Relationship Between Exposure To Organic Environmental Endocrine Disrupting Chemicals And Metal/metalloid And Risk Of Nodular Goiter/ Papillary Thyroid Carcinoma

Objective:The thyroid,the largest endocrine gland,plays a vital role in many physiological processes,such as metabolism and the development and differentiation of organs.In recent years,the incidence and detection rate of thyroid diseases,such as thyroid nodules and thyroid tumors,have increased significantly.An increasing number of people are suffering from nodular goiter（NG）and papillary thyroid cancer（PTC）.Risk factors for thyroid nodular and tumors still remain to be explored.Apart from ionizing radiation（a well-known risk factor for PTC）,the association between other definite environmental risk factors and NG/PTC development has not been elucidated.Endocrine disrupting chemicals（EDCs）are exogenous substances,which can interfere with the synthesis,secretion,transport,and metabolism of hormones,and affect the reproduction,nerves,and endocrine systems in the body.A number of EDCs are organics.The organic EDCs are considered one of the most common groups of environmental pollutants.After organic EDCs are enriched in the body,they usually produce biological effects in the form of hormones,causing the endocrine function to be disordered.Accumulating evidence from epidemiological studies has indicated that organic EDCs exposure is involved in some adverse health outcomes,including cardiovascular diseases,birth defects,asthma,and diabetes.However,there has been only limited study on the association between exposure to organic EDCs and thyroid gland disorders.Therefore,we explore whether exposure to organic EDCs is associated with the risk of NG or PTC.Metals/metalloids are widely existing substances in the natural environment.Their contents are low in the human body,but they played an important role in activities.Humans are exposed to various metals/metalloids through food,drinking water,air and public consumer goods.However,excessive exposure to certain metals/metalloids has negative effects on health,such as liver and kidney dysfunction,cardiovascular disease,nervous system damage,and malignant tumors.Studies have found that metals/metalloids are associated with the risk of NG/PTC,but the results of epidemiological studies on the relationship between metals/metalloids and NG/PTC are still inconsistent.Notably,some metals/metalloids are regarded as inorganic EDCs.Therefore,based on the first part of the study,the second part explored the relationship between common metals/metalloids and the risk of NG/PTC by carrying out a case-control study.Methods:1.Study participants:from September 2017 to July 2018 and from June 2021 and October 2021,all of the NG and PTC patients were diagnosed by surgical and pathological examinations.The controls are healthy adults from the physical exams during the same period without any history of chronic diseases,especially thyroid disease,liver and kidney system diseases,and endocrine and metabolic diseases.2.Data collection:collected information regarding gender,age,ethnicity,height,weight,and residential address（urban/rural areas）.3.Sample collection and measurement:Early morning,fasting and venous sampling were obtained in all subjects.Urine samples were collected and stored in a 15 ml container at-40°C until subsequent analysis.Thirteen common organic EDCs were measured by gas chromatography-triple-quadrupole mass spectrometry（GC-MS/MS）,namely,2-t-Octylphenol（2-t-OP）,4-nonylphenol（4-NP）,bisphenol A（BPA）,1-hydroxynaphthalene（1-OH-NAP）,2-hydroxynaphthalene（2-OH-NAP）,2-hydroxydibenzofuran（2-OH-DBF）,2-hydroxyfluorene（2-OH-FLU）,3-hydroxyfluorene（3-OH-FLU）,4-hydroxyphenanthrene（4-OH-PHE）,3/9-hydroxyphenanthrene（3/9-OH-PHE）,1-hydroxyphenanthrene（1-OH-PHE）,2-OH-PHE,and 1-hydroxypyrene（1-OH-PYR）.Seven metals/metalloids,namely,Al,Co,As,Sr,Cd,Ba and Pb were measured by inductively coupled plasma mass spectrometry（ICP-MS）.Detection of other indicators:urine