Sex-specific effect of urinary metabolites of polycyclic aromatic hydrocarbons on thyroid profiles: Results from NHANES 2011-2012

doi:10.21203/rs.3.rs-2098253/v1

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Research Article

Sex-specific effect of urinary metabolites of polycyclic aromatic hydrocarbons on thyroid profiles: Results from NHANES 2011-2012

https://doi.org/10.21203/rs.3.rs-2098253/v1

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published 03 Feb, 2023

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The current study aims to evaluate the associations between 10 urinary polycyclic aromatic hydrocarbon(PAH) metabolites and thyroid profiles. The levels of 10 PAH metabolites and thyroid profiles were obtained from National Health and Nutrition Examination Survey (NHANES) 2011-2012. Spearman analysis was utilized to evaluate the correlation coefficients among these 10 PAH metabolites. Multivariate linear and logistic regression models assessed the relationship between urinary PAH metabolites levels, thyroid hormones, and thyroid autoantibodies after adjusting potential confounders. Stratified analysis by gender was performed to evaluate sex-specific effect of urinary metabolites of PAH on thyroid profiles. 1645 eligible adult participants with complete research data were enrolled. Of note, the concentrations of the majority of urinary PAH metabolites were remarkedly higher in females compared with males. 2-hydroxyfluorene(2-FLU) was associated with higher total triiodothyronine (T3) levels in whole population (β=2.113, 95% CI: 0.339-3.888). In males, positive associations were observed in 1-hydroxynaphthalene (1-NAP) and free thyroxine (T4) (β=0.0002, 95% CI: 0.0000-0.0004), 2-FLU and total T3 (β=2.528, 95% CI: 0.115-4.940). While in female participants, 2-hydroxynaphthalene (2-NAP) was associated with free T3 (β=0.002, 95% CI: 0.000-0.005), 2-FLU was associated with total T3 (β=2.683, 95% CI: 0.038-5.328), free T3 (β=0.050, 95% CI: 0.012-0.087), and total T4 (β=0.195, 95% CI: 0.008-0.382). 2-hydroxyphenanthrene (2-OHP), 1-hydroxypyrene (1-HP) and 9-hydroxyfluorene (9-FLU) were all positively related to total T3 levels, the corresponding coefficients were 16.504, 6.587, and 3.010. 9-FLU was also associated with free T3 (β=0.049, 95% CI: 0.008-0.090). No statistical significances were found between PAH metabolites levels and increased prevalence of increased thyroglobulin antibody (TgAb)/thyroid peroxidase antibody (TPOAb) when PAH metabolites were treated as continuous variables. Meanwhile, in the quartile analyses, increased prevalence of elevated TgAb was observed in participants with quartile 2 2-NAP compared with lowest quartile (OR=1.753, 95% CI: 1.021-3.008). Male subgroup analyses indicated increased prevalence of elevated TgAb was observed in higher quartile of 1-NAP, 2-NAP and 3-hydroxyfluorene(3-FLU). Increased prevalence of elevated TPOAb was associated with higher 2-NAP quartile. However, in subgroup analysis of females, no statistical significances were found between PAH quartiles and increased TgAb/TPOAb. Significant correlations were found among these 10 PAH metabolites. In conclusion, the cross-sectional study indicated exposure to PAH might disturb the concentrations of thyroid hormones and thyroid autoantibodies. It is noteworthy that significant differences existed in males and females. Further prospective research is warranted to explore the causal relationship and underlying mechanism of PAH exposure on thyroid dysfunction.

Polycyclic aromatic hydrocarbons

thyroid hormone

thyroid autoantibody

NHANES

sex-specific effect

Polycyclic aromatic hydrocarbons (PAHs) are a group of hazardous and persistent organic pollutants with at least 2 fused benzene rings [Kim et al. 2013]. PAH are ubiquitously encountered in ambient environmental compartments, including soil, air, water and food. Incomplete combustion of carbonaceous materials and biological transformation of organic substances are the predominant anthropogenic and natural sources of PAHs [Zainal et al. 2022]. China is a country with large amount of PAH emissions, over one fifth of the global emission of PAHs were originated from China [Han et al. 2019]. Absorbed PAHs could rapidly metabolize to mono-hydroxylated PAHs (OH-PAHs) forms and mainly excreted through urine [Li et al. 2010]. Therefore, urinary OH-PAHs have been recognized as common internal biomarkers for PAH exposure [Shi et al. 2021].

Environmental endocrine disturbing chemicals (EDCs) are pervasively present in environment, and large number of exogenous agents have been identified as potential EDCs [Diamanti-Kandarakis et al. 2009]. Thyroid gland is susceptible to disturbing compounds. Considering the well-established essential role of thyroid hormones in physical development and metabolism regulation [Gilbert et al. 2020], adverse effect of thyroid dysfunction on nervous and cardiovascular system [Goodman et al. 2007, Rodondi et al. 2006], thyroid-disturbing chemicals have attracted increasing attention these years [Calsolaro et al. 2017]. Growing number of thyroid-disturbing substances have been found over the past decades [Bai et al. 2018, Zhang et al. 2022]. Mechanistically, EDCs interfere with thyroid function through hypothalamic and anterior pituitary levels [Yilmaz et al. 2020].

Effects of PAHs on human health risk have been extensively documented, including carcinogenicity, genotoxicity, teratogenicity, reproductive- and endocrine-disturbing effects, neurotoxicity, and immunotoxicity [Sun et al. 2021]. However, few previous researches have reported the association between different PAH metabolites and thyroid hormones, and the research findings remained conflicting. Study investigating the relationship between exposure to PAH and thyroid dysfunction in non-occupational population was firstly undertaken in 480 Chinese adult males, and only 2-hydroxyfluorene (2-FLU) concentration was found positively associated with thyroid stimulating hormone (TSH) [Zhu et al. 2009]. Data from 2007–2008 NHANES indicated 2-hydroxynapthalene (2-NAP), 2-hydroxyphenanthrene (2-OHP), and 1-hydroxypyrene (1-HP) were positively associated with total triiodothyronine (T3) in females, whereas 1-hydroxyphenanthrene (1-OHP), 2-OHP, and 9-hydroxypyrene (9-HP) were negatively associated with the levels of free thyroxine (T4) [Jain 2016]. Inconsistently, a nationwide survey conducted in Korean suggested no significant association of exposure to PAH and thyroid hormones [Kim et al. 2021]. The association between PAH metabolites and thyroid autoantibodies have been poorly explored. Limited studies investigated in the involvement of PAH exposure in thyroid autoantibodies. In Korean National Environmental Health Survey 2015–2017, 4 urinary PAH metabolites 1-HP,2-NAP, 2-FLU,and 1-OHP were measured, and no association was found between PAH metabolites and the presence of thyroglobulin antibody (TgAb) or thyroid peroxidase antibody (TPOAb) [Kim et al. 2021].

