Oxidative stress mediates the associations between phthalate exposures and thyroid cancer/benign nodule risk.

Epidemiological studies have suggested that phthalate exposures are associated with increased risks of thyroid cancer and benign nodule, while the underlying mechanisms are largely unknown. Here, we explored the mediation effects of oxidative stress (OS) biomarkers in the associations between phthalate exposures and the risks of thyroid cancer and benign nodule. Urine samples collected from 143 thyroid cancer, 136 nodule patients, and 141 healthy controls were analyzed for 8 phthalate metabolites and 3 OS biomarkers [8-hydroxy-2-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), and 8-iso-prostaglandin F2α (8-isoPGF2α)]. Multivariable linear or logistic regression models were used to explore the associations of OS biomarkers with phthalate metabolite concentrations and the risks of thyroid cancer and nodule. The mediation role of OS biomarkers was also investigated. Urinary monoethyl phthalate (MEP), monomethyl phthalate (MMP), mono (2-ethyl-5-oxohexyl) phthalate (MEOHP), mono (2-ethylhexyl) phthalate (MEHP), and mono (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were positively associated with at least 2 OS biomarkers (all P-values<0.01), and part of these positive associations varied in different subgroups. All 3 OS biomarkers were positively associated with the risks of thyroid nodule and cancer (P-values<0.001). The mediation analysis showed that OS biomarkers significantly mediated the associations between urinary MEHOP concentration and nodule, as well as between urinary MMP, MEHP, and MEHHP concentrations and cancer and nodule, with the estimated proportions of mediation ranging from 15.8% to 85.6%. Our results suggest that OS is a potential mediating mechanism through which phthalate exposures induce thyroid carcinogenesis and nodular formation.

Exposure to Bisphenol A increases malignancy risk of thyroid nodules in overweight/obese patients.

Bisphenol A (BPA) is a widespread thyroid disruptor, but evidence about an association with thyroid cancer is weak. Excess body weight is a risk factor for thyroid cancer and affects activity of endocrine disruptors. Aim of the study was to investigate the association between BPA exposure and thyroid cancer, verifying the effect modification related to body weight. We performed a multicentre, cross-sectional study including consecutive patients referring for nodular goiter. The quantitative determination of BPA in serum samples was performed through high performance liquid chromatography system, coupled in tandem with ultraviolet and fluorescence detection. Ninety-six patients were included: 55 benign nodules, 41 thyroid cancers, 28 normal weight, and 68 overweight/obese. BPA was detected in 79 subjects. In the overall study population and in the group with BMI<25 kg/m2 BPA exposure was not significantly correlated to thyroid cancer (p = 0.08 and 0.759, respectively). In the group with BMI≥25 kg/m2, BPA-exposed subjects showed significantly higher risk of malignancy (OR: 5.3, p = 0.028). At multivariate analysis, such association was independent of smoking, alcohol consumption, occupational exposure, and phthalates exposure (p = 0.021 and 0.016, respectively), but was lost after adjustment for the presence of metabolic syndrome (p = 0.089). In overweight/obese subjects, BPA exposure was significantly associated with higher thyroid stimulating hormone levels. Our study suggests that BPA exposure is a risk factor for thyroid cancer in overweight/obese subjects.

Association of Ozone Exposures with the risk of thyroid nodules in Hunan Province: a population-based cohort study.

BACKGROUND: Increasing evidence associates air pollution with thyroid dysfunction, whereas the potential relationship between exposure to ozone (O3) and Thyroid Nodules (TNs) is unclear. METHODS: This retrospective cohort study investigated the association between O3 exposure and TNs in Hunan province, enrolling 191,357 Chinese adults who lived in Hunan province from January 2009 to December 2019 and received voluntary medical examinations. Individual exposure levels to O3 from 2010 to 2019 were measured on account of participants' residential addresses at the district level. Associations of O3 exposure with the risk of incidental TNs were assessed by restricted cubic splines and surveyed as odds ratios after adjusting for demographic factors. RESULTS: In total, 81,900 adults were newly diagnosed with TNs during the study period. Age-standardized TNs detection rate in Hunan province increased from 25.9 to 46.3% between 2010 and 2019, with the greatest annual percent change being 8.1 [95% CI, 7.3-8.8]. A similar trend has been found in all tumor sizes, ages, and both sexes. O3 exposure presented a statistically significant dose-dependent positive correlation (greater than 0.036 ppm) with TNs. Similarly, long-term exposure to high levels of O3 (1-year average O3 concentrations exceeding 0.0417 ppm) was found positively associated with increased TSH levels. CONCLUSIONS: High-level O3 exposure in the long term was associated with an increase in TSH. Consequently, increased TSH was related to the increased risk of TNs. Being exposed to high-level O3 in the long term was related to the increased detection rates of TNs in Hunan province, which could be mediated by TSH.