iodine concentration was measured by arsenic-cerium catalytic spectrophotometry.The levels of FT3,FT4 and TSH in serum were measured by an automatic chemiluminescence immunoassay.4.Statistical analysis:The spearman correlation analysis and Bayesian Kernel Machine Regression（BKMR）model were carried out using R 4.0.5,and other data analyses were carried out using SPSS 22.0 software package.The significance of differences in the distribution of baseline characteristics between the groups was tested using student t for continuous variables.Categorical variables（i.e.,sex,marital status,ethnicity,place of residence,smoking and drinking status and iodine status）were described using percentiles,and a chi-squared test was used to examine the differences among the groups.The non-normally distributed continuous variables（UIC and EDCs concentrations）were expressed as medians（interquartile range,IQR）and were analyzed by the Mann-Whitney U test.Linear regression analysis was used to evaluate the correlation between EDCs,metals/metalloids and thyroid function.Binary logistic regression analysis was adopted to calculate the odds ratios（ORs）and corresponding95%confidence intervals（CIs）for comparing the high and low tertiles of EDCs or metals/metalloids concentrations.We used two levels of adjustment:one was a crude model not considering the impacts of other covariates,and another was adjusted for age,sex,BMI,and place of residence.We implemented a novel model of the（BKMR）model to assess the association between chemical mixture exposure and NG/PTC and thyroid function.Two-sided P<0.05 was considered statistically significant.Results:1.Participant characteristics.A total of 312 participants,including 104 NG cases,104PTC cases,and 104 normal controls,were recruited.2.Urinary iodine concentration（UIC）.There were no significant differences in UIC or iodine status among the groups.3.Thyroid hormone.FT4 levels of the NG group were higher than those of the control group,and the TSH levels were lower than that of the control group（P<0.05）.FT4levels of the PTC group were higher than those of the control group（P<0.05）.4.Concentrations of EDCs.The concentrations of 1-OH-NAP,2-OH-DBF,2-OH-FLU,and 1-OH-PHE in the NG group were significantly higher than in the controls（P<0.05）.The median levels of 2-OH-NAP and 1-OH-PHE in the PTC group were significantly higher than in the control group（P<0.05）.In women,the concentrations of 1-OH-NAP,2-OH-NAP,2-OH-DBF,2-OH-FLU and 3-OH-FLU in the NG and PTC groups were significantly higher than those in the controls（all P<0.05）.Furthermore,female patients in the NG group exhibited significantly higher levels of 1-OH-PHE than the controls（P<0.05）.There were no significant differences in any EDCs levels among the three groups in men.5.Linear correlation between EDCs concentration and thyroid hormone.The concentrations of 1-OH-NAP and 4-OH-PHE are positively correlated with FT3 level,and 2-OH-NAP concentration is positively correlated with FT4 level.The concentrations of 2-OH-NAP,2-OH-DBF,2-OH-FLU and 3-OH-FLU are negatively correlated with TSH level.6.Association between exposure to EDCs and risk of NG.After adjusting for age,sex,BMI,and place of residence,the high tertile of 2-OH-FLU remained positively associated with NG（OR=2.60,95%CI:1.01-4.20,P=0.048）.After adjustments for age,BMI and place of residence,female participants in the high tertile of 1-OH-NAP,2-OH-NAP,2-OH-DBF and 2-OH-FLU had 3.44-（95%CI=1.50-7.89,P=0.004）,2.37-（95%CI=1.06-5.30,P=0.036）,2.80-（95%CI=1.23-6.41,P=0.015）and 3.65-fold（95%CI=1.56-8.58,P=0.003）risk of NG than participants in the low tertile.7.Association between exposure to EDCs and risk of PTC.After adjusting for age,sex,BMI and place of residence,the concentrations of EDCs,including 2-OH-DBF,2-OH-FLU,3/9-OH-PHE and 1-OH-PHE,were significantly associated with the risk of PTC(P_trend=0.015,0.043,0.004 and 0.047,respectively).After adjustment for age,BMI and place of residence,the concentrations of 