The sex-specific effect of 10 urinary PAH metabolites on both thyroid hormones and thyroid autoantibodies remains uninvestigated. Hence, the objective of the present study was to provide a detailed profile of 10 urinary PAH metabolites in 1645 adult participants. Additionally, the association between these 10 PAH metabolites, thyroid hormones (total and free T3, total and free T4, TSH, and Tg), along with thyroid autoantibodies (TgAb and TPOAb) were evaluated, and stratified analysis by gender was performed. The research findings will advance our understanding of PAH exposure on thyroid dysfunction in both males and females.

Data source and study population

NHANES 2011–2012 cycle was selected because it is the latest NHANES data with obtained complete thyroid profiles. Figure 1 shows the diagram of sample selection. Among the 9756 study participants, subjects aged below 18, with thyroid cancer/diseases and pregnant females were all excluded. In the remaining 5864 participants, 4081 were absent for the data of urinary PAH metabolites or creatinine, 118 were absent for thyroid hormones or antibodies parameters. As a result, 1645 participants (836 males and 809 females) were eventually enrolled in the present study. NHANES program was approved by the National Center for Health Statistics Ethics Review Board and all participants provided written informed consent at recruitment.

PAH metabolites

Urine specimens were collected, processed, and stored under − 20℃ condition until analysis for PAH metabolites. The specific OH-PAHs were measured in this method. This procedure involves enzymatic hydrolysis of glucuronidated/sulfated OH-PAH metabolites in urine, extraction, derivatization, and subsequent analysis using isotope dilution capillary gas chromatography/tandem mass spectrometry (GC-MS/MS) [Li et al. 2006]. A total of 10 PAH metabolites were detected in urine samples, the abbreviations and lower limit of detection (LLOD) for the 10 urinary PAH metabolites were listed in Table 1. If the concentrations of PAH metabolites were below LLOD, LLOD divided by the square root of 2 was used to substitute original data. PAH metabolites levels were adjusted by urinary creatinine (CR) to correct for variable urine dilution in the spot urine samples [Wahlberg et al. 2019], and CR was measured via enzymatic assay using Roche/Hitachi Modulator P Chemistry Analyzer.

Table 1

The abbreviations and lower limit of detection for 10 PAH metabolites in urine samples.
Metabolites	Abbreviation	LLOD (ng/ml)
1-hydroxynaphthalene	1-NAP	44.0
2-hydroxynaphthalene	2-NAP	42.0
3-hydroxyfluorene	3-FLU	10.0
2-hydroxyfluorene	2-FLU	10.0
3-hydroxyphenanthrene	3-OHP	10.0
1-hydroxyphenanthrene	1-OHP	10.0
2-hydroxyphenanthrene	2-OHP	10.0
1-hydroxypyrene	1-HP	10.0
9-hydroxyfluorene	9-FLU	10.0
4-phenanthrene	4-PHE	10.0

Thyroid hormones

Thyroid blood specimens were collected, processed, stored and shipped to Collaborative Laboratory Services, Ottumwa, Iowa. Thyroid-stimulating hormone (TSH) was quantified with a 3rd generation two-site immunoenzymatic (“sandwich”) HYPERsensitive human TSH assay. Total T3, free T3, and total T4 were quantified with competitive binding immunoenzymatic assay. Free T4 was quantified with a two-step enzyme immunoassay. Tg was assessed by a simultaneous one-step "sandwich" assay. TgAb and TPOAb were quantified with a sequential two-step immunoenzymatic "sandwich" assay. The normal ranges for anti-TgAb and TPOAb were < 4.0 IU/mL and < 9.0 IU/mL, respectively [Chen et al. 2021]. The detailed description of specimen collection, processing, and laboratory method for thyroid profile could be obtained in NHANES 2011–2012.

Covariates

The covariates included demographic and questionnaire data in the current research. Demographic information included age, gender, body mass ind[Liao et al. 2020]ex (BMI), education level, and marital status. The Educational level was defined as below high school, high school, and above high school. Marital status was classified as married/living with partner, widowed/divorced/separated, and never married. Questionnaire data consisted smoking and drinking status. Smoking status was divided into never, current-smoker (smoked at least 100 cigarettes in life and currently smoked), former smoker (smoked at least 100 cigarettes in life but now quitted smoking), and non-smoker (smoked less than 100 cigarettes in life). Drinking status was classified as drinker (had at least 12 alcohol drinks per year) and non-drinker (had less than 12 alcohol drinks per year).

Statistical analysis

Normally and non-normally distributed continuous data were presented as mean ± standard deviation, and mean (interquartile range), respectively. While categorical data was presented as numbers and percentages. Student t tests, Kruskal-Wallis tests and Chi-square tests were used for comparisons of continuous and categorical variables, respectively. Spearman analysis was performed to assess the correlation between these 10 PAH metabolites. The concentrations of 10 PAH metabolites were treated as both continuous and categorical variables in the statistical analyses. Each PAH metabolite were equally divided into 4 quartiles when recognized as categorical variable. The weighed multivariate linear regression and logistic regression models adjusting for potential confounders were performed to evaluate the regression coefficients of thyroid profiles and odds ratios for thyroid autoantibodies for PAH metabolites. Furthermore, subgroup analysis stratified by gender was performed to assess the gender-specific effect of PAH exposure on thyroid profiles. Sample weights were considered accounting for complex survey design, unequal probabilities of individual sampling and nonresponse of eligible and approached participants. Statistical analyses were conducted using R software and SPSS software, and a 2-side p < 0.05 was recognized as statistically significant.

Demographic characteristics

A total of 1645 eligible participants were enrolled in the present study, the average age was 46.48 ± 18.52, and 836 was male. Table 2 shows the characteristics of study population by gender. Male participants showed higher percentage of married/living with partner and never married, higher smoking and drinking rates compared with female individuals. Meanwhile, enrolled males were less likely receive an education above high school. The distributions of age, race and BMI were similar in males and females.

Table 2

Characteristics of study population in NHANES 2011–2012, by gender.
Variables	Total (n = 1645)	Male (n = 836)	Female (n = 809)	P value
Age, mean (SD)	46.48 (18.52)	46.59 (18.60)	46.35 (18.45)	0.822
Race				0.322
Mexican American, n (%)	159 (9.67%)	87 (10.41%)	72 (8.90%)
Other Hispanic, n (%)	174 (10.58%)	78 (9.33%)	96 (11.87%)
Non-Hispanic White, n (%)	601 (36.53%)	299 (35.77%)	302 (37.33%)
Non-Hispanic Black, n (%)	412 (25.05%)	212 (25.36%)	200 (24.72%)
Other Race: Including Multi-Racial, n (%)	299 (18.18%)	160 (19.14%)	139 (17.18%)
BMI, mean (SD)	28.61 (6.98)	28.47 (6.40)	28.76 (7.54)	0.890
Education				0.040
Below high school, n (%)	380 (23.07%)	212 (25.41%)	168 (20.77%)
High school, n (%)	321 (19.54%)	168 (20.08%)	153 (18.91%)
Above high school, n (%)	944 (57.39%)	456 (54.51%)	488 (60.32%)
Marital status				< 0.001
Married/living with partner, n (%)	935 (56.85%)	509 (60.94%)	426 (52.68%)
Widowed/divorced/separated, n (%)	333 (20.26%)	122 (14.63%)	211 (26.08%)
Never married, n (%)	377 (22.89%)	204 (24.43%)	173 (21.38%)
Smoking status				< 0.001
Current smoker, n (%)	296 (17.99%)	173 (20.69%)	123 (15.20%)
Former smoker, n (%)	358 (21.76%)	230 (27.51%)	128 (15.82%)
Non-smoker, n (%)	991 (60.24%)	433 (51.79%)	558 (68.97%)
Drinking, n (%)	1081 (65.71%)	649 (77.63%)	432 (53.40%)	< 0.001

