Next Article in Journal
Participant Experiences in a Human Biomonitoring Study: Follow-Up Interviews with Participants of the Flemish Environment and Health Study
Previous Article in Journal
The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Toxics
Volume 9
Issue 3
10.3390/toxics9030068
toxics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Urinary Biomarkers of Phthalates Exposure, Blood Lead Levels, and Risks of Thyroid Nodules

by
Jingsi Chen
1,2,†,
Yi Chen
3,†,
Shaojie Liu
2,
Bo Chen
2,
Yingli Lu
3,* and
Ruihua Dong
2,*
1
Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou 215123, China
2
Key Laboratory of Public Health Safety of Ministry of Education, Collaborative Innovation Center of Social Risks Governance in Health, School of Public Health, Fudan University, Shanghai 200032, China
3
Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
*
Authors to whom correspondence should be addressed.
†
J.C. and Y.C. had equal contribution.
Toxics 2021, 9(3), 68; https://doi.org/10.3390/toxics9030068
Submission received: 1 February 2021 / Revised: 3 March 2021 / Accepted: 16 March 2021 / Published: 22 March 2021
(This article belongs to the Section Exposome)
Versions Notes

Abstract

:
Thyroid nodules (TNs) are becoming increasingly prevalent. However, few studies have reported the effects of phthalates and lead (Pb) on TNs. In this study, we aimed to explore the associations of phthalates and Pb with the risks of TN. We sex-age-matched 220 TNs patients and 220 healthy controls from Zhejiang Shangyu, China. We measured 13 phthalate metabolites in spot urine samples. Blood lead levels (BLLs) were determined by atomic absorption spectrometry. The multivariable logistic regression models were used to assess the associations between urinary phthalate metabolites and BLLs and the risks of TNs. We found BLLs were associated with increased risk of TNs in total population. Female-specific positive associations of mono-2-ethyl-5-carboxypentylphthalate (MECPP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-oxohexylphthalate (MEOHP), mono-2-carboxymethyl-hexyl phthalate (MCMHP), and mono-isononyl phthalate (MiNP) with increased risk of TNs were also observed. Moreover, the positive association between phthalates and TNs was modified by BLLs. At the highest tertile of BLLs, monoethylphthalate (MEP), MECPP, MEHHP, MEOHP, and MiNP were significantly associated with increased risk of TNs. Our results indicated that certain phthalate metabolites and BLLs may contribute to increased risks of TNs.

1. Introduction

Thyroid nodules (TNs) are becoming increasingly prevalent [1]. TNs may result in a variety of clinical sequelae, especially thyroid cancer [2,3]. China had high prevalence of TNs as being estimated to be 30–50% in healthy adults [4,5]. Women were reported to be more frequently affected than men [6]. The high prevalence of TNs may be attributed to the advancements in diagnostic technologies. However, accumulating evidence in recent years suggested that exposure to some endocrine chemicals might be also responsible for the increasing incidence of TNs [7].
One type of endocrine disruptor is phthalates, which have been reported to disrupt thyroid function and its growth. Several rodent experiments indicated that phthalates exposure might adversely influence thyroid homeostasis [8]. The epidemiologic data also reported that phthalates may adversely influence thyroid hormone levels among different populations including infants, adolescents, and adults [9,10,11,12]. Phthalates exposure alters thyroid hormone levels and disrupts thyroid hormone homeostasis, which may be responsible for TNs [13,14,15]. Nevertheless, the human data are scarce regarding the effects of phthalates on TNs.
Lead (Pb) is another chemical reported to impact thyroid function [16,17]. Several epidemiology studies reported the association between Pb exposure and thyroid hormone levels. For example, Dundar et al. (2006) found that serum Pb could significantly reduce free thyroxine (FT4) levels level in adolescents [18]. Maryam found that Pb can increase the risk of developing hypothyroidism and thyroid cancer [19]. However, the human evidence is also scarce and inconsistent. Moreover, there is no human study concerned the effect of Pb on TNs.
Both phthalates and Pb are common chemicals that are commonly used in daily consumer products, resulting in ubiquitous human exposure [20,21]. In this study, we conducted a case–control study to explore the associations of phthalates and Pb exposure as well as their interaction with the risk of having TNs.

2. Materials and Methods

2.1. Study Participants and Data Collection

All participants were a subset of Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT China). More detailed sampling information is published in previous articles [22]. For this study, 628 subjects in Shangyu city of Zhejiang province who provided urine samples were recruited. We excluded the participants who had a history of thyroid surgery (n = 14), thyroid diseases (n = 8), and missing thyroid ultrasound (US) information (n = 5). Two-hundred-and-twenty participants who were diagnosed with TNs (multiple nodules or single nodule with any lesion ≥2 mm in diameter) by ultrasound were included into TNs group. The sex-age-matched (±3 years) control group (n = 220) was recruited from healthy participants of the aforementioned Shangyu sample set. All participants were administered with a questionnaire interview to collect basic demographics characteristics and lifestyle, medical, and family history. They also received comprehensive physical and biochemical examinations and B-mode ultrasonic examinations. The detailed information of thyroid examinations and the definition of thyroid nodule were published in previous articles [23].
In addition, all participants had their blood lead levels (BLLs) measured. BLLs were determined by atomic absorption spectrometry (BH2200, China) [24]. In brief, 0.1 mL blood sample was thawed, transferred to a 1.5 mL plastic centrifuge tube, and mixed with 0.9 mL Triton solution (0.1%). Then, the mixture was analyzed by atomic absorption spectrometry. The average recoveries and relative standard deviations (RSD) were 98.7% and 0.9% at 40 μg/dL, 104.1%, and 2.5% at 1 μg/dL. The limits of detection (LOD) was 0.6 μg/dL.
All individuals provided informed consent prior to data collection. The study protocol was approved by the ethics committee of the Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine.

