健康成年人群尿中对硝基酚水平对甲状腺功能的影响——基于美国NHANES数据库

摘要:

背景

对硝基酚（PNP）是有机磷农药对硫磷和甲基对硫磷主要的特异性代谢产物。既往的研究发现对硫磷和甲基对硫磷可能具有内分泌干扰作用，但证据较为有限。

目的

探讨健康成年人群尿中PNP浓度与甲状腺功能的相关性及是否存在性别差异。

方法

基于2007—2008年美国国家营养与健康调查，将1071例同时具有尿PNP、血清甲状腺功能指标的20~64岁健康成年人纳入本研究。收集血清甲状腺刺激素（TSH）、游离三碘甲状腺原氨酸（FT3）、游离甲状腺激素（FT4）、总三碘甲状腺原氨酸(TT3)、总甲状腺激素（TT4）、甲状腺球蛋白（TG）、甲状腺球蛋白抗体（TG-Ab）数据以评估甲状腺功能。采用广义线性模型分析尿PNP与血清甲状腺功能指标的关系及剂量-反应关系，并分析性别差异。

结果

总人群中尿PNP的检出率为92.5%，肌酐校正后质量分数中位数为0.62 μg·g−1。男性和女性肌酐校正后尿PNP质量分数中位数分别是0.60、0.66 µg·g−1。总人群中主要甲状腺功能指标TSH、FT3、FT4、TT3、TT4的活性或质量浓度中位数分别为1500.00 μIU·L−1、3200.00 pg·L−1、8.00 ng·L−1、1140.00 ng·L−1、76.00 μg·L−1。在总人群中，尿PNP每增加一个对数单位，血清FT3、FT4、TT3分别下降1050.00 pg·L−1 (b=−0.02，95%CI：−0.02~−0.01)、10.50 ng·L−1 (b=−0.02，95%CI：−0.03~−0.01)和10.50 ng·L−1 (b=−0.02，95%CI：−0.03~−0.01)，且存在剂量-反应关系（均P趋势＜0.05）。性别分层后发现，在男性中，尿PNP每增加一个对数单位，血清TG-Ab水平增加1100.00 IU·L−1 (b=0.04，95%CI：0.00~0.08)，血清FT3水平降低1020.00 pg·L−1 (b=−0.01，95%CI：−0.02~0.00)，且存在剂量-反应关系（均P趋势＜0.05）。在女性中，尿PNP每增加一个对数单位，血清FT3下降1050.00 pg·L−1（b=−0.02，95%CI：−0.03~−0.01），FT4下降10.50 ng·L−1（b=−0.02，95%CI：−0.03~0.00），TT3下降10.70 ng·L−1（b=−0.03，95%CI：−0.05~−0.01），TT4下降10.50 μg·L−1（b=−0.02，95%CI：−0.04~0.00），且尿PNP水平与血清FT3和TT3水平均呈现剂量-反应关系（均P趋势＜0.001）。

结论

尿中PNP浓度变化会导致血清FT4、FT3、TT3水平变化，并表现出性别差异。

Abstract:

Background

Parathion and methyl parathion are typical organophosphorus insecticides and para−nitrophenol (PNP) is their main specific metabolite. Previous studies have shown that parathion and methyl parathion may play a role as endocrine disrupting chemicals, but the evidence is limited.

Objective

Our aim is to evaluate association between urinary PNP concentration and thyroid function among healthy adults and whether this association has gender differences.

Methods

The study was based on the 2007—2008 US National Health and Nutrition ExaminationSurvey (NHANES). A total of 1071 subjects aging from 20 to 64 years with data on both urinary PNP and serum thyroid function indicators were finally enrolled. Thyroid function was evaluated by measuring serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), total triiodothyronine (TT3), total thyroxine (TT4), thyroglobulin (TG), and thyroglobulin antibody (TG-Ab). A generalized linear model was used to analyze the relationship between urinary PNP and serum thyroid function indicators and the dose-response relationship. Gender differences were also explored.