Distribution of PAH metabolites

The concentrations of CR-adjusted PAH metabolites measured in urine samples were listed in Table 3. In addition, the detection rate of 10 PAH metabolites reached over 95% except for 4-PHE. The mean value of 2-hydroxynaphthalene (2-NAP) was the highest among these 10 PAH metabolites (4.92 µg/g), followed by 1-NAP (1.61 µg/g), 9-hydroxyfluorene (9-FLU) (0.27 µg/g), 2-FLU (0.22 µg/g), 1-hydroxyphenanthrene (1-OHP) (0.13 µg/g), 1-HP (0.11 µg/g). The mean concentration of 3-hydroxyfluorene (3-FLU), 2-OHP, 3-hydroxyphenanthrene (3-OHP), and 4-phenanthrene (4-PHE) were all below 0.1mg/g. It is worth noting that there existed significant distribution differences in PAH metabolites between men and women. Female participants displayed remarkedly higher levels of CR-adjusted PAH metabolites, including 1-NAP (1.73 vs. 1.49 µg/g, p = 0.023), 2-NAP (5.70 vs. 4.14 µg /g, p < 0.001), 1-OHP (0.15 vs. 0.11 µg/g, p < 0.001), 2-OHP (0.07 vs. 0.06 µg/g, p = 0.036), 1-HP (0.13 vs. 0.10 µg/g, p < 0.001), and 4-PHE (0.02 vs. 0.02 µg/g, p < 0.001).

Table 3

Distribution of PAH metabolites in urinary samples.
Metabolites			Male (n = 836)		Female (n = 809)		P value
	>LOD (%)	M (IQR)	>LOD (%)	M (IQR)	>LOD (%)	M (IQR)
1-NAP	100	1.61 (0.68–5.26)	100	1.49 (0.63–5.17)	100	1.73 (0.74–5.31)	0.023*
2-NAP	100	4.92 (2.50–9.70)	100	4.14 (2.15–8.23)	100	5.70 (2.96–11.90)	< 0.001*
3-FLU	97.87	0.08 (0.05–0.21)	99.16	0.08 (0.05–0.23)	96.54	0.08 (0.05–0.19)	0.934
2-FLU	100	0.22 (0.14–0.48)	100	0.21 (0.13–0.51)	100	0.22 (0.15–0.46)	0.187
3-OHP	96.66	0.06 (0.04–0.12)	98.09	0.06 (0.04–0.12)	95.18	0.07 (0.04–0.12)	0.232
1-OHP	99.88	0.13 (0.08–0.21)	100	0.11 (0.07–0.19)	99.75	0.15 (0.10–0.24)	< 0.001*
2-OHP	98.36	0.07 (0.04–0.11)	99.16	0.06 (0.04–0.11)	97.53	0.07 (0.04–0.11)	0.036*
1-HP	98.54	0.11 (0.07–0.19)	98.92	0.10 (0.06–0.18)	98.15	0.13 (0.08–0.21)	< 0.001*
9-FLU	100	0.27 (0.15–0.50)	100	0.25 (0.15–0.50)	100	0.28 (0.16–0.50)	0.058
4-PHE	76.78	0.02 (0.01–0.04)	79.78	0.02 (0.01–0.03)	73.67	0.02 (0.02–0.04)	< 0.001*
PAH metabolites were all adjusted by urinary creatinine and expressed as ug/g of urinary creatinine. LOD: limit of detection; M: median; IQR: interquartile range;

Spearman correlation analysis

Spearman correlation analysis was performed to evaluate the correlation between different PAH metabolites and the results were presented in Fig. 2. Among these 10 urinary PAH metabolites, there existed strong positive correlation among 3-OHP and 2-FLU (r = 0.74), 3-OHP and 3-FLU (r = 0.65), 1-OHP and 2-FLU (r = 0.68), 2-OHP and 2-FLU (r = 0.71), 2-OHP and 2-FLU (r = 0.64), 1-HP and 2-FLU (r = 0.71), 1-HP and 3-FLU (r = 0.70), 4-PHE and 9-FLU (r = 0.63), 4-PHE and 2-OHP (r = 0.60). Furthermore, mild to moderate positive correlations were also found between other PAH metabolites, with coefficients ranging from 0.15 to 0.58, the details were presented in Fig. 2 (p < 0.0001).

Association between PAH metabolites and thyroid hormones

Multiple linear regression analysis was performed to evaluate the association between different PAH metabolites and thyroid profiles. As shown in Table 4, after adjusting confounding factors including age, race, BMI, smoking and drinking, only 2-FLU was found positively associated with total T3 (β = 2.113, 95% CI: 0.339–3.888, p = 0.01972) in the whole population. Gender stratification was subsequently performed due to the distinctive distribution of PAH distribution. Positive associations were observed between 1-NAP and free T4 (β = 0.0002, 95% CI: 0.0000-0.0004, p = 0.01351), 2-FLU and total T3 (β = 2.528, 95% CI: 0.115–4.940, p = 0.04037) in male participants. In females, 2-NAP was found positively associated with free T3 (β = 0.002, 95% CI: 0.000-0.005, p = 0.03558), 2-FLU was positively correlated with total T3 (β = 2.683, 95% CI: 0.038–5.328, p = 0.04715), free T3 (β = 0.050, 95% CI: 0.012–0.087, p = 0.01053) and total T4 (β = 0.195, 95% CI: 0.008–0.382, p = 0.04116). Positive association were also observed in total T3 and 3 PAH metabolites: 2-OHP (β = 16.504, 95% CI: 1.486–31.521, p = 0.03154), 1-HP (β = 6.587, 95% CI: 0.646–12.529, p = 0.03008) and 9-FLU (β = 3.010, 95% CI: 0.144–5.875, p = 0.03988). Additionally, 9-FLU was positively with free T3 (β = 0.049, 95% CI: 0.008–0.090, p = 0.01856).