2.2. Measurement of Urinary Metabolites of Phthalates

We used the method of ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to detect 13 urinary metabolites of phthalates, including monomethyl phthalate (MMP), monoethylphthalate (MEP), mono-n-butylphthalate (MnBP), monoisobutylphthalate (MiBP), mono-benzylphthalate (MBzP), mono-2-ethylhexylphthalate (MEHP), mono-2-ethyl-5-oxohexylphthalate (MEOHP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-carboxypentylphthalate (MECPP), mono-2-carboxymethyl-hexyl phthalate (MCMHP), mono-(3-carboxypropyl) phthalate (MCPP), mono-isononyl phthalate (MiNP), and mono-cyclohexyl phthalate (MCHP).
The method has been described in our previous study with slight modification [25]. Briefly, we thawed 1 mL of urine sample, transferred it to a 10 mL glass tube, and incubated with β-glucuronidase (E. coli K 12; Roche, Mannheim, Germany) at 37 °C for 120 min. Subsequently, the sample was mixed with 1 mL of aqueous 2% (v/v) acetic acid and 100 μL of internal standard (100 μg/L). The mixture was loaded into a PLS column (Dikma, China; 60 mg/3 mL) previously activated with 2 mL methanol and 2 mL of aqueous 0.5% (v/v) acetic acid. After sample loading, the column was washed with 2 mL of aqueous 0.5% (v/v) acetic acid. Next, 1 mL of methanol was added to elute metabolites. Finally, the eluate was passed through a 0.2 μm filter and analyzed (2 μL) by an UPLC-MS/MS system integrated by Waters ACQUITY UPLC H-Class (Waters, Milford, MA, USA) coupled with an ABSCIEX QTRAP 6500 (AB Sciex Technologies, Framingham, MA, USA). The analytical column was a Waters ACQUITY UPLC BEH C18 Column (1.7 µm, 2.1 × 50 mm, Waters, Milford, MA, USA).
An internal standard method was used to quantify the target metabolite. For every 20 samples, a procedural blank and two matrix-spiked samples at two different spiking concentrations (5 and 15 ng/mL) were processed. The average recoveries and RSD of target metabolites ranged from 86.5% to 123.1% and from 0.5% to 12.5% at 5 μg/L, and ranged from 75.3% to 98.4% and from 0.7% to 8.8% at 15 μg/L, respectively. Sample concentrations of these metabolites were determined after subtraction of blank values. The LOD was calculated at signal-to-noise (S/N) of 3, with concentration of 0.100, 0.080, 0.006, 0.006, 0.060, 0.006, 0.010, 0.020, 0.020, 0.040,0.100, 0.010, and 0.004 μg/L for MMP, MEP, MnBP, MiBP, MBzP, MEHP, MEOHP, MEHHP, MECPP, MCMHP, MCPP, MiNP, and MCHP, respectively.

2.3. Statistical Analysis

Data analyses were performed using IBM SPSS Statistics. p values are presented as two-tailed with a significance level of 0.05. The differences in demographic characteristics, urinary phthalate metabolites, and BLLs between case and control subjects were analyzed using Mann-Whitney U test, Student t test, and χ2 test depending on the distribution of the data. The p values were adjusted using false discovery rate. We conducted multiple logistic regression analysis to assess the associations of urinary phthalate metabolites and BLLs with risk of TNs. Urinary phthalate metabolites and BLLs were modeled as continuous variables in the logistic models to calculate the odds ratios (ORs) for TNs. We adjusted several potential confounders including age, sex, BMI, current smoking status, current alcohol status and educational level in the regression models. Because the incidence of TNs has a gender disparity, we further analyzed the gender difference between the urinary phthalate metabolites, BLLs, and the risks of TNs. Furthermore, we analyzed the effect modification by BLLs between the urinary phthalate metabolites and the risk of having TNs. The BLLs were categorized into tertiles. The categorical BLLs and urinary phthalate metabolites were included into the models as interaction terms.

3. Result

3.1. Population Characteristics

The demographic information of the 418 individuals is summarized in Table 1. No differences were found between TNs patients and the controls. Concentration distribution of BLLs and urinary metabolites of phthalates are listed in Table 2. TNs patients and controls had no difference in the concentrations of phthalates metabolites and BLL.