1-OH-NAP,2-OH-NAP,2-OH-DBF,2-OH-FLU,3-OH-FLU,3/9-OH-PHE and 1-OH-PHE,were significantly associated with the risk of PTC(P_trend=0.036,0.003,0.008,0.009,0.005,0.021 and 0.022),respectively)in women.8.In the BKMR analysis,the risk of NG/PTC increased with the increasing of the overall EDCs exposure levels,when the thirteen common organic EDCs were served as a mixture.We also found that when all the other EDCs were fixed at the median exposure level,concentrations of urinary 2-OH-DBF showed a nonlinear relationship with NG,and 2-OH-DBF and 1-OH-PHE correlated with the increased incidence of PTC.There was an interaction between 2-OH-FLU and 2-OH-DBF on NG/PTC and an interaction between 2-OH-FLU and OP on NG.9.Concentrations of urine metals/metalloids.The concentration of Cd and Ba in the NG group was significantly higher than in the controls.The concentration of Ba and Pb in the PTC group was significantly higher than the control group（P<0.05）.Female patients in the NG group exhibited significantly higher levels of Al,As,Ba and Pb,and female patients in the PTC group exhibited significantly higher levels of Cd and Pb than the controls（P<0.05）.Except for the concentration of the urine Ba from the male NG patients was significantly higher than that of the control group,there was no difference in the concentration of other elements by gender stratification.10.Linear correlation between metals/metalloids concentration and thyroid hormone.Al concentration is positively correlated with TSH level in the model without adjustment,and As concentration is negatively correlated with TSH level after adjusting for several variables.11.Association between exposure to metals/metalloids and risk of NG.After adjusting for age,sex,ethnicity,BMI,and place of residence,the high tertile of Ba remained positively associated with NG（OR=2.11,95%CI:1.01-4.39,P=0.046）.The middle and high tertile of Cd remained positively associated with NG（OR=2.60,95%CI:1.13-5.99,P=0.025;OR=2.59,95%CI:1.12-6.00,P=0.026,respectively）compared with the low tertile in women,and Cd was significantly associated with the risk of PTC(P_trend=0.038).12.Association between exposure to metals/metalloids and risk of PTC.After adjusting for age,sex,ethnicity,BMI and place of residence,the high tertile of Cd and Ba remained positively associated with PTC（OR=3.76,95%CI:1.54-9.16,P=0.004;OR=2.24,95%CI:1.01-4.95,P=0.046,respectively）,and the concentrations of Cd and Ba were positively correlated with the incidence of PTC（P=0.011 and 0.045）.In crude analysis,the high tertile of Ba showed a positive association with the development of PTC in females（OR=2.49,95%CI:1.13-5.50,P=0.024）.After adjusting for age,ethnicity,BMI and place of residence,the high tertile of Cd and Ba remained negatively associated with PTC（OR=2.74,95%CI:1.07-7.02,P=0.036;OR=2.54,95%CI:1.05-6.15,P=0.038,respectively）compared with the low tertile.13.In the BKMR analysis,the risk of NG/PTC increased with the increasing of the overall metals/metalloids exposure levels,when the seven metals/metalloids were served as a mixture.We also found that when all the other metals/metalloids were fixed at the median exposure level,concentrations of urinary As,Cd and Ba showed a positive relationship with NG,and Cd correlated with the increased incidence of PTC.Urinary Co was negatively associated with PTC,and Ba and Pb showed a nonlinear relationship with PTC.Conclusion:1.Higher levels of 2-OH-FLU may contribute to the increased risk of NG in populations.2.Four EDCs,namely,2-OH-DBF,2-OH-FLU,3/9-OH-PHE and 1-OH-PHE,were positively associated with PTC development in populations.3.EDCs exposure was more likely to increase the risk of NG/PTC in women,suggesting a gender-specific effect of EDCs exposure on the development of NG/PTC.4.Higher levels of urinary As,Cd and Ba contribute to the increased risk of NG in populations.5.Urinary Cd and Ba were positively associated with PTC development,and Co was negatively associated with PTC development in populations.