Table 4

Regression coefficient of PAH metabolites and thyroid profiles in whole population, male and females.
Metabolites	Total T3	Free T3	Total T4	Free T4	TSH	TG
	β (95% CI) p value	β (95% CI) p value	β (95% CI) p value	β (95% CI) p value	β (95%CI) p value	β (95% CI) p value
Total
1-NAP	-0.003 (-0.007, 0.001) 0.10565	-0.000 (-0.000, 0.000) 0.75531	0.000 (-0.000, 0.000) 0.86977	0.000 (-0.000, 0.000) 0.05663	0.000 (-0.000, 0.000) 0.66018	0.000 (-0.004, 0.004) 0.97663
2-NAP	0.059 (-0.067, 0.184) 0.35852	0.002 (-0.000, 0.003) 0.09839	0.004 (-0.005, 0.013) 0.39205	0.000 (-0.000, 0.001) 0.25310	0.005 (-0.008, 0.018) 0.45070	-0.032 (-0.164, 0.099) 0.62869
3-FLU	1.810 (-1.252, 4.872) 0.24670	0.024 (-0.021, 0.070) 0.29402	0.095 (-0.128, 0.317) 0.40486	0.002 (-0.019, 0.023) 0.83286	0.166 (-0.147, 0.479) 0.29927	1.731 (-1.473, 4.934) 0.28992
2-FLU	2.113 (0.339, 3.888) 0.01972	0.019 (-0.008, 0.045) 0.16589	0.108 (-0.022, 0.237) 0.10272	0.001 (-0.011, 0.013) 0.84325	-0.007 (-0.188, 0.174) 0.93884	0.719 (-1.134, 2.573) 0.44695
3-OHP	-3.345 (-10.141, 3.452) 0.33490	-0.019 (-0.120, 0.083) 0.71560	-0.442 (-0.936, 0.051) 0.07909	-0.011 (-0.058, 0.035) 0.62899	0.229 (-0.464, 0.922) 0.51796	-2.755 (-9.845, 4.335) 0.44641
1-OHP	3.093 (-1.653, 7.840) 0.20169	0.038 (-0.033, 0.108) 0.29736	-0.164 (-0.509, 0.181) 0.35126	-0.014 (-0.046, 0.019) 0.40581	0.039 (-0.445, 0.524) 0.87342	-3.181 (-8.132, 1.770) 0.20814
2-OHP	1.658 (-6.672, 9.988) 0.69654	-0.015 (-0.139, 0.109) 0.81121	-0.407 (-1.012, 0.199) 0.18807	-0.030 (-0.087, 0.027) 0.29687	0.154 (-0.696, 1.003) 0.72290	-2.574 (-11.262, 6.115) 0.56158
1-HP	3.851 (-0.300, 8.003) 0.06922	0.042 (-0.020, 0.104) 0.17978	0.066 (-0.236, 0.368) 0.66849	0.014 (-0.015, 0.042) 0.33867	0.052 (-0.372, 0.475) 0.81086	-0.822 (-5.157, 3.512) 0.71010
9-FLU	0.391 (-1.152, 1.935) 0.61930	0.005 (-0.018, 0.028) 0.65895	-0.071 (-0.183, 0.041) 0.21344	-0.002 (-0.013, 0.008) 0.65955	-0.023 (-0.180, 0.134) 0.77534	-0.263 (-1.873, 1.348) 0.74908
4-PHE	6.738 (-14.522, 27.999) 0.53456	0.097 (-0.220, 0.414) 0.54998	-0.169 (-1.714, 1.376) 0.83050	-0.062 (-0.207, 0.083) 0.40105	1.151 (-1.016, 3.318) 0.29818	-10.939 (-33.112, 11.234) 0.33371
Male
1-NAP	-0.001 (-0.023, 0.021) 0.93928	0.000 (-0.000, 0.000) 0.57454	0.001 (-0.000, 0.003) 0.15128	0.0002 (0.0000, 0.0004) 0.01351	0.001 (-0.001, 0.002) 0.41259	-0.007 (-0.027, 0.012) 0.46552
2-NAP	0.075 (-0.143, 0.292) 0.50098	0.000 (-0.003, 0.004) 0.84311	0.010 (-0.007, 0.026) 0.24330	0.001 (-0.001, 0.002) 0.27459	-0.013 (-0.029, 0.002) 0.08188	-0.013 (-0.202, 0.177) 0.89571
3-FLU	2.309 (-1.313, 5.930) 0.21181	-0.001 (-0.056, 0.054) 0.96328	0.075 (-0.197, 0.347) 0.59087	-0.005 (-0.030, 0.020) 0.70014	-0.019 (-0.272, 0.234) 0.88265	2.333 (-0.831, 5.496) 0.14881
2-FLU	2.528 (0.115, 4.940) 0.04037	0.001 (-0.037, 0.038) 0.97518	0.082 (-0.100, 0.263) 0.37899	-0.006 (-0.023, 0.012) 0.52543	-0.109 (-0.277, 0.059) 0.20276	1.299 (-0.803, 3.401) 0.22617
3-OHP	-3.994 (-11.547, 3.559) 0.30032	-0.064 (-0.180, 0.052) 0.27802	-0.442 (-1.009, 0.125) 0.12699	-0.012 (-0.066, 0.041) 0.65348	0.282 (-0.242, 0.807) 0.29216	-0.873 (-7.447, 5.700) 0.79459
1-OHP	-0.502 (-8.223, 7.219) 0.89862	-0.001 (-0.120, 0.117) 0.98440	-0.440 (-1.019, 0.140) 0.13713	-0.018 (-0.073, 0.036) 0.51685	0.140 (-0.396, 0.676) 0.60858	-1.799 (-8.514, 4.916) 0.59961
2-OHP	-4.589 (-14.359, 5.181) 0.35752	-0.085 (-0.235, 0.065) 0.26846	-0.623 (-1.356, 0.110) 0.09626	-0.030 (-0.099, 0.039) 0.38976	0.214 (-0.465, 0.893) 0.53642	-1.868 (-10.369, 6.634) 0.66689
1-HP	1.874 (-3.957, 7.706) 0.52889	0.022 (-0.068, 0.111) 0.63327	0.057 (-0.381, 0.496) 0.79813	0.016 (-0.025, 0.057) 0.45282	-0.028 (-0.433, 0.377) 0.89241	-0.103 (-5.177, 4.970) 0.96817
9-FLU	-0.503 (-2.292, 1.286) 0.58159	-0.011 (-0.038, 0.016) 0.43125	-0.102 (-0.236, 0.032) 0.13700	-0.004 (-0.016, 0.009) 0.56367	-0.031 (-0.155, 0.093) 0.62561	-0.126 (-1.683, 1.430) 0.87372
4-PHE	-6.900 (-42.619, 28.818) 0.70505	-0.149 (-0.697, 0.399) 0.59365	-2.650 (-5.328, 0.028) 0.05279	-0.226 (-0.477, 0.026) 0.07946	-0.502 (-2.982, 1.979) 0.69203	-0.087 (-31.157, 30.983) 0.99564
Female
1-NAP	-0.003 (-0.007, 0.001) 0.11849	-0.000 (-0.000, 0.000) 0.52934	-0.000 (-0.000, 0.000) 0.98015	0.000 (-0.000, 0.000) 0.18634	0.000 (-0.000, 0.001) 0.76371	0.000 (-0.004, 0.005) 0.91829
2-NAP	0.078 (-0.080, 0.236) 0.33138	0.002 (0.000, 0.005) 0.03558	0.003 (-0.008, 0.014) 0.58059	0.001 (-0.001, 0.002) 0.31387	0.013 (-0.007, 0.032) 0.20082	-0.050 (-0.237, 0.136) 0.59705
3-FLU	3.041 (-2.517, 8.600) 0.28386	0.096 (0.017, 0.176) 0.01779	0.289 (-0.104, 0.682) 0.14975	0.024 (-0.013, 0.060) 0.20782	0.485 (-0.208, 1.177) 0.17034	0.160 (-6.415, 6.736) 0.96190
2-FLU	2.683 (0.038, 5.328) 0.04715	0.050 (0.012, 0.087) 0.01053	0.195 (0.008, 0.382) 0.04116	0.011 (-0.006, 0.028) 0.21755	0.084 (-0.245, 0.414) 0.61650	-0.059 (-3.188, 3.070) 0.97039
3-OHP	1.806 (-12.244, 15.856) 0.80114	0.152 (-0.049, 0.353) 0.13929	-0.215 (-1.207, 0.777) 0.67077	0.000 (-0.092, 0.093) 0.99582	-0.026 (-1.772, 1.720) 0.97658	-9.194 (-25.761, 7.372) 0.27702
1-OHP	5.818 (-0.298, 11.935) 0.06264	0.068 (-0.020, 0.155) 0.13160	0.033 (-0.400, 0.465) 0.88295	-0.012 (-0.053, 0.028) 0.55365	-0.038 (-0.799, 0.724) 0.92313	-4.072 (-11.299, 3.156) 0.26987
2-OHP	16.504 (1.486, 31.521) 0.03154	0.172 (-0.044, 0.388) 0.11861	0.169 (-0.895, 1.232) 0.75565	-0.024 (-0.123, 0.075) 0.63893	-0.048 (-1.920, 1.824) 0.96007	-4.073 (-21.843, 13.697) 0.65338
1-HP	6.587 (0.646, 12.529) 0.03008	0.083 (-0.002, 0.168) 0.05726	0.136 (-0.284, 0.557) 0.52575	0.018 (-0.021, 0.058) 0.35961	0.050 (-0.691, 0.791) 0.89484	-1.175 (-8.207, 5.857) 0.74345
9-FLU	3.010 (0.144, 5.875) 0.03988	0.049 (0.008, 0.090) 0.01856	0.028 (-0.175, 0.231) 0.78958	0.001 (-0.018, 0.020) 0.91491	-0.012 (-0.369, 0.345) 0.94887	-0.780 (-4.170, 2.611) 0.65230
4-PHE	15.462 (-11.527, 42.451) 0.26183	0.233 (-0.154, 0.620) 0.23829	1.094 (-0.812, 3.000) 0.26094	0.000 (-0.178, 0.178) 0.99853	1.905 (-1.450, 5.259) 0.26605	-18.558 (-50.404, 13.288) 0.25372
Models adjusted for: age, race, BMI, education level, marital status, smoking and drinking status. Abbreviations: T3: triiodothyronine; T4: thyroxine; TSH: thyroid stimulating hormone; TG: Thyroglobulin.

