Impact of fine particulate matter (PM_2.5) exposure on thyroid diseases and potential molecular mechanisms

Summary

Fine particulate matter (PM_2.5) refers to particulate matter with an aerodynamic diameter of 2.5 μm or less. As a major air pollutant, PM_2.5 not only damages the respiratory and cardiovascular systems but is also closely associated with thyroid diseases. To gain a deeper understanding of the link between PM_2.5 exposure and adverse thyroid outcomes, we analyzed published epidemiological studies, summarizing the effects of PM_2.5 exposure on thyroid function, structure, and related diseases, as well as its potential mechanisms. Studies have shown that PM_2.5 exposure can lead to abnormal thyroid hormone levels, increasing the risk of various thyroid diseases, including thyroid dysfunction, thyroid autoimmune diseases, thyroid nodules, and thyroid cancer. Further analysis revealed that the mechanisms involve a multi-system interaction network, including oxidative stress, inflammatory response, hypothalamic-pituitary-thyroid (HPT) axis dysfunction, direct disruption of thyroid follicular structure and function, and the emerging intestinal-thyroid axis regulatory pathways. These mechanisms collectively lead to thyroid hormone imbalance and tissue damage. Despite ongoing research, our understanding of the effects of PM_2.5 on the thyroid remains limited. Therefore, this article summarizes the effects of PM_2.5 on the thyroid gland and its potential toxic mechanisms, outlines future research directions, and provides a scientific basis for developing precise protection strategies and air quality standards.

Graphical abstract

Health sciences

Introduction

The thyroid gland is the largest endocrine organ in the human body. Its main function is to secrete thyroid hormones (THs), primarily thyroxine (T4) and triiodothyronine (T3). These hormones are involved in almost all physiological processes, including growth and development, metabolism, and nerve excitability.¹ Even subtle changes in thyroid hormone levels can significantly impact overall health. Thyroid diseases, such as thyroid dysfunction (hyperthyroidism and hypothyroidism), autoimmune thyroid diseases (AITDs), thyroid nodules, and thyroid cancer, are common endocrine disorders worldwide. These diseases place a heavy burden on public health systems and have become a significant global health problem, which is expected to be further exacerbated by an aging population.² The etiology of thyroid diseases is complex and involves multiple factors, including genetic susceptibility, lifestyle factors, autoimmunity, iodine nutritional status, and environmental exposure. In recent years, an increasing number of studies have focused on the role of environmental exposure in thyroid diseases.^3,4,5 However, the effects of such exposures on the thyroid gland and their underlying mechanisms remain poorly understood.

Environmental particulate matter (PM) has been recognized as one of the major environmental risk factors, causing a heavy disease burden and leading to health and economic losses. The 2021 Global Burden of Disease (GBD) study report shows that air pollution is the second leading risk factor for death globally. In terms of disability-adjusted life years (DALYs) across all age groups, PM pollution ranks first among the third-level risk factors, accounting for 8.0% (6.7–9.4) of total DALYs.⁶ PM is a complex mixture of tiny solid and liquid particles suspended in the air, originating from a wide range of sources that can broadly be classified into natural and anthropogenic categories. Compared with PM₁₀, PM_2.5 is characterized by a smaller particle size, larger specific surface area, higher surface charge, longer residence time in the atmosphere, and stronger capacity to absorb heavy metals and toxic organic pollutants. These features allow PM_2.5 to penetrate more deeply into the respiratory tract, enter the bloodstream, and cause systemic damage.^7,8,9 Evidence suggests that exposure to PM_2.5 is associated with the onset and progression of a wide range of diseases, including respiratory disorders,¹⁰ gastrointestinal diseases,¹¹ cardiovascular diseases,¹² neurological disorders,^13,14 metabolic diseases,¹⁵ reproductive dysfunction,¹⁶ and various cancers.¹⁷

More recently, increasing studies have focused on the effects of PM exposure on the endocrine system, including thyroid health. Substantial epidemiological studies suggest an association between PM_2.5 exposure and alterations in thyroid hormone levels, as well as outcomes of thyroid diseases.^18,19,20,21 Mechanistically, the thyroid may be particularly sensitive to PM_2.5 exposure, as thyroid hormone synthesis depends on redox processes and is precisely regulated by endocrine feedback. PM_2.5 adsorbs toxic substances such as metals and endocrine disruptors, which may affect the thyroid gland by exacerbating oxidative stress and inflammatory reactions, as well as disrupting the endocrine axis.^22,23 Therefore, this review summarizes the current epidemiological evidence and research on mechanisms concerning the association between PM_2.5 exposure and thyroid disorders, aiming to provide a more comprehensive understanding of PM_2.5-related thyroid toxicity.

Literature search and selection methodology

This work is a narrative review with a structured literature search, aiming to comprehensively summarize and interpret the association between PM_2.5 exposure and thyroid diseases. We searched the PubMed and Web of Science databases for relevant literature published from their inception to 1 September 2025. The search scope covered various thyroid diseases, including thyroid dysfunction, AITDs, thyroid nodules, and thyroid cancer. The search strategy combined Medical Subject Headings (MeSH) terms and free terms related to each thyroid disease and PM_2.5, including (“ PM_2.5” OR “fine particulate matter”) AND (“thyroid” OR “hypothyroidism” OR “hyperthyroidism” OR “thyroiditis” OR “Hashimoto” OR “Graves” OR “thyroid nodule” OR “thyroid cancer” OR “thyroid neoplasms”). We included (1) human epidemiological studies reporting associations between PM_2.5 exposure and thyroid outcomes; (2) experimental studies investigating biological mechanisms relevant to PM_2.5-induced thyroid toxicity; and (3) recent systematic reviews and meta-analyses. We restricted inclusion to articles published in English. After careful screening, the literature closely related to the topic was finally selected for exploration.

Epidemiological studies of the association between PM_2.5 exposure and thyroid diseases

Recently, an increasing number of epidemiological studies have shown associations between PM_2.5 exposure and various thyroid diseases across sensitive windows and in the general population. This suggests that PM_2.5 exposure may play an essential role in the risk of occurrence and development of thyroid disorders, including thyroid dysfunction (Table 1) (Table S1), AITDs, thyroid nodules, and thyroid cancer (Table 2). The epidemiological studies are summarized by population subgroup and thyroid-related outcomes.

Table 1.