3.2. Regression Results

The associations between urinary phthalate metabolites, BLLs, and risk of TNs in the overall population are presented in Table 3. We found that BLLs were associated with increased risk of TNs. Table 4 presents the associations stratified by gender. Increased risks of TNs were only observed among females. MECPP, MEHHP, MEOHP, MCMHP, and MINP were significantly associated with increased risk of TNs in female.

3.3. Evaluation of Effect Modification

We found effect modification by BLLs between phthalate metabolites and risks of TNs among female but not male (Table 5, data are not shown for males). At the second and third tertile of BLLs, MEP, MECPP, MEHHP, MEOHP, and MINP were significantly associated with increased risk of TNs compared to the lowest tertile of BLLs.

4. Discussions

In this study, we found some urinary phthalate metabolites and BLLs increased the risk of TNs. We also observed some sex-specific associations of specific urinary phthalate metabolites with the risk of TNs. Third, we observed effect modification by BLLs between phthalate metabolites and risk of TNs among females but not males.
Some studies have observed the association between phthalates exposure with thyroid disorders [9,10,26]. Although TNs had high prevalence in the general population, there was few epidemiological studies examining the relationships between phthalates with TNs. To our knowledge, there were only two recent studies examined the association between phthalates and the risks of TNs. For example, one study detected DEHP and MEHP concentrations in 27 TNs and 28 thyroid cancer patients, and this study found exposure to DEHP metabolites in TNs patients increases susceptibility to develop thyroid cancer [27]. Another case-control study sex-matched 138 TN patients, 144 thyroid cancer, and 144 healthy controls from China. They also found the exposure of DEHP metabolites positively associated with risks of TNs. However, MBP exposure decreased the risks of TNs and thyroid cancer [28]. Furthermore, this study found male-specific positive associations between specific phthalates exposure and the risk of thyroid cancer. On the contrary, we found female-specific positive associations between specific phthalate metabolites and the risk of TNs.
The disparate findings by previous study compared to our study may be attributable to the different population, as well as to different exposure levels to phthalates. Phthalates are widely used as plasticizers in cosmetics, food packaging, and other industrial products. Due to the reversible combination to plastic matrix, phthalates can leach out from the plastics and population may be exposed to phthalates through application of cosmetics, the ingestion of food and drinking water, and inhalation of indoor and outdoor air. As with different lifestyles, the different populations had different exposure levels to phthalates. For example, except for MMP and MEHP, the urinary concentration of other metabolites observed by Liu. et al. was higher than that in our study. MEP in Liu et al. (13.02 μg/g) was 2 times higher than that detected in this study (7.35 μg/g). Note that because of the very small sample sizes of males (n = 40) in the study conducted by Liu et al., more human studies are needed to identify the associations of the exposure to phthalates with the risks of TNs, as well as the sex difference.
Several mechanisms may explain the association of phthalates with increased TNs risk. First, previous studies found relationships of urinary phthalate metabolites with oxidative stress in different populations [29,30,31]. Thus, exposure to certain phthalates induce oxidative stress in thyroid which could impact the development and progression of TNs. Second, phthalates exposure was found to disrupt thyroid hormone homeostasis [13,32]. Third, altered thyroid hormone levels, and disrupted hypothalamus-pituitary-thyroid (HPT) axis, may also attribute to the development and progression of TNs [13,33].
A few studies have explored the relationship between BLLs and thyroid hormones, while most of them were conducted in small occupational populations [34]. In general, the BLLs in controls of our study was higher, but comparable with the levels reported in general population of China [35,36] and in several U.S. NHANES studies [37,38]. According to the recent definitions by the U.S. Centers for Disease Control and Prevention and National Institute of Occupational Safety and Health (NIOSH), BLLs greater than or equal to 5 μg/dL are considered as to be elevated in adults [39]. The median BLLs for our study participants was 3.7 μg/dL, which was lower than 5 μg/dL. Although the toxic effects of Pb at high level on thyroid function have been reported, the associations between “relatively lower level” of Pb and thyroid function in general populations are still scarce. To the best of our knowledge, this is the first study to explore associations of Pb with TNs in the general population. A recent study reported that higher content of Pb in the thyroid gland could be involved in the etiology of multinodular goiter disease [17]. Although the underlying mechanisms are still unclear, altered thyroid hormone levels and disrupted immune system may play a role in the development and progression of TNs [34].
As mentioned, phthalates and Pb disrupt thyroid function through different mechanisms. Therefore, it is not unexpected that we first explored effect modification by BLLs between phthalate metabolites and risks of TNs. There are several potential mechanisms by which phthalates and Pb may interact to affect thyroid function. On the one hand, both phthalates and Pb were positively related to TSH [34]. The rate of increased serum TSH was positively associated with the rate of the malignant nature of TNs [40,41]. On the other hand, both phthalates and Pb may modulate the immune system and alter circulating markers of inflammation [34,42]. Our results highlight the roles of phthalates and Pb in the largely unclarified etiology of TNs. Therefore, more studies are needed to reveal the potential mechanisms.
Our study has several shortcomings. First, one-spot urine was not enough to present the exposure level of phthalates because of the short half-lives of phthalates. Second, blood Pb, which mostly reflects relatively recent exposure, is an inadequate method to measure the body burden of Pb. Second, we did not take into account confounders such as the consumption of lithium, which may need to be considered. Third, the cross-sectional, case–control design could not adequately control for significant potential confounders, and limits our ability to explore the exposure–outcome associations between phthalates, Pb and TN. Finally, the cross-sectional design is not appropriate to allow the causal interpretation of the findings.