Association between PAH metabolites and thyroid autoantibodies

Table 5 presents the association between PAH metabolites (treated as continuous variables) and thyroid autoantibodies through multiple logistic regression analysis. Noteworthy, no statistical significances were found between these PAH metabolites and TbAg/TPOAb in whole population, male and female subgroups.

Table 5

Odds ratios (95% confidence interval) for thyroid autoantibodies in PAH metabolites by sex.
Exposure	Total		Male		Female
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
TgAb > 4 IU/mL
1-NAP	1.000 (0.999, 1.001)	0.87156	1.003 (0.999, 1.008)	0.18076	0.998 (0.993, 1.004)	0.50396
2-NAP	1.007 (0.987, 1.028)	0.49549	1.022 (0.985, 1.060)	0.25038	0.998 (0.972, 1.025)	0.90561
3-FLU	1.487 (0.942, 2.348)	0.08844	1.569 (0.923, 2.667)	0.09593	1.007 (0.400, 2.535)	0.98771
2-FLU	1.258 (0.939, 1.685)	0.12378	1.491 (0.967, 2.299)	0.07035	1.040 (0.679, 1.592)	0.85796
3-OHP	1.282 (0.463, 3.553)	0.63271	0.957 (0.202, 4.532)	0.95607	2.299 (0.284, 18.635)	0.43560
1-OHP	1.430 (0.623, 3.281)	0.39874	0.746 (0.115, 4.824)	0.75853	1.918 (0.691, 5.326)	0.21126
2-OHP	0.957 (0.171, 5.347)	0.95990	0.618 (0.039, 9.678)	0.73184	1.967 (0.123, 31.572)	0.63276
1-HP	0.961 (0.362, 2.548)	0.93642	0.868 (0.214, 3.529)	0.84362	1.090 (0.240, 4.943)	0.91092
9-FLU	1.094 (0.852, 1.406)	0.48041	1.021 (0.665, 1.567)	0.92501	1.215 (0.810, 1.820)	0.34650
4-PHE	2.426 (0.071, 82.294)	0.62216	1.307 (0.000, 3642.557)	0.94730	3.351 (0.057, 197.335)	0.56083
TPOAb > 9IU/mL
1-NAP	1.000 (0.999, 1.000)	0.68307	1.003 (0.998, 1.009)	0.21381	0.998 (0.991, 1.004)	0.47442
2-NAP	0.997 (0.975, 1.019)	0.78986	0.999 (0.959, 1.040)	0.95661	0.996 (0.969, 1.023)	0.76620
3-FLU	0.851 (0.456, 1.590)	0.61305	0.732 (0.279, 1.925)	0.52732	0.954 (0.399, 2.281)	0.91619
2-FLU	0.889 (0.635, 1.244)	0.49254	0.842 (0.478, 1.483)	0.55161	0.918 (0.598, 1.408)	0.69422
3-OHP	0.344 (0.048, 2.470)	0.28841	0.263 (0.011, 6.465)	0.41339	0.430 (0.034, 5.382)	0.51281
1-OHP	0.431 (0.128, 1.451)	0.17409	0.194 (0.014, 2.592)	0.21482	0.580 (0.160, 2.109)	0.40828
2-OHP	0.279 (0.032, 2.476)	0.25196	0.089 (0.002, 5.263)	0.24538	0.539 (0.044, 6.546)	0.62757
1-HP	0.317 (0.083, 1.203)	0.09131	0.215 (0.021, 2.264)	0.20083	0.383 (0.072, 2.040)	0.26092
9-FLU	0.937 (0.681, 1.289)	0.68810	0.891 (0.533, 1.489)	0.65876	0.981 (0.635, 1.517)	0.93221
4-PHE	0.151 (0.001, 16.543)	0.42981	0.000 (0.000, 239.996)	0.24484	0.516 (0.006, 44.467)	0.77082
Models adjusted for: age, race, BMI, educational level, marital status, smoking and drinking status. TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibody; OR: odds ratio; CI: confidence interval.