Epidemiological studies reveal the association between PM_2.5 exposure and thyroid dysfunction

Author, year	Location	Sample size	Study population	Study duration	Exposure window	Thyroid outcome measured	Reference
Guo et al. 2025	Zhejiang, China	443	pregnant woman	2019–2021	full pregnancy	FT3; FT4; TSH	Guo et al.24
Yang et al. 2025	Los Angeles, United States	1,065	pregnant woman	2015–2023	first trimester	FT4; TSH	Yang et al.18
Zhang et al. 2024	Beijing, China	15,664	pregnant woman	2018–2020	first trimester	TPOAb; FT4; TSH	Zhang et al.25
Ilias et al. 2020	Athens, Greece	293	pregnant woman	2012–2018	nine months preceding second and third trimester	TSH	Ilias et al.26
Zhao et al. 2019	Shanghai, China	8,077	pregnant woman	2014–2015	first and second trimester	FT4; TSH; TPOAb; hypothyroxinemia	Zhao et al.27
Ghassabian et al. 2019	Amsterdam, Netherlands	9,931	pregnant woman	2003–2004	first trimester	FT4; TSH; TPOAb; hypothyroxinemia	Ghassabian et al.28
	Rotterdam, Netherlands			2002–2006
	Spain			2003–2008
	Crete, Greece			2007–2008
	Massachusetts, United States			1999–2002
Qiu et al. 2022	Jinhua, China	2,528	pregnant woman	2018	first trimester	FT3; FT4; FT4/FT3 ratio; TSH	Qiu et al.29
Zhang et al. 2025	Beijing, China	4,647	pregnant woman	2017–2018	first trimester	FT4; TSH	Zhang et al.30
Zhou et al. 2024	Uygur Autonomous Region, Xinjiang	157, 145	pregnant woman	2023	first trimester	FT3; FT4; TSH	Zhou et al.31
Zhang et al. 2022	Wuhan, China	921	pregnant woman	2013–2014	first trimester	FT3; FT4; FT4/FT3 ratio; TSH	Zhang et al.32
Nourouzi et al. 2021	Isfahan, Iran	200	newborn	2020	full pregnancy	TSH	Nourouzi et al.33
Zeng et al. 2022	Guiyu and Haojiang, China	204	newborn	2011–2012	full pregnancy	FT3; FT4; TSH	Zeng et al.34
Chamot et al.2023	Picardy, France	6,249	newborn	2021	third trimester	TSH	Chamot et al.35
Howe et al. 2018	California, United States	2,050	newborn	1994–1997	full pregnancy	TT4	Howe et al.36
Shang et al. 2019	China	30 provinces	newborn	2014–2015	full pregnancy	CHT	Shang et al.37
Neven et al. 2021	Belgium	470	newborn	2013–2017	full pregnancy	FT3; FT4; TSH	Neven et al.38
Irizar et al. 2021	Gipuzkoa, Spain	463	newborn	2006–2008	full pregnancy	TT4	Irizar et al.39
Heo et al. 2024	Seoul, Incheon, and Gyeonggi, Korea	684	children	2012–2015	full pregnancy; childhood	T3; FT4; TSH	Heo et al.40
Gong et al. 2023	Henan, China	1,049	pregnant woman; newborn	2017–2019	first trimester	FT4; TSH; TPOAb (maternal)	Gong et al.41
Zhou et al. 2022	Shanghai, China	1,060 (329 in the sub-cohort)	pregnant woman; fetus	2016–2018	first trimester	FT3; FT4; FT4/FT3 ratio; TSH (maternal)	Zhou et al.42
Li et al. 2021	Wuhan, China	1,329 (551 in the sub-cohort)	pregnant woman; newborn	2013–2015	preconceptional; first trimester	FT3; FT4; FT4/FT3 ratio; TSH (maternal)	Li et al.43
Wang et al. 2019	Nanjing, China	443	pregnant woman; newborn	2014–2015	first trimester	FT4; TPOAb (maternal); TSH (maternal and neonatal)	Wang et al.44
Janssen et al. 2017	Genk, Belgium	499 (cord blood); 411 (maternal blood)	pregnant woman; fetus	2010–2014	third trimester	FT3′FT4; TSH (maternal and fetal)	Janssen et al.45
Zhang et al.2024	Ma’anshan, China	446	pregnant woman; newborn	2021–2022	full pregnancy	FT3; FT4; TSH (maternal and fetal)	Zhang et al.46
Valdes et al. 2022	Spain	3,859	adult	2008–2010	–	FT3; FT4; TSH; TPOAb	Valdes et al.47
Kim et al. 2024	Korea	5,626	general population	2013–2015	–	FT4; TSH; TPOAb	Kim et al.48
Wang et al. 2024	China	1.38 million	20- to 49-year-old woman	2014–2019	–	TSH	Wang et al.49
Zeng et al. 2021	Sichuan, China	327,913	healthy population	2013–2018	–	FT3; FT4; FT4/FT3 ratio; TSH	Zeng et al.50
Yang et al. 2024	China	73,900	adult	2015–2017	–	FT3; FT4; TSH; TPOAb; TgAb	Yang et al.19
Liang et al. 2024	UK Biobank	432,340	37–73 years old	2006–2010	–	hyperthyroidism; hypothyroidism	Liang et al.51
Zhang et al.2022	UK Biobank	423,796; 462,933	general population	–	–	hypothyroidism	Zhang et al.52

Table 2.

Epidemiological studies reveal the association between PM_2.5 exposure and other thyroid diseases (AITDs, thyroid nodule, and thyroid cancer)

Disease	Author, year	Location	Sample size	Study population	Study duration	Main findings	Reference
AITDs	Ghassabian et al. 2019	Rotterdam, Netherlands	2,605	pregnant woman	2002–2006	The association between PM2.5 exposure and TPOAb positivity was observed only in the Generation R study (Rotterdam, the Netherlands), suggesting to some extent that early-pregnancy PM2.5 exposure may be linked to an increased risk of thyroid autoimmunity.	Ghassabian28
	Wang et al. 2019	Nanjing, China	443	pregnant woman	2014–2015	Higher levels of maternal exposure to PM2.5 and its components were associated with decreased maternal FT4 levels and increased TPOAb concentrations after adjustment for potential confounders.	Wang44
	Zhang et al. 2024	Beijing, China	15,664	pregnant woman	2018–2020	Single-pollutant models using generalized linear models (GLMs) showed that each 10 μg/m3 increase in PM2.5 was related with 6% (1.06[1.01, 1.12]) increases in the risk of thyroid autoimmunity.	Zhang25
	Yang et al. 2024	China	73,900	adult	2015–2017	Compared with those in the first quartile (17.58–46.38 μg/m3), participants in the highest PM2.5 quartile (73.78–120.40 μg/m3) presented an increased risk of autoimmune thyroiditis (1.09 [1.00–1.18]) and TgAb positivity (1.17 [1.07–1.29]).	Yang19
Thyroid Nodule	Zhang et al. 2021	China	4,920,536	adult	2015–2017	PM2.5 exposure was significantly and linearly associated with the risk for thyroid nodules. The adjusted OR [95% CI] for every increase of 10 μg/m3 for PM2.5 was 1.062 [1.061, 1.064].	Zhang53
	Liu et al. 2025	Jiangsu, China	10,739	primary and junior high school student	2021	The C-R relationship curve between thyroid nodules and PM2.5 had a J-shaped structure with a threshold value of 39.7 μg/m3. The OR and 95% CI linked to thyroid nodules were 1.515 (1.199, 1.915) for a per SD increase in 2-year average PM2.5 concentrations (>39.7 μg/m3).	Liu20
Thyroid cancer	Karzai et al. 2022	Johns Hopkins, United States	5,970 (1,990 cases and 3,980 controls)	adult	2013–2016	The odds of developing PTC after a 5 μg/m3 increase in 2-year PM2.5 exposure was 18% (OR:1.18, 95% CI: 1.00–1.40) and increased to 23% after 3 years of exposure (OR:1.23, 95% CI: 1.05–1.44).	Karzai54
	Crepeau et al. 2023	Johns Hopkins, United States	8,909 (1,990 cases and 6,919 controls)	adult	2013–2016	3-year cumulative PM2.5 exposure was associated with a 1.41-fold increased odds of PTC diagnosis (95% CI: 1.23–1.62).	Crepeau21
	Deziel et al. 2025	California, United States	37,536 (736 cases and 36,800 controls)	0–19 years old	1982–2011	A statistically significant association between PM2.5 exposure and papillary thyroid cancer risk was observed (OR per 10 μg/m3 increase in PM2.5 = 1.07, 95% CI: 1.01–1.14).	Deziel55
	Yu et al. 2022	Jinan, China	–	–	2014–2020	A 7-year monitoring program of low-ring PAHs (<4 rings) and high-ring PAHs (>3 rings) adsorbed to PM2.5 suggests that the high incidence of thyroid cancer should be considered at least partially attributable to PAH.	Yu56