Results

In the total population, the positive rate of PNP was 92.5%, and the median urinary PNP concentration adjusted for urinary creatinine was 0.62 μg·g−1. The median creatinine-adjusted urinary PNP concentrations in the male and female populations were 0.60 and 0.66 µg·g−1 respectively. The median activities or concentrations of serum thyroid function indicators TSH, FT3, FT4, TT3, and TT4 in the total population were 1500.00 μIU·L−1, 3200.00 pg·L−1, 8.00 ng·L−1, 1140.00 ng·L−1, and 76.00 μg·L−1 respectively. In the total population, a logarithmic unit increase of urinary PNP was associated with 1050.00 pg·L−1 decrease in serum FT3 levels (b=−0.02, 95%CI: −0.02-−0.01), 10.50 ng·L−1 decrease in FT4 levels (b=−0.02, 95%CI: −0.03-−0.01), and 10.50 ng·L−1 decrease in TT3 levels (b=−0.02, 95%CI: −0.03-−0.01), all in a dose-response manner (all Ptrend<0.05). After sex stratification, for every logarithmic unit increase of urinary PNP, the serum TG-Ab level was increased by 1100.00 IU·L−1 (b=0.04, 95%CI: 0.00-0.08) and the serum FT3 level was reduced by 1020.00 pg·L−1 (b=−0.01, 95%CI: −0.02-0.00) among males, and both showed dose-response relationships (both Ptrend<0.05); every logarithmic unit increase of urinary PNP was associated with 1050.00 pg·L−1 decrease in FT3 levels (b=−0.02, 95%CI: −0.03-−0.01), 10.50 ng·L−1decrease in FT4 levels (b=−0.02, 95%CI: −0.03-0.00), 10.70 ng·L−1 decrease in TT3 levels (b=−0.03, 95%CI: −0.05-−0.01), and 10.50 μg·L−1 decrease in TT4 levels (b=−0.02, 95%CI: −0.04-0.00) among females, and there were dose-response relationships of urinary PNP concentration with serum FT3 and TT3 levels (both Ptrend<0.001).

Conclusion

Changes in the concentration of PNP in urine are associated with changes in serum FT4, FT3, and TT3 levels and the results also show gender differences.

图  1   研究对象筛选流程

Figure  1.   Flowchart depicting the inclusion process

表  1   2007—2008年NHANES数据库中20~64岁健康成年人的一般人口学特征（n=1071）

Table  1   General demographic characteristics of healthy adults aged 20-64 years from the NHANES 2007—2008 (n=1071)

特征n构成比/%性别　男性57453.6　女性49746.4种族　墨西哥裔美国人21219.8　其他西班牙裔12511.7　非西班牙裔白人44741.7　非西班牙裔黑人22521.0　其他种族625.8教育水平　初中及以下10810.1　高中46443.3　大专及以上49946.6吸烟状态　吸烟者37234.7　非吸烟者69965.3碘状态　碘充足74769.7　碘缺乏32430.3饮酒状态　是71566.8　否17015.9　缺失18617.3

表  2   2007—2008年NHANES数据库中20~64岁健康成年人尿PNP浓度和血清甲状腺功能指标水平[中位数（P25，P75）]

Table  2   Urinary PNP concentration and serum thyroid function indicator levels of healthy adults aged 20-64 years from the NHANES 2007—2008 [M (P25, P75)]

检测指标总人群（n=1071）男性（n=574）女性（n=479）PNP　肌酐校正前尿PNP质量
　浓度/(μg·L−1)0.76 (0.34, 1.50)0.85 (0.42, 1.60)0.66 (0.26, 1.37)　肌酐校正后尿PNP质量
　分数/(μg·g−1)0.62 (0.34, 1.20)0.60 (0.35, 1.13)0.66 (0.33, 1.28)甲状腺功能　TSH活性/(μIU·L−1)1500.00 (1020.00, 2220.00)1460.00 (990.00, 2220.00)1520.00 (1050.00, 2220.00)　FT3质量浓度/(pg·L−1)3200.00 (3000.00, 3500.00)3300.00 (3100.00, 3600.00)3100.00 (2900.00, 3400.00)　FT4质量浓度/(ng·L−1)8.00 (7.00, 8.00)8.00 (7.00, 8.00)8.00 (7.00, 8.00)　TT3质量浓度/(ng·L−1)1140.00
(1020.00, 1280.00)1160.00
(1040.00, 1290.00)1120.00
(990.00, 1260.00)　TT4质量浓度/(μg·L−1)76.00 (66.00, 86.00)74.00 (65.00, 84.00)79.00 (69.00, 89.00)　TG质量浓度/(μg·L−1)10.46 (6.53, 16.92)10.12 (6.62, 15.87)10.94 (6.31, 18.27)　TG-Ab活性/(IU·L−1)600.00 (600.00, 2100.00)600.00 (600.00, 1290.00)600.00 (600.00, 3220.00)

表  3   2007—2008年NHANES数据库中20~64岁健康成年人尿PNP浓度和血清甲状腺功能指标水平的相关性[b（95%CI）]

Table  3   Correlation of urinary PNP concentration and serum thyroid function indicator levels of healthy adults aged 20-64 years from the NHANES 2007—2008 [b (95%CI)]