5. Conclusions

We observed increased risks of TNs for specific urinary phthalate metabolites and BLLs. Moreover, some specific phthalate metabolites increased risks of TNs only in females but not males. Finally, we found the positive associations between phthalates and TNs were modified by BLLs among females.

Author Contributions

We thank all participants for their participation and kind assistance. Y.L. and Y.C. contributed to the conception and study design; R.D., J.C., and Y.C. contributed to the acquisition of data; R.D. and J.C. performed data analysis; S.L., R.D., J.C., and Y.C. contributed to the interpretation of data; B.C., R.D., Y.L., and Y.C. contributed to manuscript writing, and critically revised the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 82003412), the National Key Research and Development Program of China (grant numbers 2017YFC1600504), and the China Postdoctoral Science Foundation Grant (grant numbers 2019M651380).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the ethics committee of the Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (SH9H-2019-T11-1, 2019-01-29).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to them containing information that could compromise research participant privacy.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Haugen, B.R.; Alexander, E.K.; Bible, K.C.; Doherty, G.M.; Mandel, S.J.; Nikiforov, Y.E.; Pacini, F.; Randolph, G.W.; Sawka, A.M.; Schlumberger, M.; et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016, 26, 1–133. [Google Scholar] [CrossRef] [Green Version]
  2. Chen, Z.; Xu, W.; Huang, Y.; Jin, X.; Deng, J.; Zhu, S.; Liu, H.; Zhang, S.; Yu, Y. Associations of noniodized salt and thyroid nodule among the Chinese population: A large cross-sectional study. Am. J. Clin. Nutr. 2013, 98, 684–692. [Google Scholar] [CrossRef] [Green Version]
  3. Polyzos, S.; Kita, M.; Avramidis, A. Thyroid nodules—Stepwise diagnosis and management. Hormones 2007, 6, 101–119. [Google Scholar] [CrossRef] [Green Version]
  4. Song, J.; Zou, S.R.; Guo, C.Y.; Zang, J.J.; Ni Zhu, Z.; Mi, M.; Huang, C.H.; Yu, H.T.; Lu, X.; Ruan, Y.; et al. Prevalence of Thyroid Nodules and Its Relationship with Iodine Status in Shanghai: A Population-based Study. Biomed. Environ. Sci. 2016, 29, 398–407. [Google Scholar] [PubMed]
  5. Jiang, H.; Tian, Y.; Yan, W.; Kong, Y.; Wang, H.; Wang, A.; Dou, J.; Liang, P.; Mu, Y. The Prevalence of Thyroid Nodules and an Analysis of Related Lifestyle Factors in Beijing Communities. Int. J. Environ. Res. Public Health 2016, 13, 442. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Fisher, S.B.; Perrier, N.D. The incidental thyroid nodule. CA A Cancer J. Clin. 2018, 68, 97–105. [Google Scholar] [CrossRef] [PubMed]
  7. Li, L.; Ying, Y.; Zhang, C.; Wang, W.; Li, Y.; Feng, Y.; Liang, J.; Song, H.; Wang, Y. Bisphenol A exposure and risk of thyroid nodules in Chinese women: A case-control study. Environ. Int. 2019, 126, 321–328. [Google Scholar] [CrossRef] [PubMed]
  8. Mathieu-Denoncourt, J.; Wallace, S.J.; de Solla, S.R.; Langlois, V.S. Plasticizer endocrine disruption: Highlighting developmental and reproductive effects in mammals and non-mammalian aquatic species. Gen. Comp. Endocrinol. 2015, 219, 74–88. [Google Scholar] [CrossRef] [Green Version]
  9. Johns, L.E.; Ferguson, K.K.; McElrath, T.F.; Mukherjee, B.; Meeker, J.D. Associations between Repeated Measures of Maternal Urinary Phthalate Metabolites and Thyroid Hormone Parameters during Pregnancy. Environ. Health Perspect. 2016, 124, 1808–1815. [Google Scholar] [CrossRef] [Green Version]
  10. Park, C.; Choi, W.; Hwang, M.; Lee, Y.; Kim, S.; Yu, S.; Lee, I.; Paek, D.; Choi, K. Associations between urinary phthalate metabolites and bisphenol A levels, and serum thyroid hormones among the Korean adult population—Korean National Environmental Health Survey (KoNEHS) 2012–2014. Sci. Total Environ. 2017, 584–585, 950–957. [Google Scholar] [CrossRef]