Effects of PM_2.5 exposure on thyroid function in pregnant women and their offspring

Pregnant women are an extremely susceptible population to PM_2.5 exposure. Maternal exposure during pregnancy may disrupt thyroid hormone homeostasis and indirectly affect the thyroid hormone levels in the offspring via the placenta, thereby impairing fetal growth and neurocognitive development. Consequently, thyroid dysfunction during pregnancy is closely associated with adverse outcomes and an increased risk of long-term developmental deficits in offspring. Numerous epidemiological studies have focused on elucidating how exposure to PM_2.5 during this critical window interferes with maternal and offspring thyroid function.

Effects of PM_2.5 exposure on maternal thyroid function

Most epidemiological studies have observed a significant association between PM_2.5 exposure and thyroid-related hormone levels in pregnant women. These associations are primarily manifested as decreased free thyroxine (FT4) levels and increased thyroid-stimulating hormone (TSH) levels, indicating a shift in thyroid function toward hypothyroidism.^{18,24,25,26,27,57} A large prospective cohort study from China involving 15,664 participants provides strong evidence.²⁵ This study reported decreasing FT4 and increasing TSH with increasing early-pregnancy PM_2.5 exposure percentiles. These findings suggest that PM_2.5 may impair thyroid gland function, leading to decreased production and secretion of thyroid hormones and, through negative feedback, a compensatory increase in pituitary TSH.

In addition, a meta-analysis also demonstrated that exposure to PM_2.5 during the early stage of pregnancy is significantly associated with lower maternal FT4 levels, higher TSH levels, and an increased risk of hypothyroxinemia.⁵⁷ More importantly, this meta-analysis further demonstrated that the chemical composition of PM_2.5 is crucial to its toxicity, with manganese (Mn) identified as one of the key components affecting thyroid hormone levels. As a cofactor of thyroid peroxidase (TPO), Mn is essential for thyroid hormone synthesis at physiological concentrations. However, excessive exposure can produce competitive inhibition or direct toxic effects, thereby disrupting the balance of hormone synthesis. Another cross-sectional study further deepened our understanding of the role of PM_2.5 components.²⁹ The study showed that exposure to a combination of PM_2.5 and PM_2.5-bound metals in early pregnancy was associated with lower free triiodothyronine (FT3) and FT4 levels and significantly altered the FT4/FT3 ratio. The FT4/FT3 ratio is an important indicator of peripheral thyroid hormone metabolism. An alteration to this ratio suggests that PM_2.5 exposure may not only disrupt hormone synthesis within the thyroid but also affect deiodinase activity in peripheral tissues, which converts FT4 into the active FT3. This study also observed heterogeneity in the direction and extent of the effects of different metals on the FT4/FT3 ratio, highlighting the complexity and component specificity of PM_2.5 toxicity. However, this study did not find a significant association between PM_2.5 (and its metal complexes) and TSH levels in pregnant women. This indicates a degree of heterogeneity among different studies, as some epidemiological surveys also failed to detect a significant association between PM_2.5 exposure and TSH levels.^30,31,32

This heterogeneity may arise from multiple factors. First, the exposure window is critical because the thyroid system exhibits different sensitivities at various stages of pregnancy. Second, the concentration and composition of PM_2.5 vary geographically, which may lead to differences in toxic effects across regions. Finally, demographic characteristics such as iodine nutritional status, genetic background, and underlying diseases may influence the association between PM_2.5 exposure and thyroid function. In conclusion, this heterogeneity underscores the need for further in-depth research, shifting the focus from total PM_2.5 concentration to specific toxic components and key exposure windows.

Effects of PM_2.5 exposure on thyroid function in offspring

The effects of PM_2.5 exposure are not confined to the mother. PM_2.5 can cross the placental barrier and affect the fetus indirectly by inducing maternal inflammation and stress, thereby disturbing offspring thyroid function and subsequent growth and development. These effects may extend from the neonatal period into childhood.

Multiple birth cohort studies have demonstrated a significant association between maternal exposure to PM_2.5 during pregnancy and alterations in neonatal thyroid function indicators. These changes involve fluctuations in neonatal TSH^33,34,35 and T4^36,37,38,39 levels. A prospective birth cohort study of 470 mother-infant pairs reported that each 5 μg/m³ increase in maternal PM_2.5 exposure during pregnancy was associated with an average decrease of 0.33 pmol/L in FT4 levels in cord blood.³⁸ However, some studies have reported associations in the opposite direction. For example, Irizar et al.³⁹ and Howe et al.³⁶ found that prenatal PM_2.5 exposure was associated with higher neonatal total thyroxine (TT4) levels. The discrepant directions of FT4 and TT4 changes may be explained by PM_2.5-induced stimulation of fetal production of thyroid hormone transport proteins, such as thyroxine-binding globulin (TBG).³⁶ In circulation, the majority of T4 is bound to TBG and thus maintained in a biologically inactive storage form. When TBG levels increase, more FT4 is bound, leading to a reduction in measured FT4, whereas TT4 levels may remain unchanged or even increase due to the larger pool of T4 bound to transport proteins. This reflects a complex compensatory mechanism under stress. However, the reduction in active FT4 may still have functional consequences for tissues that depend on free hormone, such as the brain.

Beyond the neonatal period, evidence also suggested potential persistence into childhood. A prospective cohort study in South Korea reported that higher PM_2.5 during early pregnancy was associated with lower TSH at ages 4 and 6 years, whereas PM_2.5 exposure during childhood was positively associated with contemporaneous TSH levels.⁴⁰ These findings collectively suggest that early-life PM_2.5 exposure is associated with thyroid function alterations, but the direction and clinical meaning may depend on developmental timing, exposure window, and the specific thyroid markers assessed.

Mediating role of maternal thyroid hormones in the effects of PM_2.5 exposure on offspring health

Several prospective cohort studies used mediation analysis to evaluate whether maternal thyroid hormones (particularly FT4) may partially explain associations between PM_2.5 exposure and adverse offspring outcomes such as birth weight and neurodevelopment.^{41,42,43,44,45,46} In general, these current studies suggest that maternal thyroid hormones may be potential mediators of the association between PM_2.5 and offspring outcomes, but it does not establish a definitive causal pathway. Notably, the mediating proportions exhibit considerable complexity in terms of exposure timing and direction of impact.

