiological and experimental research has established that bisphenol substances disrupt the synthesis, metabolism, regulation, and receptor-mediated signaling of thyroid hormones. Recent studies present distinct advantages, including the incorporation of diverse populations (adults, pregnant women, newborns, and clinical patients), enabling the identification of susceptibility characteristics in specific groups. Additionally, combining epidemiological data with mechanistic and toxicological insights strengthens the biological validity of the established associations.

This study has limitations, and caution is needed when interpreting the results. The selection of BPA structural analogues focused on representative compounds with wide industrial use, high human exposure, and sufficient research data (e.g., BPS, BPF, and BPAF), without including all potential alternatives (e.g., BPZ, BPAP, and BPFL). Limited by research resources and detection technologies, and based on the design logic of prioritizing high-exposure-risk compounds, this selection may underestimate the thyroid-disrupting effects of some emerging analogues or those with low exposure and high activity, failing to fully reflect the potential health risks of the entire BPA analogues. Mechanistic studies mostly use zebrafish and rodent models, with limited extrapolation to humans due to species-specific thyroid regulation, differences in BPs toxicokinetics, and dependence on exposure parameters. Epidemiological evidence is mainly from cross-sectional designs, making it difficult to establish causal relationships. Significant inter-study heterogeneity reflects incomplete understanding of effect modifiers such as gender, developmental stage, genetic background, and iodine nutrition. Human data on the individual and combined toxicity of BPA analogues are scarce, safe intake levels are unclear, and the molecular links between BPs and AITD or thyroid cancer require further investigation.

BPA and its analogues (e.g., BPS and BPF) influence thyroid health through various mechanisms. Central to their effect is hormone interference, which disrupts TH synthesis, secretion, and signal transduction by binding to ER and TR, while also mimicking estrogen’s impact on Treg function. Additionally, BPA can induce oxidative stress by stimulating thyroid follicular cells to generate ROS, inhibit hormone synthesis and transport, and cause mitochondrial dysfunction and DNA damage. It further promotes tumorigenesis through epigenetic modification by upregulating HDAC6 expression. Moreover, BPA activates the NF-κB signaling pathway, which induces the release of pro-inflammatory cytokines, such as TNF-α and IL-6, thus increasing the risk of AITD in conjunction with Treg abnormalities, exacerbating thyroid injury in multiple ways.

Future research should prioritize the following directions. One focus should be conducting animal studies with internal exposure doses during key developmental periods, establishing a standardized thyroid function assessment system, and enabling dynamic monitoring to capture thyroid disruptions over time. Another important direction is the construction of a large-scale prospective cohort, along with the implementation of longitudinal cohort designs and randomized controlled trials, as these methods are better suited to identifying causal relationships. Longitudinal studies will, in particular, help clarify how long-term bisphenol exposure may affect thyroid function and disease progression. In addition, promoting standardized exposure assessments and dose-response analyses, developing realistic co-exposure models, and integrating biological factors will be critical for identifying susceptible populations. A further key direction is the evaluation of exposure control strategies through experimental and short-term intervention studies, utilizing advanced models such as organoids and three-dimensional tumor spheroids to elucidate the molecular mechanisms by which bisphenol substances impact thyroid function. Moreover, conducting meta-analyses of existing cross-sectional data would help identify consistent trends and strengthen causal hypotheses.

Acknowledgments

This work was supported by the Jilin Provincial Science and Technology Department Talent Special Project—Outstanding Talent (Team) Program for Innovation of Young and Middle-aged Scientific and Technological Innovators and Entrepreneurs (Innovation Category) (grant no 20240601007RC) and the National Natural Science Foundation of China (grant no 32371429).

Author contributions

Formal analysis & writing: X.H.; literature search & review: H.C.; data curation: B.S.; chart making: C.B.; literature review & writing: X.L.; review & editing: X.M.

Declaration of interests

The authors declare no competing interests.