  11. Huang, P.-C.; Kuo, P.-L.; Guo, Y.-L.; Liao, P.-C.; Lee, C.-C. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum. Reprod. 2007, 22, 2715–2722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Minatoya, M.; Jima, S.N.; Sasaki, S.; Araki, A.; Miyashita, C.; Ikeno, T.; Nakajima, T.; Goto, Y.; Kishi, R. Effects of prenatal phthalate exposure on thyroid hormone levels, mental and psychomotor development of infants: The Hokkaido Study on Environment and Children’s Health. Sci. Total Environ. 2016, 565, 1037–1043. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Kim, S.; Park, G.-Y.; Yoo, Y.J.; Jeong, J.S.; Nam, K.T.; Jee, S.-H.; Lim, K.-M.; Lee, Y.-S. Di-2-ethylhexylphthalate promotes thyroid cell proliferation and DNA damage through activating thyrotropin-receptor-mediated pathways in vitro and in vivo. Food Chem. Toxicol. 2019, 124, 265–272. [Google Scholar] [CrossRef]
  14. Erkekoglu, P.; Giray, B.K.; Kizilgun, M.; Hininger-Favier, I.; Rachidi, W.; Roussel, A.-M.; Favier, A.; Hincal, F. Thyroidal effects of di-(2-ethylhexyl) phthalate in rats of different selenium status. J. Environ. Pathol. Toxicol. Oncol. 2012, 31, 143–153. [Google Scholar] [CrossRef]
  15. Erkekoglu, P.; Giray, B.K.; Kızilgün, M.; Rachidi, W.; Hininger-Favier, I.; Roussel, A.-M.; Favier, A.; Hincal, F. Di(2-ethylhexyl)phthalate-induced renal oxidative stress in rats and protective effect of selenium. Toxicol. Mech. Methods 2012, 22, 415–423. [Google Scholar] [CrossRef]
  16. Liu, Y.; Liu, S.; Mao, J.; Piao, S.; Qin, J.; Peng, S.; Xie, X.; Guan, H.; Li, Y.; Shan, Z.; et al. Serum Trace Elements Profile in Graves’ Disease Patients with or without Orbitopathy in Northeast China. BioMed Res. Int. 2018, 2018, 1–8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Stojsavljević, A.; Rovčanin, B.; Krstić, Đ.; Borković-Mitić, S.; Paunović, I.; Kodranov, I.; Gavrović-Jankulović, M.; Manojlović, D. Evaluation of trace metals in thyroid tissues: Comparative analysis with benign and malignant thyroid diseases. Ecotoxicol. Environ. Saf. 2019, 183, 109479. [Google Scholar] [CrossRef] [PubMed]
  18. Dundar, B.; Öktem, F.; Arslan, M.K.; Delibas, N.; Baykal, B.; Arslan, Ç.; Gultepe, M.; Ilhan, I.E. The effect of long-term low-dose lead exposure on thyroid function in adolescents. Environ. Res. 2006, 101, 140–145. [Google Scholar] [CrossRef] [PubMed]
  19. Rezaei, M.; JavadMoosavi, S.Y.; Mansouri, B.; Azadi, N.A.; Mehrpour, O.; Nakhaee, S. Thyroid dysfunction: How concentration of toxic and essential elements contribute to risk of hypothyroidism, hyperthyroidism, and thyroid cancer. Environ. Sci. Pollut. Res. 2019, 26, 35787–35796. [Google Scholar] [CrossRef] [PubMed]
  20. Hauser, R.; Calafat, A. Phthalates and human health. Occup. Environ. Med. 2005, 62, 806–818. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Koch, H.M.; Rossbach, B.; Drexler, H.; Angerer, J. Internal exposure of the general population to DEHP and other phthalates—determination of secondary and primary phthalate monoester metabolites in urine. Environ. Res. 2003, 93, 177–185. [Google Scholar] [CrossRef]
  22. Jiang, B.; Zheng, Y.; Chen, Y.; Chen, Y.; Li, Q.; Zhu, C.; Wang, N.; Han, B.; Zhai, H.; Lin, D.; et al. Age and gender-specific distribution of metabolic syndrome components in East China: Role of hypertriglyceridemia in the SPECT-China study. Lipids Health Dis. 2018, 17, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Chen, Y.; Zhu, C.; Chen, Y.; Wang, N.; Li, Q.; Han, B.; Zhao, L.; Chen, C.; Zhai, H.; Lu, Y. The Association of Thyroid Nodules with Metabolic Status: A Cross-Sectional SPECT-China Study. Int. J. Endocrinol. 2018, 2018, 1–8. [Google Scholar] [CrossRef]