With respect to birth weight, studies consistently report that maternal PM_2.5 exposure is associated with lower birth weight, and this relationship is partly mediated by maternal thyroid hormones. A 2019 study (n = 433) found that early pregnancy exposure to PM_2.5 and its components (black carbon and ammonium) decreased maternal FT4 levels and increased thyroid peroxidase antibody (TPOAb) concentrations. Mediation analyses showed that maternal FT4 accounted for 15.9%, 18.4%, and 20.9% of the associations between exposure to PM_2.5, black carbon, and ammonium and reduced birth weight, respectively.⁴⁴ However, a 2017 Belgian prospective cohort study focused on late pregnancy and found a negative correlation between PM_2.5 exposure and umbilical cord blood FT4 levels during this period. Umbilical cord blood FT4 partially mediated the relationship between PM_2.5 exposure and lower neonatal birth weight, with a mediation rate as high as 21%.⁴⁵ However, a 2024 study by Zhang et al. (n = 446) reported an exception. This study found that exposure to PM_2.5 during late pregnancy may reduce birth weight by increasing maternal serum FT4 levels.⁴⁶ This may reflect a hyperthyroid-like effect, whereby abnormally elevated FT4 accelerates maternal metabolic rate, leading to relatively insufficient nutrient supply to the fetus and reduced fetal weight, consequently.⁵⁸ This inverse correlation highlights the criticality of exposure time and the complexity of physiological changes at different stages of pregnancy.

Regarding neurodevelopment, studies indicate that prenatal PM_2.5 exposure is associated with impaired neurodevelopment in offspring. And maternal thyroid hormones, particularly FT4 and the FT4/FT3 ratio, again played potential mediating roles. A 2021 birth cohort study (n = 551) showed that exposure to PM_2.5 in preconceptional and early pregnancy was associated with reduced maternal FT4 levels and FT4/FT3 ratios, but with increased FT3 levels. Mediation analyses indicated that maternal FT4 and the FT4/FT3 ratio mediated 7.7% and 8.6% of the effects of preconceptional PM_2.5 exposure on offspring psychomotor development index (PDI), respectively.⁴³ Another study in 2022 (n = 329) supported these findings, reporting that early pregnancy PM_2.5 exposure was associated with decreased maternal FT4 levels, with each 10 μg/m³ increase in PM_2.5 linked to a 5.82% reduction in FT4. FT4 was suggested to mediate the relationship between PM_2.5 exposure and fetal growth restriction, while fetal growth restriction may indirectly influence neurodevelopment.⁴²

Effects of PM_2.5 exposure on thyroid function in the general adult population

Although pregnant women are considered a high-risk group due to their unique physiological state, thyroid health in the general adult population is also challenged by residence in polluted environments. Evidence suggests that the impact of PM_2.5 on thyroid function in adults varies with exposure duration, showing distinct patterns for short-term and long-term exposure.

Acute effects of short-term exposure

Short-term exposure to high concentrations of PM_2.5 can rapidly disrupt thyroid hormone homeostasis in several studies. For example, Spanish and Korean population studies reported associations consistent with higher TSH and lower levels of FT4 and FT3 following higher short-term PM_2.5 exposure.^47,48 Furthermore, a nationwide longitudinal analysis covering 1.38 million women in 29 provinces of China (2014–2019) provides large-scale evidence to support these findings.⁴⁹ The study found that over a 7-day cumulative exposure window, each interquartile range (IQR) increase in PM_2.5 (40.3 μg/m³) was associated with a 0.89% increase in TSH levels. These results indicate that the thyroid responds rapidly to air pollution. However, the direction of change in thyroid hormone indicators following short-term PM_2.5 exposure is not entirely consistent. A cross-sectional study found that increasing PM2.5 exposure was associated with lower FT4, higher FT3, and a reduced FT4/FT3 ratio (coefficient −0.06, p < 0.01).⁵⁰ This pattern may reflect a compensatory mechanism whereby, under restricted FT4 production, peripheral tissues enhance deiodinase activity to convert a greater proportion of the limited FT4 into the more active FT3 to maintain metabolic demands. The underlying mechanisms of these acute effects likely involve PM_2.5-induced systemic inflammation and oxidative stress. Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), and IL-6, have been shown to inhibit TPO activity and interfere with the normal feedback regulation of the HPT axis.

Chronic risks associated with long-term exposure

In contrast to the transient and potentially reversible disturbances linked with short-term exposure, long-term PM_2.5 exposure has been associated with a higher incidence of permanent thyroid dysfunction. A cross-sectional study of 73,900 adults across 31 provinces in China showed that high exposure to PM_2.5 was associated with a significantly increased prevalence of clinical hypothyroidism (odds ratio [OR]: 1.23, 95% confidence interval [CI]: 0.94–1.61) and subclinical hypothyroidism (OR: 1.10, 95% CI: 1.01–1.21).¹⁹ Similarly, a nationwide prospective cohort study reported that long-term exposure to PM was associated with an increased risk of incident hypothyroidism and, in some analyses, hyperthyroidism.⁵¹ These findings suggest that long-term exposure is associated with a higher risk of thyroid disorders. This may manifest as hypothyroidism, primarily caused by chronic inflammation and dysfunction. In some cases, it may also trigger an autoimmune response, increasing the risk of Graves disease and subsequent hyperthyroidism. The study also explored potential mechanisms, finding that these associations may be partly mediated by accelerated biological aging (e.g., telomere shortening), providing a new explanation for how environmental exposure leads to endocrine disorders. Advances in causal inference techniques further provide complementary evidence. A two-sample Mendelian randomized (MR) study using genetic variation as an instrumental variable provided evidence of a potential causal relationship between PM_2.5 exposure and hypothyroidism. By effectively controlling for confounding factors inherent in traditional observational studies, this approach highlights the importance of air pollution control in preventing thyroid dysfunction.⁵² Nonetheless, MR findings depend on instrumental variable assumptions and should be viewed as supportive rather than definitive, particularly given the complexity of air pollution exposures and potential pleiotropy.

Effects of PM_2.5 exposure on AITDs

AITDs, such as Hashimoto’s thyroiditis, are among the leading causes of thyroid dysfunction and are characterized by elevated titers of TPOAb and thyroglobulin antibodies (TgAb). As an exogenous stimulus, PM_2.5 may exert adjuvant-like effects on the immune system, breaking tolerance to thyroid autoantigens and thereby initiating or exacerbating autoimmune responses. In pregnant women, several studies have suggested that PM_2.5 exposure is associated with an increased risk of thyroid autoimmunity (e.g., higher odds of TPOAb positivity). A large cohort study showed that, in early pregnancy, each 10 μg/m³ increase in PM_2.5 exposure was associated with an elevated risk of maternal TPOAb positivity (OR: 1.06, 95% CI: 1.01–1.12).²⁵ Moreover, a prospective birth cohort study found that higher exposure to PM_2.5 and its components in early pregnancy significantly increased TPOAb concentrations (β = 0.19).⁴⁴ However, a study by Ghassabian et al. found that antibody associations may not be consistently observed in all cohorts. They only observed an association between air pollution exposure and TPOAb positivity in the Dutch Generation R cohort.²⁸ Notably, the pattern of PM_2.5 effects on thyroid autoimmunity in the general adult population may differ from that observed in pregnant women. A large cross-sectional study reported an increased risk of autoimmune thyroiditis and TgAb positivity in groups with higher exposure to PM2.5, while no clear association was observed with TPOAb positivity.¹⁹ Differences between TPOAb and TgAb patterns may reflect biological differences in autoantigen response. Collectively, these studies indicate that PM_2.5 exposure may indeed be associated with an increased risk of thyroid autoimmunity by disturbing immune homeostasis, although the patterns of association differ across populations. Such discrepancies may be related to differences in antigenicity, PM_2.5 composition, and dose-response relationships. This warrants further investigation in the future.