Analysis of the correlation between high iodized salt intake and the risk of thyroid nodules: a large retrospective study.

BACKGROUND: Currently, whether daily excess iodized salt intake increases the risk of thyroid nodules and even thyroid cancer remains controversial. Our research group aimed to provide a theoretical basis for the clinical guidance of daily iodized salt intake and the prevention of thyroid nodules through a retrospective analysis of the correlation between daily iodized salt intake and the risk of thyroid nodules and thyroid cancer in Hunan, China. METHODS: This study retrospectively analyzed the data of subjects who underwent a physical examination at the Health Management Center, Third Xiangya Hospital of Central South University, between January 1, 2017, and December 31, 2019. Subjects enrolled in this study underwent thyroid ultrasonography and tests to urine routines and liver and kidney function, and all subjects completed a questionnaire survey. The daily iodized salt intake of the study subjects was estimated based on spot urine methods (Tanaka). A multivariate logistic regression model was used to analyze the relationship between daily iodized salt intake and thyroid nodules and thyroid cancer. RESULTS: Among the 51,637 subjects included in this study, the prevalence of thyroid nodules was 40.25%, and the prevalence of thyroid cancer was 0.76%; among all enrolled subjects, only 3.59% had a daily iodized salt intake less than 5 g. In addition, we found that a daily intake of more than 5 g of iodized salt was not only an independent risk factor for the occurrence of thyroid nodules (odds ratio (OR): 2.08, 95% confidence interval (CI): 1.86-2.31, p < 0.001) but also an independent risk factor for the occurrence of thyroid cancer (OR: 5.81, 95% CI: 1.44-23.42, p = 0.012). A pooled analysis showed a significantly higher risk of thyroid nodules in subjects aged > 60 years with a daily iodized salt intake of more than 5 g compared to subjects aged < 60 years with a daily iodized salt intake of no more than 5 g (OR: 4.88, 95% CI: 4.29-5.54, p < 0.001); the risk of thyroid cancer was not significantly different between subjects aged > 60 years with a daily iodized salt intake of more than 5 g and those aged < 60 years with a daily iodized salt intake of no more than 5 g (OR: 2.15, 95% CI: 0.52-8.95, p = 0.281). The risk of thyroid nodules was not increased in physically active subjects with a daily iodized salt intake of more than 5 g compared to physically inactive subjects with a daily iodized salt intake of no more than 5 g (OR: 1.12, 95% CI: 0.97-1.28, p = 0.111). The same protective effect of physical activity was observed for thyroid cancer in subjects whose daily iodized salt intake exceeded 5 g. The risk of thyroid nodules was reduced for subjects with an education level of postgraduate and above, even when the daily iodized salt intake exceeded 5 g, compared to those with high school education and below and a daily iodized salt intake of no more than 5 g (OR: 0.79, 95% CI: 0.66-0.93, p = 0.005); however, a protective effect of education level on the occurrence of thyroid cancer was not observed. Independent risk factors affecting daily iodized salt intake greater than 5 g included age, triglycerides, family history of tumors, physical activity, and marital status. CONCLUSIONS: Daily intake of more than 5 g of iodized salt increased the risk of thyroid nodules and thyroid cancer, while increased physical activity and education level reduced the risk of thyroid nodules and thyroid cancer caused by iodized salt intake.

Excessive iodine intake is associated with formation of thyroid nodules in pregnant Chinese women.