  24. Wang, N.; Chen, C.; Nie, X.; Han, B.; Li, Q.; Chen, Y.; Zhu, C.; Chen, Y.; Xia, F.; Cang, Z.; et al. Blood lead level and its association with body mass index and obesity in China—Results from SPECT-China study. Sci. Rep. 2015, 5, 18299. [Google Scholar] [CrossRef]
  25. Chen, J.; Shi, X.; Zhou, X.; Dong, R.; Yuan, Y.; Wu, M.; Chen, W.; Liu, X.; Jia, F.; Li, S.; et al. Renal function and the exposure to melamine and phthalates in Shanghai adults. Chemosphere 2020, 246, 125820. [Google Scholar] [CrossRef] [PubMed]
  26. Gao, H.; Wu, W.; Xu, Y.; Jin, Z.; Bao, H.; Zhu, P.; Su, P.; Sheng, J.; Hao, J.; Tao, F. Effects of Prenatal Phthalate Exposure on Thyroid Hormone Concentrations Beginning at The Embryonic Stage. Sci. Rep. 2017, 7, 13106. [Google Scholar] [CrossRef] [Green Version]
  27. Marotta, V.; Russo, G.; Gambardella, C.; Grasso, M.; La Sala, D.; Chiofalo, M.G.; D’Anna, R.; Puzziello, A.; Docimo, G.; Masone, S.; et al. Human exposure to bisphenol AF and diethylhexylphthalate increases susceptibility to develop differentiated thyroid cancer in patients with thyroid nodules. Chemosphere 2019, 218, 885–894. [Google Scholar] [CrossRef]
  28. Liu, C.; Deng, Y.-L.; Zheng, T.-Z.; Yang, P.; Jiang, X.-Q.; Liu, E.-N.; Miao, X.-P.; Wang, L.-Q.; Jiang, M.; Zeng, Q. Urinary biomarkers of phthalates exposure and risks of thyroid cancer and benign nodule. J. Hazard. Mater. 2020, 383, 121189. [Google Scholar] [CrossRef]
  29. Franken, C.; Lambrechts, N.; Govarts, E.; Koppen, G.; Hond, E.D.; Ooms, D.; Voorspoels, S.; Bruckers, L.; Loots, I.; Nelen, V.; et al. Phthalate-induced oxidative stress and association with asthma-related airway inflammation in adolescents. Int. J. Hyg. Environ. Health 2017, 220, 468–477. [Google Scholar] [CrossRef] [PubMed]
  30. Holland, N.; Huen, K.; Tran, V.; Street, K.; Nguyen, B.; Bradman, A.; Eskenazi, B. Urinary Phthalate Metabolites and Biomarkers of Oxidative Stress in a Mexican-American Cohort: Variability in Early and Late Pregnancy. Toxics 2016, 4, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  31. Dong, R.; Chen, J.; Zheng, J.; Zhang, M.; Zhang, H.; Wu, M.; Li, S.; Chen, B. The role of oxidative stress in cardiometabolic risk related to phthalate exposure in elderly diabetic patients from Shanghai. Environ. Int. 2018, 121, 340–348. [Google Scholar] [CrossRef]
  32. Dong, X.; Dong, J.; Zhao, Y.; Guo, J.; Wang, Z.; Liu, M.; Zhang, Y.; Na, X. Effects of Long-Term In Vivo Exposure to Di-2-Ethylhexylphthalate on Thyroid Hormones and the TSH/TSHR Signaling Pathways in Wistar Rats. Int. J. Environ. Res. Public Health 2017, 14, 44. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Sun, D.; Zhou, L.; Wang, S.; Liu, T.; Zhu, J.; Jia, Y.; Xu, J.; Chen, H.; Wang, Q.; Xu, F.; et al. Effect of Di-(2-ethylhexyl) phthalate on the hypothalamus-pituitary-thyroid axis in adolescent rat. Endocr. J. 2018, 65, 261–268. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Nie, X.; Chen, Y.; Chen, Y.; Chen, C.; Han, B.; Li, Q.; Zhu, C.; Xia, F.; Zhai, H.; Wang, N.; et al. Lead and cadmium exposure, higher thyroid antibodies and thyroid dysfunction in Chinese women. Environ. Pollut. 2017, 230, 320–328. [Google Scholar] [CrossRef]
  35. Zeng, H.-L.; Li, H.; Lu, J.; Guan, Q.; Cheng, L. Assessment of 12 Metals and Metalloids in Blood of General Populations Living in Wuhan of China by ICP-MS. Biol. Trace Element Res. 2018, 189, 344–353. [Google Scholar] [CrossRef] [PubMed]
  36. Chen, C.; Wang, N.; Zhai, H.; Nie, X.; Sun, H.; Han, B.; Li, Q.; Chen, Y.; Cheng, J.; Xia, F.; et al. Associations of blood lead levels with reproductive hormone levels in men and postmenopausal women: Results from the SPECT-China Study. Sci. Rep. 2016, 6, 37809. [Google Scholar] [CrossRef] [Green Version]