Effects of PM_2.5 exposure on thyroid nodules and thyroid cancer

Thyroid nodules and thyroid cancer are the most common endocrine tumors in clinical practice, and their prevalence is increasing globally. As a pollutant with multiple carcinogenic potentials, PM_2.5 may act as a promoting factor in the development and progression of thyroid lesions, including benign nodules and malignant tumors.

Impact of PM_2.5 exposure on thyroid nodules

Recent large-scale studies have provided compelling evidence for an association between PM_2.5 exposure and thyroid nodules. A large-scale study including nearly five million Chinese adults showed that, after fine adjustment for numerous confounders (including age, sex, lifestyle, metabolic indicators, urinary iodine levels, and regional economic status), each 10 μg/m³ increase in PM_2.5 concentration was associated with an odds ratio of 1.062 (95% CI: 1.061–1.064) for thyroid nodules occurrence. The association derived from such an enormous sample size greatly strengthens the evidence supporting PM exposure as an independent risk factor for thyroid nodules.⁵³ Evidence in children and adolescents is similarly robust. A large cross-sectional study of 10,739 school-aged children and adolescents revealed a nonlinear (J-shaped) concentration-response relationship with an identified threshold around 39.7 μg/m³ for the two-year average PM2.5 exposure. This implies that once the annual average PM_2.5 concentration exceeds this threshold, the risk of thyroid nodules increases sharply.²⁰ These findings have important public health implications, providing direct scientific evidence to support the establishment of more stringent air quality standards, particularly for protecting vulnerable groups like children. However, because thyroid nodules are often detected via ultrasound screening, potential detection bias should be considered.

Risk of thyroid cancer associated with PM_2.5 exposure

Even more concerning is the association between PM_2.5 exposure and thyroid cancer risk. A review study clearly indicated that PM_2.5 exposure is associated with increased risks of 10 types of cancer, including thyroid cancer.⁵⁹ Specifically, case-control studies have reported a higher likelihood of papillary thyroid carcinoma associated with multi-year exposure to PM_2.5.^21,54 These findings indicate that exposure to PM_2.5 may have a measurable impact on thyroid cancer incidence. The potential consequences of early-life exposure are particularly concerning. A 2025 case-control study from California (736 cases, 36,800 controls) specifically focused on this issue. The study found a significant increase in the risk of papillary thyroid cancer in childhood per 10 μg/m³ increment in PM_2.5 exposure during the perinatal period (OR = 1.07, 95% CI: 1.01–1.14).⁵⁵ The perinatal period is defined as the month before delivery, the month of delivery, and the month after delivery. This environmental epidemiological evidence reiterates the necessity of shifting public health interventions upstream to this critical period of pregnancy and early infancy. Furthermore, a 7-year environmental monitoring study suggested that the high incidence of thyroid cancer may be partly attributed to polycyclic aromatic hydrocarbons (PAHs) adsorbed on PM_2.5. This finding underscores the need to consider the specific chemical composition of PM_2.5 when assessing its health risks.⁵⁶ Thyroid cancer incidence is also influenced by diagnostic intensity and screening patterns, so more prospective evidence is needed to strengthen the conclusion, especially with careful adjustment for healthcare utilization and screening intensity.

PM_2.5 exposure affects thyroid diseases through a multi-system interactive mechanistic network

Although current epidemiological evidence supports PM_2.5 exposure as an important environmental risk factor for thyroid diseases, the precise mechanisms remain incompletely elucidated. This section details the potential biological mechanisms underlying the relationship between PM_2.5 exposure and thyroid diseases, including oxidative stress, inflammation, disruption of the HPT axis, direct structural and functional damage to the thyroid, and the emerging “intestinal-thyroid axis” (Figure 1). These mechanisms are not isolated but involve multi-level perturbations from molecules and cells to organs and the entire neuroendocrine system, forming an interconnected network. These pathways are interwoven and mutually reinforcing, collectively leading to the disruption of thyroid hormone homeostasis and structural damage, and thereby posing a serious threat to the structure and function of the thyroid.

Figure 1.

A multi-system interactive mechanistic network

These mechanisms include oxidative stress, inflammatory response, disruption of the HPT axis, direct damage to the thyroid, and the impact of the intestinal-thyroid axis.

Oxidative stress

Numerous studies have shown that PM_2.5-induced oxidative stress is a key mechanism underlying its adverse health effects.^{60,61,62,63,64} The generation of reactive oxygen species (ROS) is central to oxidative stress. PM_2.5 can generate ROS through multiple pathways. First, environmentally persistent free radicals (EPFRs) present within PM_2.5 can continuously generate ROS via redox cycling, particularly in combustion-derived particles.⁶⁵ Second, many organic chemicals adsorbed on PM_2.5 can be metabolically activated to reactive intermediates, thereby generating or augmenting intracellular ROS. Third, transition metals such as Fe, Cu, V, and Mn adsorbed on PM_2.5 may generate ROS via Fenton-like reactions or by interfering with the function of redox-related enzymes.^66,67

Dong et al. exposed female rats to PM_2.5 and found it significantly reduced levels of serum T3, T4, and TSH, as well as markedly elevated plasma oxidative stress markers, including ROS and malondialdehyde (MDA). There was also a significant decrease in the activity of key antioxidant enzymes such as superoxide dismutase (SOD), which resulted in a profound imbalance between the oxidative and antioxidative systems.⁶⁸ Moreover, the same group reached similar conclusions in another study.⁶⁹ In that study, exposure to PM_2.5 resulted in thyroid tissue injury in rats. This was marked by reductions in body weight, the thyroid-to-body weight ratio, and serum levels of TSH, FT4, and FT3. This study further identified that PM_2.5-induced ROS accumulation and iron overload trigger ferroptosis, an iron-dependent form of cell death, in thyroid tissue. As a key regulator of ferroptosis, the inhibition of glutathione peroxidase 4 (GPX4) activity directly correlates with thyroid tissue injury and hormone insufficiency. These findings suggest that PM_2.5 exposure may induce ferroptosis in thyroid tissue, thereby amplifying oxidative stress and exacerbating thyroid injury. Furthermore, Zhang et al. used omics approaches and human disease databases to identify ferroptosis as a major target pathway of PM_2.5 exposure. They found that PM_2.5 substantially affected oxidoreductase function, thereby inducing oxidative stress. Further analysis of differentially expressed genes showed that nuclear-factor-erythroid-2-related factor 2 (NFE2L2), a master regulator of antioxidant responses, is an important target of PM_2.5 in endocrine diseases.⁷⁰ Dysregulation of NFE2L2 is closely linked to the pathogenesis of papillary thyroid carcinoma and hyperthyroidism, suggesting that oxidative stress not only impairs function but may also drive tumorigenesis.⁷¹

The thyroid itself is a highly oxygen-consuming organ with robust ROS generation. Thus, disturbances in redox balance are particularly consequential for thyroid function. During thyroid hormone synthesis, H₂O₂ is generated by the dual oxidase family at the apical membrane of thyroid follicular cells and serves as a substrate for TPO to oxidize iodide.⁷² This process is highly sensitive to systemic oxidative stress. Therefore, oxidative stress may impair thyroid hormone synthesis and disrupt hormone homeostasis.⁶⁸ Moreover, oxidative stress can act as an upstream signal to activate key inflammatory pathways such as nuclear factor κB (NF-κB)⁷³ and interact with the HPT axis to form a vicious cycle of “oxidative stress-inflammation-endocrine disturbance,” which further aggravates damage to thyroid tissue.