In recent decades, the prevalence of thyroid nodules (TNs) has steadily increased in pregnant women. Therefore, this study aimed to investigate associations between TNs and iodine intake in pregnant women. From March 2016 to May 2017, serum and spot urine samples, as well as demographic data and medical history, were collected from 2353 pregnant women. Urine iodine concentration (UIC) and creatinine (Cr) level were determined in spot urine samples; serum thyroid hormones and thyroid autoantibodies were also determined. We examined the hypothesis that excess iodine intake influences incidence of TNs. Herein, TNs were diagnosed by ultrasonography, whereas demographic data and medical history were collected by questionnaire. Multivariate logistic regression models were used to calculate the odds ratios and their corresponding confidence intervals for TN risk factors. Generalized linear mixed model was used to assess the random effects of the regions. The UIC and UIC to creatinine ratio (I/Cr ratio) were significantly higher in pregnant women with TNs (168 and 190 µg/L, respectively, for UIC [P < .01]; 139 and 155 µg/g, respectively, for I/Cr ratio [P < .01]). Thyroglobulin, age, pre-pregnancy body mass index, and iodine-excessive region were associated with TNs (odds ratio = 1.01, 1.06, 1.04, and 2.38, respectively). Whereas I/Cr ratio was not a significant risk factor for TNs in pregnant women when adjusted for potential confounders, iodine excess (I/Cr ratio >500 µg/g) was a risk factor in pregnant women in their second trimester. People living in areas with excessive iodine in drinking water should decrease their iodine intake, and a safe water source should be provided to ensure that the I/Cr ratio of pregnant women can be maintained at an optimal level.

Human exposure to bisphenol AF and diethylhexylphthalate increases susceptibility to develop differentiated thyroid cancer in patients with thyroid nodules.

Pollutants represent potential threats to the human health, being ubiquitous in the environment and exerting toxicity even at low doses. This study aims at investigating the role of fifteen multiclass organic pollutants, assumed as markers of environmental pollution, most of which exerting endocrine-disrupting activity, in thyroid cancer development. The increasing incidence of differentiated thyroid cancer (DTC) may be related to the rising production and environmental dissemination of pollutants. Fifty-five patients, twenty-seven with diagnosis of benign thyroid nodules and twenty-eight suffering from differentiated thyroid cancer, were enrolled and the concentration levels of seven bisphenols, two phthalates (i.e. di(2-ethylhexyl) phthalate (DEHP) and its main metabolite, mono-(2-ethyl-hexyl) phthalate) (MEHP)), two chlorobenzenes, (1,4-dichlorobenzene and 1,2,4,5-tetrachlorobenzene), and 3 phenol derivatives (2-chlorophenol, 4- nonylphenol, and triclosan) were determined in their serum by using a validated analytical method based on high performance liquid chromatography with ultraviolet tandem fluorescence detection. A significant relationship was found between malignancy and the detection in the serum of both bisphenol AF and DEHP. Indeed, their presence confers a more than fourteen times higher risk of developing differentiated thyroid cancer. Relationship between these two pollutants and the risk of malignancy was dose-independent and not mediated by higher thyroid stimulating hormone levels. Even if a conclusive evidence cannot still be drawn and larger prospective studies are needed, the exposure to low doses of environmental endocrine-disrupting contaminants can be considered consistent with the development of thyroid cancer.

Prevalence of Thyroid Nodules and Its Relationship with Iodine Status in Shanghai: a Population-based Study.

OBJECTIVE: This study was designed to evaluate the prevalence of thyroid nodules (TNs) and its relationship with urine iodine concentrations (UICs) after the regional rapid economic growth and lifestyle changes. METHODS: A cross-sectional survey was conducted in the general population aged 15-69 years. A questionnaire regarding general and personal characteristics and relevant information was administered. Ultrasonography of the thyroid was performed, and serum triiodothyronine (T3), tetraiodothyronine (T4), serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroglobulin antibody (TgAb), thyroid peroxidase antibody (TPOAb), and TSH receptor antibody (TRAb) levels were measured for each individual subject. RESULTS: The prevalence rates of TNs in the whole population, females and males were 27.76%, 34.04%, and 21.60%, respectively. The prevalence of multiple nodules increased with age, whereas the prevalence peaks differed between males and females. The median UICs in the whole population and females with non-TNs were higher than those of subjects with TNs (P=0.0035, P=0.0068). The median UICs in subjects with a single TN were higher than those in subjects with multiple TNs (P=0.0164, P=0.0127). The result showed a U-shaped curve relationship between UIC and prevalence of TNs. The prevalence of TNs was the lowest when the UIC was 140-400 µg/L. CONCLUSION: The prevalence of TNs was nearly 30% and increased with age. The relationship between UIC and prevalence of TNs is U-shaped, with an increase in risk when the UIC was <140 µg/L and >400 µg/L. Very low or high UIC levels need attention and correction.