In addition, each kind of PAH metabolites was divided into 4 quartiles, and logistic regression analyses were performed to assess the independent association between PAH metabolites and the presence of TgAb and TPOAb after adjusting confounders. As presented in Table 6, Q2 2-NAP was associated with 1.753 higher risk for the presence of TgAb compared with Q1 (95% CI: 1.021–3.008, p = 0.04168). In males, the third and highest quartile of 1-NAP were related to 3.492 and 2.812 higher risk for elevated TgAb, respectively. Positive associations were also found between 1-NAP and TgAb (Q2 vs. Q1: OR = 2.360, 95% CI: 1.054, 5.288, p = 0.03688; Q3 vs. Q1:OR = 2.629, 95% CI: 1.087, 6.360, p = 0.03193; Q4 vs. Q1: OR = 3.272, 95% CI: 1.172, 9.139, p = 0.02366), 3-FLU and TgAb (Q2 vs. Q1: OR = 2.689, 95% CI: 1.117–6.472, p = 0.02729). However, no significant associations between the occurrence of TgAb and PAH metabolites were observed in females. In terms of TPOAb, most PAH metabolites were not associated with TPOAb, except for the second (OR = 0.415, 95% CI: 0.196–0.880, p = 0.02186) and third quartile (OR = 0.396, 95% CI: 0.171–0.918, p = 0.03071) of 2-OHP in males.

Table 6

Odds ratios (95% confidence interval) for thyroid autoantibodies among quartile subgroups of PAT metabolites by sex.
Metabolites	Total		Male		Female
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
TgAb > 4 IU/mL	117/1645		50/836		67/809
1-NAP
Q1	Reference		Reference		Reference
Q2	1.324 (0.738, 2.374)	0.34700	2.276 (0.930, 5.567)	0.07161	0.857 (0.387, 1.898)	0.70409
Q3	1.538 (0.865, 2.734)	0.14267	2.812 (1.136, 6.961)	0.02533*	1.003 (0.467, 2.152)	0.99477
Q4	1.746 (0.915, 3.333)	0.09095	3.492 (1.298, 9.388)	0.01323*	0.886 (0.371, 2.117)	0.78534
2-NAP
Q1	Reference		Reference		Reference
Q2	1.753 (1.021, 3.008)	0.04168*	2.360 (1.054, 5.288)	0.03688*	1.463 (0.691, 3.099)	0.31975
Q3	1.426 (0.785, 2.589)	0.24405	2.629 (1.087, 6.360)	0.03193*	0.906 (0.397, 2.066)	0.81361
Q4	1.784 (0.938, 3.392)	0.07736	3.272 (1.172, 9.139)	0.02366*	1.201 (0.520, 2.773)	0.66846
3-FLU
Q1	Reference		Reference		Reference
Q2	1.452 (0.843, 2.500)	0.17883	2.689 (1.117, 6.472)	0.02729*	0.908 (0.443, 1.863)	0.79289
Q3	1.415 (0.816, 2.455)	0.21665	2.386 (0.972, 5.853)	0.05758	0.918 (0.447, 1.886)	0.81647
Q4	1.552 (0.753, 3.199)	0.23317	2.955 (0.996, 8.761)	0.05077	0.884 (0.311, 2.513)	0.81654
2-FLU
Q1	Reference		Reference		Reference
Q2	1.321 (0.750, 2.325)	0.33517	0.920 (0.393, 2.153)	0.84796	1.741 (0.777, 3.901)	0.17768
Q3	1.691 (0.981, 2.917)	0.05876	1.603 (0.748, 3.435)	0.22483	1.822 (0.818, 4.058)	0.14177
Q4	1.784 (0.899, 3.541)	0.09770	1.608 (0.621, 4.159)	0.32761	2.106 (0.751, 5.909)	0.15703
3-OHP
Q1	Reference		Reference		Reference
Q2	0.788 (0.449, 1.382)	0.40554	1.125 (0.496, 2.551)	0.77741	0.567 (0.259, 1.241)	0.15582
Q3	1.143 (0.671, 1.949)	0.62203	1.298 (0.564, 2.988)	0.53933	1.004 (0.495, 2.037)	0.99100
Q4	1.180 (0.661,2.107)	0.57550	1.642 (0.703, 3.834)	0.25202	0.841 (0.370, 1.912)	0.67933
1-OHP
Q1	Reference		Reference		Reference
Q2	1.115 (0.628, 1.981)	0.70961	1.141 (0.542, 2.398)	0.72857	1.168 (0.459, 2.968)	0.74477
Q3	1.031 (0.573, 1.857)	0.91808	0.752 (0.310, 1.826)	0.52918	1.489 (0.614, 3.608)	0.37795
Q4	1.568 (0.891, 2.760)	0.11894	1.246 (0.542, 2.868)	0.60475	2.062 (0.870, 4.888)	0.10015
2-OHP
Q1	Reference		Reference		Reference
Q2	1.021 (0.587, 1.775)	0.94220	1.057 (0.497, 2.250)	0.88498	1.076 (0.471, 2.457)	0.86148
Q3	1.095 (0.633, 1.893)	0.74546	0.646 (0.254, 1.642)	0.35853	1.624 (0.782, 3.369)	0.19320
Q4	1.231 (0.702, 2.158)	0.46862	1.166 (0.519, 2.619)	0.70981	1.434 (0.643, 3.196)	0.37852
1-HP
Q1	Reference		Reference		Reference
Q2	0.946 (0.546, 1.637)	0.84213	0.773 (0.361, 1.657)	0.50791	1.480 (0.640, 3.422)	0.35974
Q3	1.082 (0.618, 1.895)	0.78203	0.800 (0.344, 1.865)	0.60603	1.805 (0.791, 4.117)	0.16047
Q4	1.254 (0.691, 2.278)	0.45654	1.007 (0.424, 2.390)	0.98750	1.973 (0.809, 4.808)	0.13492
9-FLU
Q1	Reference		Reference		Reference
Q2	0.970 (0.548, 1.716)	0.91610	1.775 (0.794, 3.967)	0.16231	0.525 (0.221, 1.245)	0.14351
Q3	1.386 (0.812, 2.366)	0.23145	1.181 (0.484, 2.884)	0.71473	1.476 (0.741, 2.941)	0.26813
Q4	1.389 (0.779, 2.478)	0.26538	1.999 (0.830, 4.815)	0.12236	1.105 (0.498, 2.450)	0.80594
4-PHE
Q1	Reference		Reference		Reference
Q2	1.039 (0.594, 1.819)	0.89365	0.583 (0.253, 1.343)	0.20511	2.212 (0.936, 5.225)	0.07027
Q3	1.266 (0.734, 2.182)	0.39665	1.006 (0.470, 2.153)	0.98862	1.857 (0.798, 4.322)	0.15118
Q4	1.290 (0.731, 2.274)	0.37963	1.042 (0.452, 2.399)	0.92374	1.997 (0.840, 4.747)	0.11731
TPOAb > 9IU/mL	152/645		61/836		91/809
1-NAP
Q1	Reference		Reference		Reference
Q2	1.204 (0.736, 1.972)	0.45971	1.085 (0.508, 2.318)	0.83336	1.290 (0.665, 2.502)	0.45159
Q3	1.179 (0.716, 1.942)	0.51703	1.398 (0.657, 2.975)	0.38476	1.061 (0.540, 2.084)	0.86469
Q4	0.834 (0.453, 1.536)	0.56054	1.325 (0.547, 3.212)	0.53346	0.569 (0.244, 1.327)	0.19163
2-NAP
Q1	Reference		Reference		Reference
Q2	1.325 (0.819, 2.145)	0.25146	1.704 (0.858, 3.382)	0.12777	1.010 (0.508, 2.011)	0.97632
Q3	1.389 (0.838, 2.304)	0.20286	1.385 (0.623, 3.081)	0.42410	1.298 (0.663, 2.543)	0.44667
Q4	1.155 (0.644, 2.071)	0.62883	1.311 (0.484, 3.550)	0.59358	1.011 (0.483, 2.118)	0.97632
3-FLU
Q1	Reference		Reference		Reference
Q2	1.058 (0.669, 1.672)	0.80955	0.725 (0.349, 1.509)	0.39037	1.350 (0.730, 2.498)	0.33865
Q3	0.749 (0.456, 1.229)	0.25310	0.735 (0.352, 1.534)	0.41247	0.771 (0.391, 1.522)	0.45378
Q4	0.917 (0.475, 1.772)	0.79714	0.929 (0.350, 2.465)	0.88162	0.951 (0.383, 2.364)	0.91417
2-FLU
Q1	Reference		Reference		Reference
Q2	0.935 (0.584, 1.495)	0.77772	0.530 (0.243, 1.154)	0.10986	1.348 (0.710, 2.561)	0.36146
Q3	0.981 (0.614, 1.568)	0.93649	0.781 (0.384, 1.587)	0.49380	1.238 (0.646, 2.373)	0.51925
Q4	0.735 (0.381, 1.418)	0.35845	0.791 (0.318, 1.970)	0.61466	0.694 (0.262, 1.836)	0.46128
3-OHP
Q1	Reference		Reference		Reference
Q2	0.771 (0.486, 1.225)	0.27134	0.540 (0.254, 1.149)	0.10985	0.926 (0.503, 1.705)	0.80531
Q3	0.706 (0.434, 1.149)	0.16107	0.615 (0.285, 1.329)	0.21633	0.766 (0.403, 1.455)	0.41506
Q4	0.629 (0.365, 1.086)	0.09610	0.745 (0.344, 1.613)	0.45525	0.541 (0.248, 1.179)	0.12222
1-OHP
Q1	Reference		Reference		Reference
Q2	1.145 (0.702, 1.866)	0.58775	0.903 (0.458, 1.779)	0.76771	1.554 (0.738, 3.275)	0.24598
Q3	0.853 (0.509, 1.429)	0.54595	0.528 (0.233, 1.201)	0.12773	1.310 (0.621, 2.766)	0.47865
Q4	0.932 (0.552, 1.572)	0.79174	0.816 (0.374, 1.780)	0.60974	1.202 (0.562, 2.570)	0.63452
2-OHP
Q1	Reference		Reference		Reference
Q2	0.888 (0.549, 1.438)	0.62953	0.415 (0.196, 0.880)	0.02186*	1.740 (0.882, 3.432)	0.10988
Q3	0.921 (0.569, 1.491)	0.73854	0.396 (0.171, 0.918)	0.03071*	1.672 (0.865, 3.232)	0.12617
Q4	0.835 (0.499, 1.397)	0.49224	0.638 (0.309, 1.316)	0.22384	1.148 (0.539, 2.443)	0.72027
1-HP
Q1	Reference		Reference		Reference
Q2	1.085 (0.685, 1.717)	0.72837	0.624 (0.313, 1.243)	0.17977	1.863 (0.944, 3.674)	0.07263
Q3	0.825 (0.499, 1.366)	0.45492	0.651 (0.303, 1.400)	0.27222	1.194 (0.581, 2.455)	0.62961
Q4	0.618 (0.346, 1.104)	0.10373	0.433 (0.173, 1.080)	0.07262	0.937 (0.417, 2.109)	0.87554
9-FLU
Q1	Reference		Reference		Reference
Q2	0.760 (0.464, 1.245)	0.27555	0.602 (0.277, 1.309)	0.20064	0.927 (0.480, 1.790)	0.82121
Q3	1.063 (0.666, 1.696)	0.79905	0.839 (0.404, 1.739)	0.63622	1.263 (0.676, 2.357)	0.46423
Q4	0.835 (0.494, 1.412)	0.50082	0.910 (0.423, 1.958)	0.81003	0.820 (0.395, 1.703)	0.59433
4-PHE
Q1	Reference		Reference		Reference
Q2	0.928 (0.579, 1.487)	0.75530	0.710 (0.357, 1.412)	0.32897	1.263 (0.641, 2.486)	0.49953
Q3	0.887 (0.549, 1.433)	0.62434	0.716 (0.347, 1.478)	0.36614	1.096 (0.562, 2.138)	0.78728
Q4	0.708 (0.420, 1.193)	0.19454	0.453 (0.191, 1.078)	0.07344	0.997 (0.493, 2.016)	0.99282
Models adjusted for: age, race, BMI, education level, marital status, smoking and drinking status. TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibody; OR: odds ratio; CI: confidence interval. *P < 0.05.