  37. Eggers, S.; Safdar, N.; Mc Malecki, K. Heavy metal exposure and nasal Staphylococcus aureus colonization: Analysis of the National Health and Nutrition Examination Survey (NHANES). Environ. Health 2018, 17, 2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Awata, H.; Linder, S.; Mitchell, L.E.; Delclos, G.L. Association of Dietary Intake and Biomarker Levels of Arsenic, Cadmium, Lead, and Mercury among Asian Populations in the United States: NHANES 2011–2012. Environ. Health Perspect. 2017, 125, 314–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Nakhaee, S.; Amirabadizadeh, A.; Brent, J.; Mehrpour, O. Impact of chronic lead exposure on liver and kidney function and haematologic parameters. Basic Clin. Pharmacol. Toxicol. 2019, 124, 621–628. [Google Scholar] [CrossRef] [PubMed]
  40. Fiore, E.; Rago, T.; A Provenzale, M.; Scutari, M.; Ugolini, C.; Basolo, F.; Di Coscio, G.; Berti, P.; Grasso, L.; Elisei, R.; et al. Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: Thyroid autonomy may play a protective role. Endocr. Relat. Cancer 2009, 16, 1251–1260. [Google Scholar] [CrossRef] [Green Version]
  41. Fiore, E.; Vitti, P. Serum TSH and Risk of Papillary Thyroid Cancer in Nodular Thyroid Disease. J. Clin. Endocrinol. Metab. 2012, 97, 1134–1145. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Ferguson, K.K.; McElrath, T.F.; Mukherjee, B.; Loch-Caruso, R.; Meeker, J.D. Associations between Maternal Biomarkers of Phthalate Exposure and Inflammation Using Repeated Measurements across Pregnancy. PLoS ONE 2015, 10, e0135601. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Characteristics of thyroid nodule and corresponding health controls (n = 440).
Table 1. Characteristics of thyroid nodule and corresponding health controls (n = 440).
CharacteristicCases (n = 220)Controls (n = 220)p-Values
Sex, n (%) 1.000
Male101 (45.9)101 (45.9)
Female119 (54.1)119 (54.1)
Age, median (IQR), years62 (54, 69)62 (53, 69)0.912
BMI, kg/m223.5 (21.5, 25.8)23.6 (21.0, 25.7)0.340
Education, n (%)
≤Primary school37 (16.8)39 (17.7)0.931
High school or technical
Secondary school		160 (72.7)172 (78.2)
≥College graduate23 (10.5)9 (4.1)
Smoke, n (%) 0.829
Yes52 (23.6)50 (22.7)
No142 (64.5)149 (67.7)
Quit26 (11.8)21 (9.6)
Alcohol consumpution, n (%) 0.673
Current drinker88 (40.0)92 (41.8)
Non-drinker115 (52.3)112 (50.9)
Former drinker17 (7.7)16 (7.3)
Urinary iodine, median (IQR), μg/L141.3 (84.3, 205.2)148.8 (97.0, 199.8)0.462
IQR: interquartile range.
Table
Table 2. Urinary concentrations of phthalate metabolites (μg/g) and blood lead levels (μg/dL) in study population.
Table 2. Urinary concentrations of phthalate metabolites (μg/g) and blood lead levels (μg/dL) in study population.
ConcentrationsCases (n = 220)Controls (n = 220)p-Adjusted Values
MMP3.14 (1.38, 8.49)3.20 (1.64, 6.27)0.815
MEP6.04 (2.4, 18.91)7.28 (2.76, 24.25)0.815
MiBP9.58 (4.01, 23.94)10.21 (4.63, 23.53)0.815
MnBP9.01 (2.3, 25.25)10.87 (1.66, 26.38)0.815
MBzP0.40 (0.23, 0.89)0.44 (0.23, 0.69)0.815
MEHP2.87 (0.98, 37.76)2.66 (1.00, 31.99)0.985
MECPP7.3 (3.74, 15.33)6.39 (3.42, 11.22)0.815
MEHHP7.59 (3.17, 19.85)6.56 (2.87, 13.48)0.495
MEOHP3.76 (1.99, 9.25)3.46 (1.70, 6.32)0.787
MCMHP0.67 (0.26, 3.7)0.65 (0.21, 1.93)0.787
MCPP1.93 (1.18, 3.53)1.77 (1.12, 2.97)0.815
MiNP8.13 (4.02, 18.8)7.49 (3.77, 13.87)0.815
MCHP0.03 (0.02, 0.06)0.02 (0.01, 0.04)0.495
BLLs4.00 (3.00, 5.30)3.60 (2.70, 4.88)0.322
p-adjusted values: p-values between control and thyroid nodule group, adjusted using false discovery rate.
Table
Table 3. Adjusted ORs for urinary phthalate metabolites, blood lead levels, and thyroid nodule.
Table 3. Adjusted ORs for urinary phthalate metabolites, blood lead levels, and thyroid nodule.