Inflammatory response

Several studies have shown that inhaled PM_2.5 can elicit pulmonary inflammation and consequently cause cardiopulmonary diseases.^74,75,76,77 Inflammation serves as a critical bridge between PM_2.5 exposure and thyroid pathology, extending from local tissue damage to systemic autoimmune reactions. In an in vivo exposure experiment, Liu et al. demonstrated that PM_2.5 exposure increased mRNA levels of major inflammatory cytokines (IL-6, IL-1β, and TNF-α) in both blood and thyroid tissue of male and female rats, while reducing thyrotropin-releasing hormone (TRH) and T4 levels.⁷⁸ The same group subsequently exposed 2-month-old rats to PM_2.5 for 16 months to establish an aging rat model of chronic exposure and reached similar conclusions. They observed that exposure to PM_2.5 significantly decreased serum levels of TRH and T3 and increased serum levels of IL-6 and TNF-α. Furthermore, real-time quantitative polymerase chain reaction (RT-qPCR) analysis showed that PM_2.5 exposure increased the mRNA expression of IL-6 and TNF-α in the hypothalamus.⁷⁹ These results suggest that PM_2.5 may affect thyroid function through a deeper mechanism, namely by inducing hypothalamic inflammation. As a central regulator of neuroendocrine function, an inflamed hypothalamus may disrupt the neuroendocrine control of the HPT axis, potentially leading to central thyroid disorders characterized by altered TRH and TSH secretion. Consistent with this, studies by Ying⁸⁰ and Xu⁸¹ found that PM_2.5 exposure induced hypothalamic inflammation with marked upregulation of inflammatory cytokine mRNA, potentially mediated by the IKK/NF-κB signaling pathway.

At the molecular level, inflammation and oxidative stress are tightly linked through a positive feedback cycle (Figure 2). PM_2.5-induced ROS can directly activate the NF-κB signaling pathway, thereby inducing the production of a large number of inflammatory cytokines (such as TNF-α, IL-6, and IL-1β), which in turn exacerbates oxidative damage.⁶⁸ Furthermore, the IL-17 family plays a central role in immune defense and is a key pathogenic driver in many autoimmune inflammatory diseases, with IL-17A being the most potent pro-inflammatory member.⁸² IL-17 exerts its effects mainly by binding to its receptors and engaging adaptor proteins such as Act1 (NF-κB activator 1) and TRAFs (TNF-receptor-associated factors), thereby activating pivotal pro-inflammatory pathways, including NF-κB and mitogen-activated protein kinase (MAPK).⁸³ These activated inflammatory signaling pathways promote the production of CC and CXC family chemokines by stromal cells,⁸⁴ thereby recruiting monocytes to sites of inflammation. Once activated at specific sites, these monocytes release more pro-inflammatory cytokines to amplify the inflammatory response. Previous studies have highlighted the importance of IL-17 in Hashimoto’s thyroiditis.^85,86,87 Using transcriptomic analysis, Dong et al. found that differentially expressed genes following PM_2.5 exposure were enriched in the IL-17 pathway, and ELISA assays confirmed increased CCL2 expression in the rat thyroid tissue.⁸⁸ In another study, the same group showed that PM_2.5 exposure also promoted thyroid ferroptosis by activating the IL-17A/IL-17RA/Act1 axis in thyroid tissue. In contrast, vitamin C protected the thyroid by inhibiting IL-17A signaling and ferroptosis, indicating crosstalk between ferroptosis and pro-inflammatory mechanisms in thyroid injury.⁶⁹

Figure 2.

PM_2.5 affects the thyroid through oxidative stress and inflammatory responses

The two mechanisms are tightly linked through a positive feedback cycle.

(A) PM_2.5 can cause elevated levels of ROS and MDA, as well as decreased levels of SOD, GPX4, and GSH. Ferroptosis can enhance this process. Oxidative stress induced by PM_2.5 impairs the production of H₂O₂ by DUOX and activates the NF-κB signaling pathway.

(B) PM_2.5 can increase pro-inflammatory factors, such as TNF-α, IL-6, IL-1β, and IL-17. These pro-inflammatory factors can be stimulated by oxidative stress and may further exacerbate oxidative stress. PM_2.5 can further activate NF-κB and promote ferroptosis through the IL-17A/IL-17RA/Act1/TRAF signaling pathway.

Disruption of the HPT axis

The HPT axis is a core component of the neuroendocrine system and maintains thyroid hormone homeostasis via negative feedback. In this axis, the hypothalamus secretes TRH, which stimulates the anterior pituitary to produce and release TSH. In turn, TSH acts on thyroid follicular cells to promote the synthesis and secretion of T4 and T3. Circulating T4 and T3 levels finely regulate TRH and TSH secretion via classic negative feedback, forming a closed-loop control system.⁸⁹ Recent studies indicate that PM_2.5 can interfere with the normal operation of this axis by inducing pathological changes in the central nervous system, particularly in the hypothalamus and pituitary.^80,81,90 As discussed above, PM_2.5 exposure induces hypothalamic inflammation and oxidative stress, leading to significant reductions in serum TRH, T3, and T4 in rats and thereby impairing thyroid function.^78,79 In addition, PM_2.5 exposure has been shown to activate the paraventricular nucleus (PVN) of the hypothalamus.⁹¹ The PVN is a key site for TRH synthesis and release,⁹² and its activation can trigger sympathetic nervous system activity and stress pathways, potentially culminating in overall activation of the HPT axis (Figure 3).

Figure 3.

PM_2.5 disrupts the negative feedback regulation of the HPT axis

The HPT axis maintains thyroid hormone homeostasis via negative feedback. PM_2.5 can induce damage of hypothalamus and pituitary, and alter TRH/TSH signaling and feedback regulation, resulting in abnormal thyroid hormone levels.

Disruption of the negative feedback mechanism of the HPT axis is another major cause of abnormal hormone levels after PM_2.5 exposure. Dong et al. observed that in female rats exposed to PM_2.5, the levels of thyroid-stimulating hormone β subunit (TSHβ) and thyrotropin-releasing hormone receptor (TRHR) were elevated, and the expression of thyroid-stimulating hormone receptor (TSHR) was significantly reduced, which was accompanied by significant hypothyroidism. This indicates that PM_2.5 exposure reduces TSHR expression and disrupts the binding of TSHR to TSH, leading to decreased TT3 and TT4 levels. However, the downregulation of THs and the upregulation of TSHβ did not stimulate increased TSH synthesis. This suggests that pituitary cells may still be able to sense low THs signals and upregulate the TSHβ gene expression. However, due to pituitary cell damage, the secretory capacity of TSH remains impaired. This demonstrates how PM_2.5 exposure disrupts the negative feedback regulation of the HPT axis.⁶⁸ In contrast, another study found that PM_2.5 exposure in male rats significantly increased serum TT4 and TSH levels and upregulated TSHβ, while markedly downregulating TRHR expression. These results imply that elevated TT4 and reduced TRHR failed to suppress TSH effectively, which indicates overactivation of the HPT axis and a breakdown of feedback control.⁹³ Although the direction of hormone changes may differ by sex, both studies confirm that PM_2.5 exposure seriously disrupts the feedback regulation of the HPT axis, resulting in a loss of thyroid hormone homeostasis.