To our best knowledge, this is the first research addressing the effect of 10 urinary PAH metabolites on thyroid hormones and thyroid autoantibodies in a gender-specific analysis. The present study provided 10 kinds of CR-adjusted urinary PAH metabolites distribution. Additionally, mild to strong positive correlations were identified among these 10 PAH metabolites, with the coefficients ranging from 0.15 to 0.74. Multiple linear regression analysis revealed the significant positive association between 2-FLU and total T3 (β = 2.113, 95% CI: 0.339–3.888, p = 0.01972) in the whole population. 1.753 higher risk for the presence of TgAb was determined in quartile 2 of 2-NAP compared with lowest quartile of 2-NAP (95% CI: 1.021–3.008, p = 0.04168) after adjusting potential confounders, while no statistical significances were observed between higher quartile of PAH metabolites and the prevalence of TPOAb in the whole population. Gender-specific effect of PAH exposure on thyroid profiles were evaluated, and significant different results were found between males and females. Thus, the present research revealed the positive association between PAH and thyroid dysfunction, and warranted the necessity for enhanced surveillance of PAH exposure in environment media.

PAH is one kind of widely distributed environmental persistent organic pollutants [Famiyeh et al. 2021]. Acute and chronic exposure to PAH could contribute to skin irritation, liver dysfunction, kidney dysfunction, DNA damage, and even lead to gastrointestinal carcinoma and increased cardiopulmonary mortality [Cheng et al. 2021, Lawal 2017, Lee et al. 2011, Zhu et al. 2018]. However, the relationship between PAH exposure and thyroid effect remains largely uninvestigated. OH-PAHs in urine samples were most frequently used for evaluation of internal exposure to PAH due to its high excretion rates in urine, convenient and invasive sampling method [Chetiyanukornkul et al. 2006]. Therefore, the current study used urinary PAH metabolites to evaluate the exposure of PAH on thyroid hormones, and thyroid autoantibodies.