PNPlgTSHalgFT3 algFT4algTT3algTT4algTGalgTG-Aba总人群 (n=1071)连续变量b0.01(−0.03~0.05)−0.02(−0.02~−0.01)**−0.02(−0.03~−0.01)*−0.02(−0.03~−0.01)*−0.01(−0.02~0.00)0.02(−0.01~0.05)0.02(−0.04~0.07)分类变量 c　Q1参照参照参照参照参照参照参照　Q2−0.01(−0.05~0.04)0.00(−0.01~0.00)−0.01(−0.02~0.00)−0.01(−0.02~0.01)−0.01(−0.02~0.00)0.01(−0.02~0.05)−0.02(−0.08~0.04)　Q3−0.01(−0.06~0.04)−0.01(−0.02~0.00)−0.01(−0.02~0.00)−0.02(−0.03~−0.01)*−0.01(−0.02~0.01)0.00(−0.04~0.04)0.01(−0.05~0.07)　Q42.00(−0.05~0.05)−0.02(−0.03~−0.01)**−0.02(−0.03~0.00)*−0.03(−0.04~−0.01)**−0.01(−0.02~0.01)0.02(−0.01~0.06)0.01(−0.06~0.07)　 P趋势0.811<0.0010.021<0.0010.2420.2870.657男性 (n=575)连续变量b0.02(−0.03~0.08)−0.01(−0.02~0.00)*−0.01(−0.03~0.00)−0.01(−0.02~0.01)0.00(−0.02~0.01)0.02(−0.05~0.08)0.04(0.00~0.08)*分类变量 c　Q1参照参照参照参照参照参照参照　Q2−0.22(−0.09~0.04)−0.01(−0.02~0.00)−0.01(−0.02~0.01)0.00(−0.02~0.02)0.00(−0.02~0.02)0.02(−0.06~0.10)−0.01(−0.05~0.04)　Q3−0.04(−0.10~0.02)−0.01(−0.02~0.01)−0.01(−0.03~0.00)−0.02(−0.03~0.00)−0.01(−0.02~0.01)0.05(−0.03~0.12)−0.02(−0.07~0.02)　Q40.02(−0.04~0.09)−0.02(−0.03~−0.01)*−0.01(−0.03~0.00)−0.01(−0.03~0.01)0.00(−0.02~0.02)0.01(−0.07~0.08)0.06(0.02~0.10)*　 P趋势0.2590.0030.1440.1660.9330.9260.002女性 (n=497)连续变量b0.00(−0.06~0.05)−0.02(−0.03~−0.01)*−0.02(−0.03~0.00)*−0.03(−0.05~−0.01)*−0.02(−0.04~0.00)*0.01(−0.07~0.09)0.00(−0.05~0.05)分类变量c　Q1参照参照参照参照参照参照参照　Q20.01(−0.06~0.08)−0.01(−0.02~0.01)−0.01(−0.03~0.01)−0.02(−0.04~0.01)−0.01(−0.03~0.01)−0.04(−0.14~0.05)0.02(−0.04~0.09)　Q30.04(−0.03~0.11)−0.01(−0.03~0.00)−0.01(−0.03~0.01)−0.02(−0.04~0.00)*−0.01(−0.03~0.01)0.03(−0.07~0.13）−0.03(−0.09~0.04)　Q4−0.02(−0.09~0.06)−0.02(−0.04~−0.01)*−0.02(−0.04~0.00)−0.04(−0.06~−0.02)*−0.02(−0.04~0.00)0.01(−0.09~0.12)−0.01(−0.08~0.05)　 P趋势0.562<0.0010.128<0.0010.1080.5870.431[注]*：P＜0.05；**：P＜0.001。a：协变量为种族、性别、吸烟状态、碘状态。b：肌酐校正后的PNP质量分数经lg10转换。c：肌酐校正后的PNP质量分数分为Q1（＜0.34 μg·g−1）、Q2（0.34~＜0.62 μg·g−1）、Q3（0.62~＜1.20 μg·g−1）、Q4（≥1.20 μg·g−1）组。其中男性分为Q1（＜0.35μg·g−1）、 Q2（0.35~＜0.59 μg·g−1）、Q3（0.59~＜1.13 μg·g−1）、Q4（≥1.13 μg·g−1）组；女性分为Q1（＜0.33 μg·g−1）、Q2（0.33~＜0.66 μg·g−1）、Q3（0.66~＜1.29 μg·g−1）、Q4（≥1.29 μg·g−1）组。 [1]

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