Influence of Bisphenol A on Thyroid Volume and Structure Independent of Iodine in School Children.

BACKGROUND: Although several studies have evaluated the relationship between bisphenol A (BPA) and thyroid functions, their results are not entirely consistent. Little is known about BPA in relation to thyroid volume and structure. METHODS: We examined the association of BPA with thyroid volume and thyroid nodules using data from 718 Chinese children living in the East Coast of China in 2012. First morning urine samples were collected for the determination of urinary BPA, creatinine, and urinary iodine concentrations (UIC). Thyroid volume (TV) and nodules were assessed by thyroid ultrasonography. RESULTS: The median of TV was 3.14ml. 459(63.9%) children took iodized salt at home and the median of UIC was 159µg/l. BPA was detected in 99.9% of the urine samples and the medians for boys and girls were 2.64 and 2.35µg/g creatinine, respectively. Of all participants 14.0% had thyroid nodules. Urinary BPA concentration was inversely associated with thyroid volume (ß = -0.033, 95% CI: -0.053, -0.013) and the risk for multiple nodules (OR = 0.78; 95% CI: 0.63, 0.97). The associations above were similar for children who consumed iodized salt and those consumed non-iodized salt. CONCLUSIONS: The data suggest that BPA may be one of the influencing factors for TV and thyroid nodules and its effects are independent of iodine nutrition status in children.

Effects of GH replacement therapy on thyroid volume and nodule development in GH deficient adults: a retrospective cohort study.

OBJECTIVE: Despite the well-known effects of GH/IGF1 signaling on the thyroid, few data are available on the risk of developing nodular goiter in hypopituitary subjects during GH replacement therapy (GHRT). We aimed to define the effects of GH therapy on thyroid volume (TV) and nodular growth. DESIGN: The records of 96 subjects (47 males and 49 females, median age 48 years) with GH deficit (GHD) were investigated. Seventy also had central hypothyroidism (CH). At the time of our retrospective evaluation, median treatment duration was 5 years. RESULTS: Pre-treatment TV was smaller in GHD patients than in healthy subjects (P=0.030). During GH treatment, TV significantly increased (P=0.016 for the entire group and P=0.014 in euthyroid GHD patients). Before starting GH therapy, 17 patients harbored thyroid nodules. During GH therapy, nodule size increased slightly in seven patients, and new thyroid nodules occurred in nine patients. Among the 79 patients without pre-existing thyroid nodules, 17 developed one or more nodules. There was no difference in the prevalence of CH in GHD patients with or without thyroid nodules (P=0.915; P=0.841, when patients with pre-therapy nodular goiter were excluded), the main predictor for nodule development being serum IGF1 (P=0.038). CONCLUSIONS: GHRT is associated with TV's increase in GHD patients. Thyroid nodules developed in 27% of patients, mainly in relation to pre-therapy IGF1 levels, independently of normal or impaired TSH stimulation.

Thyroid nodules and thyroid autoimmunity in the context of environmental pollution.

Evidence suggests that in most industrialized countries autoimmune disorders, including chronic lymphocytic thyroiditis, are increasing. This increase parallels the one regarding differentiated thyroid cancer, the increment of which is mainly due to the papillary histotype. A number of studies have pointed to an association between chronic lymphocytic thyroiditis and differentiated thyroid cancer. The upward trend of these two thyroid diseases is sustained by certain environmental factors, such as polluting substances acting as endocrine disrupting chemicals. Herein we will review the experimental and clinical literature that highlights the effects of environmental and occupational exposure to polluting chemicals in the development of autoimmune thyroid disease or differentiated thyroid cancer. Stakeholders, starting from policymarkers, should become more sensitive to the consequences for the thyroid resulting from exposure to EDC. Indeed, the economic burden resulting from such consequences has not been quantified thus far.

