摘要:

背景

對(duì)硝基酚（PNP）是有機(jī)磷農(nóng)藥對(duì)硫磷和甲基對(duì)硫磷主要的特異性代謝產(chǎn)物。既往的研究發(fā)現(xiàn)對(duì)硫磷和甲基對(duì)硫磷可能具有內(nèi)分泌干擾作用，但證據(jù)較為有限。

目的

探討健康成年人群尿中PNP濃度與甲狀腺功能的相關(guān)性及是否存在性別差異。

方法

基于2007—2008年美國國家營養(yǎng)與健康調(diào)查，將1071例同時(shí)具有尿PNP、血清甲狀腺功能指標(biāo)的20~64歲健康成年人納入本研究。收集血清甲狀腺刺激素（TSH）、游離三碘甲狀腺原氨酸（FT3）、游離甲狀腺激素（FT4）、總?cè)饧谞钕僭彼?TT3)、總甲狀腺激素（TT4）、甲狀腺球蛋白（TG）、甲狀腺球蛋白抗體（TG-Ab）數(shù)據(jù)以評(píng)估甲狀腺功能。采用廣義線性模型分析尿PNP與血清甲狀腺功能指標(biāo)的關(guān)系及劑量-反應(yīng)關(guān)系，并分析性別差異。

結(jié)果

總?cè)巳褐心騊NP的檢出率為92.5%，肌酐校正后質(zhì)量分?jǐn)?shù)中位數(shù)為0.62 μg·g?1。男性和女性肌酐校正后尿PNP質(zhì)量分?jǐn)?shù)中位數(shù)分別是0.60、0.66 μg·g?1?？?cè)巳褐兄饕谞钕俟δ苤笜?biāo)TSH、FT3、FT4、TT3、TT4的活性或質(zhì)量濃度中位數(shù)分別為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。在總?cè)巳褐?，尿PNP每增加一個(gè)對(duì)數(shù)單位，血清FT3、FT4、TT3分別下降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)，且存在劑量-反應(yīng)關(guān)系（均P趨勢(shì)＜0.05）。性別分層后發(fā)現(xiàn)，在男性中，尿PNP每增加一個(gè)對(duì)數(shù)單位，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)，且存在劑量-反應(yīng)關(guān)系（均P趨勢(shì)＜0.05）。在女性中，尿PNP每增加一個(gè)對(duì)數(shù)單位，血清FT3下降1050.00 pg·L?1（b=?0.02，95%CI：?0.03~?0.01），F(xiàn)T4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水平與血清FT3和TT3水平均呈現(xiàn)劑量-反應(yīng)關(guān)系（均P趨勢(shì)＜0.001）。

結(jié)論

尿中PNP濃度變化會(huì)導(dǎo)致血清FT4、FT3、TT3水平變化，并表現(xiàn)出性別差異。

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.

圖  1   研究對(duì)象篩選流程

Figure  1.   Flowchart depicting the inclusion process

表  1   2007—2008年NHANES數(shù)據(jù)庫中20~64歲健康成年人的一般人口學(xué)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構(gòu)成比/%性別　男性57453.6　女性49746.4種族　墨西哥裔美國人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　其他種族625.8教育水平　初中及以下10810.1　高中46443.3　大專及以上49946.6吸煙狀態(tài)　吸煙者37234.7　非吸煙者69965.3碘狀態(tài)　碘充足74769.7　碘缺乏32430.3飲酒狀態(tài)　是71566.8　否17015.9　缺失18617.3

表  2   2007—2008年NHANES數(shù)據(jù)庫中20~64歲健康成年人尿PNP濃度和血清甲狀腺功能指標(biāo)水平[中位數(shù)（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)]

檢測指標(biāo)總?cè)巳海╪=1071）男性（n=574）女性（n=479）PNP　肌酐校正前尿PNP質(zhì)量
　濃度/(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質(zhì)量
　分?jǐn)?shù)/(μg·g?1)0.62 (0.34, 1.20)0.60 (0.35, 1.13)0.66 (0.33, 1.28)甲狀腺功能　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質(zhì)量濃度/(pg·L?1)3200.00 (3000.00, 3500.00)3300.00 (3100.00, 3600.00)3100.00 (2900.00, 3400.00)　FT4質(zhì)量濃度/(ng·L?1)8.00 (7.00, 8.00)8.00 (7.00, 8.00)8.00 (7.00, 8.00)　TT3質(zhì)量濃度/(ng·L?1)1140.00
(1020.00, 1280.00)1160.00
(1040.00, 1290.00)1120.00
(990.00, 1260.00)　TT4質(zhì)量濃度/(μg·L?1)76.00 (66.00, 86.00)74.00 (65.00, 84.00)79.00 (69.00, 89.00)　TG質(zhì)量濃度/(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數(shù)據(jù)庫中20~64歲健康成年人尿PNP濃度和血清甲狀腺功能指標(biāo)水平的相關(guān)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總?cè)巳?(n=1071)連續(xù)變量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)分類變量 c　Q1參照參照參照參照參照參照參照　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趨勢(shì)0.811<0.0010.021<0.0010.2420.2870.657男性 (n=575)連續(xù)變量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)*分類變量 c　Q1參照參照參照參照參照參照參照　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趨勢(shì)0.2590.0030.1440.1660.9330.9260.002女性 (n=497)連續(xù)變量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)分類變量c　Q1參照參照參照參照參照參照參照　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趨勢(shì)0.562<0.0010.128<0.0010.1080.5870.431[注]*：P＜0.05；**：P＜0.001。a：協(xié)變量為種族、性別、吸煙狀態(tài)、碘狀態(tài)。b：肌酐校正后的PNP質(zhì)量分?jǐn)?shù)經(jīng)lg10轉(zhuǎn)換。c：肌酐校正后的PNP質(zhì)量分?jǐn)?shù)分為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）組。其中男性分為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）組；女性分為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）組。 [1]

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