Direct damage to thyroid structure and function

Beyond indirect regulation through the HPT axis, PM_2.5 and its specific components can directly target thyroid tissue, disrupting follicular structure and changing the expression of thyroid-related functional proteins, thereby disturbing hormone homeostasis (Figure 4).

Figure 4.

Exposure to PM_2.5 directly impairs thyroid structure and function

(A) Structural injury: PM_2.5 impairs epithelial adhesion by perturbing the CD151/integrin α3β1/Rac1 signaling pathway.

(B) Functional impairment: PM_2.5 disrupts the expression of key proteins and transcription factors involved in the synthesis, activation, and transport of hormones.

The basic functional unit of the thyroid is the follicle, a spherical structure composed of a single layer of follicular epithelial cells surrounding a central colloid-filled lumen.⁹⁴ Integrity of the follicular structure is essential not only for hormone synthesis, storage, and secretion, but also for maintaining cell polarity, intercellular communication, and directional transport of substances. Guo et al. focused on diesel exhaust particles (DEPs), a major component of urban PM_2.5.⁹⁵ In a mouse model, DEP exposure induced typical histopathological changes in the thyroid gland, including follicular destruction, colloid thinning and depletion, and the formation of follicular cavities. These morphological changes directly indicate impaired follicular barrier function. To elucidate the underlying mechanism, the authors performed KEGG pathway enrichment analysis and molecular detection, revealing that DEP impairs epithelial cell adhesion by disrupting the CD151/integrin α3β1/Rac1 signaling pathway. Dysregulation of this pathway weakens intercellular connections between follicular epithelial cells, impairing follicular integrity and ultimately leading to thyroid dysfunction.⁹⁶ Furthermore, Tang et al. found that PM_2.5 exposure in mice led to marked histological disruption of the thyroid. Subsequently, the experiment revealed that PM_2.5 activated GLIS3 through the Rap1/PI3K-AKT pathway, thereby enhancing thyroid hormone synthesis and affecting its regulation.⁹⁷ This mechanism indicated that the direct effects of PM_2.5 on the thyroid are not invariably suppressive. Such aberrant activation may also disturb hormone homeostasis, potentially causing transient dysfunction and increasing metabolic load on thyroid cells, thereby promoting tissue injury.

PM_2.5 exposure not only damages follicular architecture but also disrupts the expression of key proteins and transcription factors involved in the synthesis, activation, and transport of hormones, thereby altering the levels of hormones and inducing thyroid injury.^68,93,97 Key functional proteins related to the thyroid include the sodium-iodide symporter (NIS), which mediates iodide uptake; TPO, which catalyzes iodide oxidation and tyrosine iodination; thyroglobulin (TG), which is the substrate for hormone synthesis; transthyretin (TTR), a transport protein, and transcription factors such as forkhead box E1 (FOXE1), thyroid transcription factor-1 (TTF-1),⁹⁸ and paired box gene 8 (PAX-8),⁹⁹ which are crucial for thyroid development and differentiation. However, the results of different studies on the effects of PM_2.5 on these functional proteins are not entirely consistent. For instance, Dong et al. observed that exposure to PM_2.5 elevated levels of NIS, TPO, TG, and TTR in male rats, while simultaneously reducing levels of TTF-1 and PAX-8.⁹³ In contrast, a study of female rats showed that PM_2.5 exposure increased NIS and decreased TPO expression, thereby impairing both iodide concentration and its activation in follicular cells. The resultant iodine deficiency prevented the adequate iodination of tyrosine residues, leading to TG accumulation and insufficient T4 and T3 synthesis. Interestingly, PM_2.5 exposure also significantly increased TTF-1, FOXE1, and PAX-8 levels but decreased TTR levels in female rats.⁶⁸ These seemingly contradictory patterns highlight the complexity of regulatory mechanisms involved. On one hand, upregulation of functional proteins may reflect compensatory responses to stress, driven by increased TSH and TRH secretion to stimulate thyroid activity. On the other hand, downregulation of these proteins and core transcription factors implies fundamental impairment of thyroid cell differentiation and functional capacity, leading to inefficient hormone synthesis. Finally, the discrepancies across studies may reflect differences in animal sex or the specific composition and dose of PM_2.5.

The intestine-thyroid axis

Recently, a large number of studies have found that alterations in the intestinal microbiota and their effects on physiological and metabolic processes significantly influence the progression of thyroid diseases, including primary hypothyroidism, Graves disease, autoimmune thyroiditis, and thyroid nodules.^{100,101,102,103,104,105} These findings suggest a bidirectional and complex relationship between the intestinal microbiota and the thyroid, known as the “intestine-thyroid axis.” The composition of intestinal microbiota can be shaped by diet, environmental chemicals, antibiotics, and pathogenic infections. Several studies have reported an association between the intestinal microbiota and environmental contaminants such as mercury, arsenic, polychlorinated biphenyls, and PM_2.5.^{106,107,108,109,110,111,112} These observations suggest that toxic environmental chemicals may influence human health in part by altering the intestinal microbiota. However, it remains unclear whether changes in the intestinal microbiota and its metabolites induced by PM_2.5 are directly related to thyroid function and which bacterial taxa are specifically involved. Recent advances in high-throughput technologies, such as 16S rRNA sequencing, transcriptomics, proteomics, metabolomics, and metagenomics, have opened new avenues to investigate links between PM_2.5 exposure, the intestinal microbiota, and thyroid toxicity.

Dong et al. were the first to combine LC-MS-based metabolomics with 16S rRNA gene sequencing to examine the impact of PM_2.5 exposure on the intestinal microbiota and metabolome in relation to thyroid dysfunction.⁹³ They found that PM_2.5 exposure induced significant shifts in intestinal microbial composition in male rats. Compared with the control group, rats with PM_2.5-induced thyroid toxicity exhibited higher community diversity and richness. These results are consistent with previous studies showing dysbiosis of the intestinal microbiota in patients with hyperthyroidism and hypothyroidism.¹⁰¹ Several key differentially abundant taxa were also identified in the study, such as Candidatus Obscuribacter and Lactobacillus. These changed intestinal microbiota showed negative correlations with serum TT4, TT3, and TSH levels. These findings suggest that PM_2.5 exposure reshapes the intestinal microbiota and contributes to thyroid dysfunction. The authors further showed that PM_2.5-induced thyroid toxicity was accompanied by alterations in urinary metabolite profiles. Differential metabolites were significantly enriched in pathways related to thyroid hormone synthesis, glutathione metabolism, tryptophan metabolism, and histidine metabolism. Glutathione, an intermediate in thyroid hormone synthesis and a major antioxidant, was significantly reduced in PM_2.5-exposed rats, indicating impaired hormone synthesis capacity and antioxidant defense. Altered urinary metabolites were also significantly correlated with thyroid functional proteins and transcription factors (NIS, TPO, TG, TTR, TTF-1, and PAX-8), suggesting that these metabolites may modulate the effects of PM_2.5 on thyroid function. Moreover, the study revealed strong correlations between altered bacterial taxa and key metabolites, enabling the construction of an integrated “intestinal microbiota-host metabolites-thyroid function” regulatory network.