The association of thyroid nodule with non-iodized salt among Chinese children.

OBJECTIVE: The controversy that iodized salt may increase the risk of thyroid disorders has been aroused in China during the past decade. Most of studies focused on adult rather than children. We aimed to explore whether iodized salt was associated with an increased risk of thyroid nodule in Chinese children. METHODS: The cross-sectional study was conducted in Hangzhou, China, in 2010. Iodized salt intake, urine iodine concentration (UIC) and thyroid nodule (by ultrasonography) were measured in 3026 children. The associations of iodized salt with thyroid nodule were evaluated using multiple logistic regression models. RESULTS: The prevalence of thyroid nodule was 10.59% among Chinese children. Girls (11.89%) had higher prevalence of thyroid nodule than boys (9.26%). No significant association was observed between type of salt and thyroid nodule in pooled samples, boys and girls, respectively. Similar associations were observed between UIC and thyroid nodule. There was no significant association between milk consumption and thyroid nodule as well. CONCLUSION: The present study indicated that non-iodized salt may not increase the risk of thyroid nodules among Chinese children. Similar associations were observed between milk consumption, UIC and thyroid nodules.

Thyroid disrupting chemicals in plastic additives and thyroid health.

The globally escalating thyroid nodule incidence rates may be only partially ascribed to better diagnostics, allowing for the assessment of environmental risk factors on thyroid disease. Endocrine disruptors or thyroid-disrupting chemicals (TDC) like bisphenol A, phthalates, and polybrominated diphenyl ethers are widely used as plastic additives in consumer products. This comprehensive review studied the magnitude and uncertainty of TDC exposures and their effects on thyroid hormones for sensitive subpopulation groups like pregnant women, infants, and children. Our findings qualitatively suggest the mixed, significant (α = 0.05) TDC associations with natural thyroid hormones (positive or negative sign). Future studies should undertake systematic meta-analyses to elucidate pooled TDC effect estimates on thyroid health indicators and outcomes.

Fluoride-induced thyroid dysfunction in rats: roles of dietary protein and calcium level.

To assess the roles of dietary protein (Pr) and calcium (Ca) level associated with excessive fluoride (F) intake and the impact of dietary Pr, Ca, and F on thyroid function, 144 30-day-old Wistar albino rats were randomly allotted to six groups of 24 (female:male = 1:1). The six groups were fed (1) a normal control (NC) diet (17.92% Pr, 0.85% Ca = NC group); (2) the NC diet and high F (338 mg NaF [=150 mg F ion]/L in their drinking water = NC+F group); (3) low Pr and low Ca diet (10.01% Pr, 0.24% Ca = LPrLCa group); (4) low Pr and low Ca diet plus high F = LPrLCa+F group; (5) high Pr and low Ca diet plus high F (25.52% Pr, 0.25% Ca = HPrLCa+F group); and (6) low Pr and high Ca diet plus high F (10.60% Pr, 1.93% Ca = LPrHCa+F group). The areas of thyroid follicles were determined by Image-Proplus 5.1, and triiodothyronine (T3), free T3 (FT3), thyroxine (T4), and free T4 (FT4) levels in serum were measured by radioimmunoassay. The histopathological study revealed obviously flatted follicular epithelia cells and hyperplastic nodules, consisting of thyroid parafollicular cells that appeared by excessive F ingestion, on the 120th day. Pr or Ca supplementation reverses the F-induced damage in malnutrition. The serum T3, FT3, T4, and FT4 levels in the NC+F group were significantly decreased and significantly increased in the LPrLCa+F group. Thus, excessive F administration induces thyroid dysfunction in rats; dietary Pr and Ca level play key roles in F-induced thyroid dysfunction.

Induction of thyroid proliferative changes in rats treated with antithyroid compound.

This study was designed to investigate the histologic changes in goitrogen-induced thyroid growth of the rat. The animals were orally treated by 1% potassium perchlorate except the controls and were sacrificed in intervals ranging from 1 to 12 months. The thyroid weight increased progressively along the treatment and after 2 months showed a diffuse homogenous hypertrophy and hyperplasia of follicular cells, decreased amount of colloid and increased vascularity. After sixth month of treatment true nodules appeared with complex morphology.