There existed some evidence showing the association between exposure to PAH and thyroid effect. However, the research findings of previous reports remained remarkably controversial. 2-Flu in urine samples were found related to increased male TSH levels [Zhu et al. 2009], whereas no significant relationship was observed between 4 PAH metabolites and thyroid hormones in the Korean National Environmental Health Survey [Kim et al. 2021]. Additionally, recent research assessing PAH exposure in Iran pregnant women indicated acenaphthene concentrations in maternal blood samples were negatively associated with neonatal TSH levels (β=-0.99) [Dehghani et al. 2022]. The research population with different demographic background and distinct exposure to PAH might explain the discrepancies between these research results. Moreover, different studies focused on and detected distinctive kinds of PAH metabolites, no uniform regulation was formed. However, limited research explored gender-specific effect of a total of 10 PAH metabolites on both thyroid hormones and thyroid autoantibodies in adults.

The gender-specific effect of PAH exposure on adverse health outcomes have been investigated, including depression symptoms [Zhang et al. 2021], skeletal muscle atrophy [Sun et al. 2022]. Moreover, the gender-specific effect was also observed in thyroid nodular goiter and papillary thyroid carcinoma [Liu et al. 2021]. However, gender-dependent association between PAH and thyroid hormones were limited. In the present research, positive associations were observed between 1-NAP and free T4, 2-Flu and total T3 in males. While in females, 2-FLU, 2-OHP, 1-HP, and 9-FLU were positively related to total T3. 2-NAP, 2-FLU, and 9-FLU were associated with increased free T3 levels. Higher 2-FLU levels were also associated with increased concentrations of total T4. Consistently, previous findings showed different effects of PAH exposure on thyroid hormones in men and women. Furthermore, they also revealed that elevated total T3 levels were associated with 1-HP in adult females [Jain 2016]. The reasons for discrepancies might be as follows: Affected by the interaction between the hypothalamus-pituitary-thyroid axis and the hypothalamic-pituitary-gonadal axis, the relationship between thyroid hormones and sex hormones is inseparable [Kjaergaard et al. 2021]. Compared with males, females are more susceptible to chromosome damage and oxidative stress induced by PAH exposure [Guo et al. 2014]. According to previous reports, 2-FLU and 2-OHP were booth 3-ring OH-PAHs presenting some estrogenic activity [Hayakawa et al. 2007], and the structural characteristic and estrogenic activities might explain the significant association between 2-FLU, total T3, free T3, and total T4, 2-OHP and total T3 in females. Furthermore, 4-ring OHPAH 1-HP also presented some estrogenic activity [Hayakawa et al. 2007], and statistical significant relationship between 1-HP and total T3 was observed in adult females. Considering the distinct distribution of PAH metabolites, and dramatically distinctive associations between PAH and thyroid profiles in males and females, more work is needed to further elucidate the mechanisms of PAH exposure on thyroid dysfunction in participants with different gender.

Experimental researches have conducted preliminary exploration on the mechanisms of the adverse development and function of thyroid gland induced by PAH exposure. Gentes and his colleagues firstly reported altered thyroid content in nestling in Athabasca Oil Sands Region (AOSR), where PAH concentration was naturally heavy, was the results of PAH exposure [Gentes et al. 2006]. In rockfish embryos, pyrene exposure decreased the expression of thyroid primordium markers and thyroid receptor genes, thyroid development and function related genes, including Fgfr2, Hoxa3a, Deio1, Ttr, and Tg were all altered after PAH exposure [He et al. 2012]. TPO acts as a crucial factor in thyroid hormone (TH) synthesis through catalyzation iodine transfer to thyroglobulin [Taurog et al. 1996]. Previous research determined that PAH disturbed TH axis via alteration of TPO activity. Specifically, dibenzo(a,h)anthracene increased TPO activity, whereas 3-methylchloranthracene, benzo(k)fluoranthene, pyrene, and benzo(e)pyrene suppressed TPO activity [Song et al. 2012]. The current research suggested higher 2-OHP levels were related to the prevalence of TPOAb in males. The association between PAH, thyroid autoantibodies, and thyroid autoimmune disorders remains largely unknow. Future research is merited to investigate the relationship between PAH and thyroid autoantibodies, and explore the underlying mechanisms of the involvement of thyroid autoantibodies in the effect of PAH exposure on thyroid dysfunction.

The present research has several advantages. Firstly, this is a nationwide, representative research with relatively large sample. Secondly, a total of 10 PAH metabolites were measured in urine samples for each participant, which provided abundant information for PAH exposure. Lastly, gender stratification analysis broadened our understanding of PAH exposure on thyroid dysfunction. However, the study has some limitations. Firstly, the association between PAH metabolites in urine samples and thyroid dysfunction were assessed in a cross-sectional study, further prospective research is warranted for exploration of the causal relationship between PAH exposure and thyroid dysfunction. In addition, data of urinary PAH metabolites and/or thyroid profiles in many NHANES cycles were absent, therefore, the latest dataset in NHANES 2011–2012 was selected for analysis. Future research with larger sample and complete research data is need to be conducted to expand our understanding of PAH and abnormal thyroid hormones/autoantibodies. Lastly, the research population was non-occupational exposed general population with relatively low exposure to PAH. Different research findings might be obtained in participants with heavy exposure to PAH.

In conclusion, the current research provided the diverse distribution of a total of 10 PAH metabolites in males and females. The findings also suggested a positive association between 2-FLU and total T3. Higher quartile of 2-NAP was associated with the prevalence of elevated TgAb. Furthermore, significant gender differences were observed on the relationship between PAH metabolite, thyroid hormones, and thyroid autoantibodies. Further studies were needed to confirm the association between these urinary PAH metabolites and thyroid profiles and explore the underlying mechanisms.

Acknowledgement

We thank the research staff of the National Center for Health Statistics of the Centers for Disease Control (CDC) and Prevention for their time and effort, and the participants who enrolled in the NHANES project, we also appreciate CDC for publicizing the HNANES database.

Author contribution

Study conception and design: Weilong Xing, Lei Wang; data collection: Weilong Xing, Lei Wang, Wen Gu; data analysis and interpretation: Weilong Xing, Lei Wang, Wen Gu, Mengyuan Liang, Zhen Wang, Deling Fan, Bing Zhang; manuscript writing and reviewing: Weilong Xing; study supervision: Weilong Xing. All authors read and approved the final manuscript.

Funding

The study was supported by the grants from Central Scientific Research Projects for Public Welfare Research Institutes (ZX2022QT020) and the Doctoral Program of Entrepreneurship and Innovation in Jiangsu Province (JSSCBS20211323).

Data availability

Publicly available datasets were analyzed in this study. This data can be found at: https://www.cdc.gov/nchs/nhanes/index.htm.

Ethical approval and consent to participate

The program was approved by the National Center for Health Statistics Ethics Review Board. All of the participants provided written informed consent.

Consent for publication

Not applicable

Competing interests

The authors declared no competing interests.

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Sex-specific effect of urinary metabolites of polycyclic aromatic hydrocarbons on thyroid profiles: Results from NHANES 2011-2012

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