Subsequent work by Dong further deepened this mechanistic understanding. Following PM_2.5 exposure, they again observed changes in specific intestinal microbiota. Transcriptomic analysis of thyroid tissue showed that the differentially expressed genes (FOS, UCP1, Gadd45g, EGF, CCL2, and Cleb3L4) after PM_2.5 exposure were enriched in IL-17, FOXO, thyroid hormone synthesis, and PPAR signaling pathways. Altered genes were significantly correlated with both serum thyroid function markers and these differentially expressed genes.⁸⁸ These data suggest that PM_2.5 may initially disrupt the intestinal microenvironment and subsequently modulate thyroid molecular pathways and cellular functions through immune, metabolic, inflammatory, and neural signaling. This ultimately disrupts hormone homeostasis.

Integrated mechanistic network and clinical implications

In summary, the mechanisms by which PM_2.5 affects the thyroid are highly complex and multifaceted. These processes form a tightly interconnected and self-amplifying systems network that drives the onset and progression of thyroid diseases.

This complex toxicity originates from inhaling PM_2.5, triggering systemic oxidative stress and inflammation, which are two primary mechanisms. The potential translocation effects of PM_2.5 exert a dual impact on both the thyroid gland and the central nervous system. Within the thyroid gland, a positive feedback cycle of oxidative stress and inflammation is established. ROS accumulation triggers ferroptosis and activates the NF-κB/IL-17 signaling pathway, while the resultant inflammation further exacerbates oxidative damage and depletes antioxidant reserves. This can directly cause cell death and disrupt the structure and function of glands, impairing the thyroid gland’s secretion of hormones. Moreover, the gland damage and the central nervous system inflammation can inhibit the compensatory neuroendocrine response, preventing the HPT axis from effectively restoring hormone homeostasis. For the intestine-thyroid axis, PM_2.5-induced gut microbiota dysbiosis is associated with the expression of differentially expressed genes related to inflammation and thyroid-associated functional proteins.

Clinically, these molecular interactions manifest as specific pathological conditions. Direct follicular collapse (mediated by disruption of the integrin pathway), iron-dependent cell death (ferroptosis), and diminished compensatory neuroendocrine responses due to hypothalamic inflammation collectively lead to abnormal thyroid hormone secretion, inducing hypothyroidism and subclinical thyroid dysfunction. Concurrently, the activation of signal pathways, such as IL-17/NF-κB, coupled with the release of autoantigens from damaged thyroid cells, collectively disrupts immune tolerance. This provides a mechanistic basis for the increased incidence of autoimmune thyroiditis, such as Hashimoto’s thyroiditis. Furthermore, the activation of pathways (such as GLIS3) creates a pro-tumorigenic niche that fosters the development of thyroid nodules and papillary thyroid carcinoma. Thus, PM_2.5 exposure acts as a systemic stressor where the failure of homeostatic resilience determines the progression from subclinical physiological perturbations to overt clinical disease.

Current limitations and future research directions

Despite increasing evidence, several limitations still constrain current understanding of PM_2.5-thyroid associations. First, most studies rely on ambient PM_2.5 chemical concentration, whereas toxicity likely also depends on chemical constituents (e.g., metals and PAHs) and particle sources. Component-specific thyroid evidence remains limited and may contribute to inconsistent findings across studies. Second, the marked regional and seasonal variations in PM_2.5 levels and components, together with differences in exposure assessment approaches, may introduce non-comparable exposure errors.^113,114 This is particularly true for extended exposure windows, thereby complicating cross-study comparisons and the interpretation of results. Third, iodine status serves as a critical effect modifier for thyroid outcomes, yet the measurement methods are inconsistent. Current evidence suggests that iodine nutrition may modify the relationships between pollution and thyroid, highlighting the need for more systematic iodine assessment in future studies. Fourth, the heterogeneity of gender and age remains insufficiently explored. Experimental findings indicate sex differences in the HPT axis and thyroid-associated protein expression, while epidemiological vulnerability varies across pregnancy, early life, and the elderly stages. Nevertheless, many studies still lack stratified analyses of these differential susceptibilities. Finally, causal inference for long-term exposure remains challenging, because many factors can introduce substantial confounding effects, such as residential mobility, occupational exposures, and correlated co-pollutants. Although MR provides supportive evidence for a causal association between PM_2.5 and hypothyroidism, evidence for other endpoints (such as thyroid autoimmunity, nodules, and cancer) still requires more robust validation through multiple study designs.

To better understand its potential impact, future research should address several key aspects. First, most existing studies treat PM_2.5 as a single entity. However, the specific contributions and relative importance of individual chemical components (e.g., metals and PAHs) to thyroid toxicity remain unclear. Therefore, future research should use in vitro fractionation and component-specific analyses to precisely establish the links between characteristic PM_2.5 components and their adverse thyroid effects.¹¹⁵ Second, both the timing and intensity of PM_2.5 exposure can have a differential influence on thyroid outcomes in epidemiological studies. Well-designed prospective studies with repeated measurements are needed to clarify sensitive exposure windows, temporal dynamics, and identify dose ranges. Third, future research should explicitly evaluate the modifying effects of iodine status, sex, and age on outcomes, thereby improving risk stratification and identification of vulnerable subgroups. Fourth, given the substantial harm posed by PM_2.5, it will be crucial to integrate multi-omics technologies (such as genomics, metabolomics, and proteomics) to identify biomarkers of susceptibility to PM_2.5-induced thyroid toxicity. This will be crucial for early recognition of high-risk individuals. Fifth, causal inference should be strengthened through the integration of complementary analytical designs, including MR, natural intervention studies, and negative control strategies, particularly for outcomes beyond hypothyroidism such as thyroid autoimmunity, nodules, and cancer. Finally, mechanism-based precision interventions should be developed. These should include nutritional or pharmacological strategies (e.g., antioxidant vitamins)⁶⁹ and behavioral modifications (e.g., using air purifiers and limiting outdoor activity during high-pollution periods) to mitigate PM_2.5-related thyroid toxicity. Such efforts will provide direct scientific evidence for the formulation of stricter air quality standards, more accurate risk prediction models, and effective public health guidelines. These have great scientific and societal value.

Conclusion

This review summarizes the environmental risks and toxicological mechanisms by which PM_2.5 influences the development of thyroid diseases. The available evidence indicates that PM_2.5 exposure can promote the development of various thyroid disorders through multiple mechanisms, including oxidative stress, inflammatory responses, HPT axis disruption, direct thyroid injury, and alterations in the intestinal microbiota. These findings have important implications for public health policy. To meet or exceed air quality standards, governments should implement regulatory measures to substantially reduce emissions of gaseous precursors and primary particles, thereby lowering the concentration of ambient PM_2.5. In addition, individuals, particularly susceptible groups such as pregnant women, should pay close attention to local air quality reports and adjust outdoor activities promptly when high-risk conditions are identified. However, substantial heterogeneity has been observed in outcomes and mechanisms depending on PM_2.5 composition, exposure level and duration, animal models, and population characteristics. This suggests that research on PM_2.5-related thyroid toxicity is still in its early stages, with future studies requiring further in-depth exploration.

Acknowledgments

This work was supported by the Jilin Provincial Science and Technology Department Talent Special Project (grant no. 20240601007RC) and the National Natural Science Foundation of China (grant no. 32371429). All figures in this article were drawn by Figdraw (https://www.figdraw.com/#/).

Author contributions

Conceptualization, writing—original draft, and visualization, B.S. and H.C.; writing—original draft, X.H.; writing—review & editing, B.D.; investigation, X.L.; chart making, H.S.; writing—review & editing and project administration, X.M.

Declaration of interests

The authors declare no competing interests.