MetabolitesTotal Population
OR (95% CI) a p-Values
MMP0.96 (0.80, 1.15)0.663
MEP0.95 (0.85, 1.06)0.324
MiBP0.96 (0.87, 1.05)0.370
MnBP0.98 (0.92, 1.03)0.412
MBzP0.90 (0.72, 1.13)0.347
MEHP0.97 (0.89, 1.04)0.387
MECPP1.11 (0.92, 1.34)0.290
MEHHP1.07 (0.95, 1.21)0.277
MEOHP1.01 (0.88, 1.17)0.851
MCMHP1.08 (0.96, 1.22)0.219
MCPP0.96 (0.73, 1.26)0.766
MiNP1.09 (0.92, 1.29)0.305
MCHP1.16 (0.90, 1.50)0.251
BLLs1.10 (1.01, 1.19)0.028 *
a The model was constructed with adjusting age, sex, BMI, smoking status, drink status, education level, and urinary iodine. Bold italic *: p < 0.05; ORs: odds ratios.
Table
Table 4. Adjusted ORs for urinary phthalate metabolites, blood lead levels, and thyroid nodule stratified by gender.
Table 4. Adjusted ORs for urinary phthalate metabolites, blood lead levels, and thyroid nodule stratified by gender.
MetabolitesFemale Male
OR (95% CI) ap-ValuesOR (95% CI)p-Values
MMP1.17 (0.91, 1.50)0.2350.77 (0.59, 1.01)0.061
MEP1.10 (0.95, 1.27)0.2180.79 (0.66, 0.93)0.006*
MiBP1.03 (0.90, 1.17)0.6620.86 (0.74, 1.01)0.070
MnBP1.03 (0.95, 1.11)0.4970.93 (0.82, 1.04)0.083
MBzP1.26 (0.89, 1.78)0.1900.68 (0.50, 0.94)0.018*
MEHP0.96 (0.86, 1.07)0.4700.97 (0.87, 1.09)0.623
MECPP1.36 (1.02, 1.81)0.034*0.92 (0.70, 1.20)0.532
MEHHP1.22 (1.02, 1.47)0.030*0.93 (0.77, 1.12)0.433
MEOHP1.38 (1.07, 1.78)0.015*0.85 (0.71, 1.03)0.103
MCMHP1.21 (1.02, 1.45)0.034*0.97 (0.81, 1.15)0.691
MCPP1.01 (0.68, 1.49)0.9570.92 (0.63, 1.33)0.647
MiNP1.39 (1.04, 1.86)0.026*0.92 (0.73, 1.15)0.472
MCHP1.34 (0.92, 1.96)0.1261.03 (0.72, 1.45)0.888
BLLs1.01 (1.00, 1.02)0.0561.01 (1.00, 1.03)0.055
a The model was constructed with adjusting age, sex, BMI, smoking status, drink status, education level, and urinary iodine. Bold italic *: p < 0.05; ORs: odds ratios.
Table
Table 5. ORs for the association between urinary phthalate metabolites and thyroid nodule according to blood lead levels in female.
Table 5. ORs for the association between urinary phthalate metabolites and thyroid nodule according to blood lead levels in female.
MetabolitesQ1Q2 Q3
OR (95% CI) a p-ValuesOR (95% CI)p-Valuesp-Interaction
MMP11.32 (0.97, 1.80)0.0751.30 (0.86, 1.98)0.2150.090
MEP11.21 (0.95, 1.56)0.1201.38 (1.08, 1.75)0.010 *0.018 *
MiBP11.12 (0.94, 1.33)0.2161.16 (0.93, 1.44)0.1840.224
MnBP11.11 (0.98, 1.25)0.1190.97 (0.84, 1.11)0.6080.611
MBzP10.89 (0.56, 1.41)0.6170.82 (0.49, 1.37)0.4440.950
MEHP10.97 (0.82, 1.16)0.7521.04 (0.87, 1.25)0.6530.865
MECPP11.38 (1.05, 1.81)0.022 *1.44 (1.04, 2.00)0.027 *0.007 *
MEHHP11.33 (1.04, 1.70)0.024 *1.21 (0.93, 1.56)0.1520.025 *
MEOHP11.36 (1.03, 1.80)0.030 *1.46 (1.07, 2.00)0.017 *0.013 *
MCMHP11.18 (0.89, 1.57)0.2551.18 (0.83, 1.66)0.3570.065
MCPP11.39 (0.79, 2.47)0.2581.09 (0.57, 2.10)0.7860.652
MiNP11.33 (1.02, 1.73)0.034 *1.51 (1.11, 2.06)0.009 *0.003 *
MCHP10.86 (0.71, 1.05)0.1370.84 (0.67, 1.02)0.0740.180
a The model was constructed with adjusting age, sex, BMI, smoking status, drink status, education level, and urinary iodine. Bold italic *: p < 0.05.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Chen, J.; Chen, Y.; Liu, S.; Chen, B.; Lu, Y.; Dong, R. Urinary Biomarkers of Phthalates Exposure, Blood Lead Levels, and Risks of Thyroid Nodules. Toxics 2021, 9, 68. https://doi.org/10.3390/toxics9030068

AMA Style

Chen J, Chen Y, Liu S, Chen B, Lu Y, Dong R. Urinary Biomarkers of Phthalates Exposure, Blood Lead Levels, and Risks of Thyroid Nodules. Toxics. 2021; 9(3):68. https://doi.org/10.3390/toxics9030068

Chicago/Turabian Style

Chen, Jingsi, Yi Chen, Shaojie Liu, Bo Chen, Yingli Lu, and Ruihua Dong. 2021. "Urinary Biomarkers of Phthalates Exposure, Blood Lead Levels, and Risks of Thyroid Nodules" Toxics 9, no. 3: 68. https://doi.org/10.3390/toxics9030068

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop