全氟和多氟烷基物质暴露与动脉硬化相关指标存在正向关联及性激素水平的交互作用

doi:10.12122/j.issn.1673-4254.2026.10.16

摘要/Abstract

摘要：

目的探讨全氟和多氟烷基物质（PFAS）暴露与估测脉搏波传导速度（ePWV）的关联，并分析内源性性激素（雌二醇和睾酮）在其中的交互作用。方法基于2013~2016年美国国家健康和营养调查（NHANES）数据，以健康成年参与者为研究对象。采用加权多元线性回归和限制性立方样条模型（RCS）评估单一PFAS组分与ePWV的线性及非线性关联；采用加权分位数和（WQS）回归评估PFAS混合暴露与ePWV的关联，并进一步开展年龄分层WQS分析。为评估混合暴露结果的稳健性，进一步采用双重稳健估计分析高、低PFAS混合暴露组间ePWV水平差异。最后分别在加法和乘法尺度下检验性激素与PFAS的交互作用。结果调整混杂因素后，所有5种纳入分析的PFAS单体均与ePWV呈显著正向关联。RCS分析显示，仅PFOS与ePWV呈显著非线性关联。WQS回归分析结果显示PFAS混合暴露与ePWV显著正向关联。本研究纳入的两种全氟磺酸类物质：全氟辛烷磺酸（PFOS）和全氟己烷磺酸（PFHS）占据了主导地位，权重分别为47.5%和24.3%，是驱动该关联的主要贡献组分。年龄分层WQS分析显示，PFAS混合暴露与ePWV的正向关联主要见于中老年人群，且PFOS和PFHS在不同年龄层中仍具有较高权重。双重稳健估计结果表示，高PFAS混合暴露组人群的ePWV相比低暴露组平均升高了1.284m/s（95% CI：1.078~1.490；P<0.001）。乘法尺度交互分析显示，PFAS与ePWV的正向关联在高水平雌二醇和高水平睾酮人群中相对较弱。具体表现为，这两种性激素均与全氟己烷磺酸（PFHS）存在显著负向交互。此外，雌二醇特异性地与全氟辛烷磺酸（PFOS）及全氟壬酸（PFNA）存在负向交互，而睾酮特异性地与全氟辛酸（PFOA）呈现负向交互。结论 PFAS暴露与ePWV升高存在关联，全氟磺酸类物质（PFOS、PFHS）为关键驱动组分，双重稳健估计进一步支持了该关联。此外，乘法尺度交互分析显示，PFAS与ePWV的正向关联在高水平性激素人群中相对较弱。

关键词: 全氟和多氟烷基物质, 动脉硬化, 性激素, 交互作用

Abstract:

Objective To examine the associations of per- and polyfluoroalkyl substances (PFAS) with estimated pulse wave velocity (ePWV) and assess their interactions with estradiol and testosterone. Methods Based on the data of healthy adults with measurements of 5 PFAS from NHANES 2013-2016, we assessed linear and nonlinear associations of exposure to a single PFAS with ePWV using weighted linear regression and restricted cubic spline (RCS) models; weighted quantile sum (WQS) regression was used to estimate the association of PFAS mixture exposure with ePWV with additional age-stratified WQS analyses, and ePWVs between high and low mixture exposure groups were compared using doubly robust estimation. Additive and multiplicative interactions between PFAS and sex hormones were evaluated. Results After covariate adjustment, all the 5 PFAS were positively associated with ePWV. RCS analyses indicated that only PFOS had a significant nonlinear association with ePWV. WQS regression showed a positive association between PFAS mixture exposure and ePWV. Perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHS) contributed the most to the WQS index with weights of 47.5% and 24.3%, respectively. Age-stratified WQS analyses showed that positive association was mainly observed in middle-aged and older adults, with PFOS and PFHS retaining high weights across different age groups. In doubly robust analysis, ePWV was 1.284 m/s higher in the high- than in low-mixture exposure group (95%CI:1.078-1.490; P<0.001). Multiplicative interaction analyses suggested weaker positive PFAS-ePWV associations in participants with high estradiol or testosterone levels. Both of the sex hormones showed negative interactions with PFHS; estradiol also interacted negatively with PFOS and PFNA, whereas testosterone interacted negatively with PFOA. Conclusion PFAS exposure is associated with an elevated ePWV, with PFOS and PFHS as the key driving components. The positive association between PFAS and ePWV is relatively weaker in individuals with high levels of sex hormones.

Key words: per- and polyfluoroalkyl substances, arterial stiffness, sex hormones, interaction effect

郑朝元, 于瑛蕾, 张颢严, 李盈, 郭冰. 全氟和多氟烷基物质暴露与动脉硬化相关指标存在正向关联及性激素水平的交互作用[J]. 南方医科大学学报, 2026, 46(10): 2471-2481.

Chaoyuan ZHENG, Yinglei YU, Haoyan ZHANG, Ying LI, Bing GUO. Positive association of exposure to per- and polyfluoroalkyl substances with arterial stiffness parameters and its interaction with sex hormone levels[J]. Journal of Southern Medical University, 2026, 46(10): 2471-2481.

图/表 10

参考文献 35

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Variable	Overall (n=1869)	2013-2014 (n=918)	2015-2016 (n=951)	P
Age (years)	42.4±15.5	42.5±15.4	42.2±-15.6	0.582
Gender				0.917
Male	864 (46.2%)	426 (46.4%)	438 (46.1%)
Female	1005 (53.8%)	492 (53.6%)	513 (53.9%)
Race/ethnicity				<0.001
Mexican american	289 (15.5%)	125 (13.6%)	164 (17.2%)
Other hispanic	219 (11.7%)	86 (9.4%)	133 (14.0%)
Non-hispanic white	675 (36.1%)	377 (41.1%)	298 (31.3%)
Non-hispanic black	373 (20.0%)	170 (18.5%)	203 (21.3%)
Other	313 (16.7%)	160 (17.4%)	153 (16.1%)
Education level				0.247
Low	364 (19.5%)	189 (20.6%)	175 (18.4%)
High	1503 (80.5%)	727 (79.4%)	776 (81.6%)
Missing	2	2	0
BMI category				0.459
Underweight	31 (1.7%)	17 (1.9%)	14 (1.5%)
Normal	558 (30.0%)	269 (29.5%)	289 (30.5%)
Overweight	616 (33.1%)	316 (34.6%)	300 (31.6%)
Obese	657 (35.3%)	311 (34.1%)	346 (36.5%)
Missing	7	5	2
Smoking status				0.919
Never	1158 (62.1%)	565(61.6%)	593 (62.5%)
Former	322 (17.3%)	161(17.6%)	161 (17.0%)
Current	386 (20.7%)	191(20.8%)	195 (20.5%)
Missing	3	1	2
Alcohol drinking				0.078
No	,043 (67.9%)	494 (65.7%)	549 (70.0%)
Yes	493 (32.1%)	258 (34.3%)	235 (30.0%)
Missing	333	166	167
Physical activity				0.168
Inactive	240 (16.7%)	127 (18.1%)	113 (15.3%)
Active	1199 (83.3%)	573 (81.9%)	626 (84.7%)
Missing	430	218	212
Menopausal status				0.560
Postmenopausal	304 (17.2%)	142 (16.3%)	162 (18.0%)
Premenopausal	602 (34.0%)	304 (34.9%)	298 (33.2%)
Missing	99 (5.3%)	46 (5.0%)	53 (5.6%)
Ever used female hormone therapy				0.978
No	798 (45.1%)	391 (44.9%)	407 (45.3%)
Yes	108 (6.1%)	54 (6.2%)	54 (6.0%)
Missing	99 (5.3%)	47 (5.1%)	52 (5.5%)
Dietary types				0.265
Normal	1532 (87.0%)	761 (88.2%)	771 (86.0%)
Low calorie diet	146 (8.3%)	66 (7.6%)	80 (8.9%)
Low fat diet	32 (1.8%)	12 (1.4%)	20 (2.2%)
Low salt diet	11 (0.6%)	3 (0.3%)	8 (0.9%)
Other special diet	39 (2.3%)	21 (2.4%)	18 (2.0%)
Missing	109 (5.8%)	55 (6.0%)	54 (5.7%)
Ever thyroid problem				0.711
No	1717 (92.0%)	846 (92.3%)	871 (91.7%)
Yes	150 (8.0%)	71 (7.7%)	79 (8.3%)
Missing	2 (0.1%)	1 (0.1%)	1 (0.1%)
Decreased kidney function or albuminuria				0.253
No	1712 (91.6%)	834 (90.8%)	878 (92.4%)
Yes	156 (8.4%)	84 (9.2%)	72 (7.6%)
Missing	1 (0.1%)	0 (0.0%)	1 (0.1%)
Elevated triglycerides				0.208
No	1686 (90.3%)	820 (89.3%)	866 (91.2%)
es	182 (9.7%)	98 (10.7%)	84 (8.8%)
Missing	1 (0.1%)	0 (0.0%)	1 (0.1%)
High total cholesterol				0.510
No	1204 (64.5%)	599 (65.3%)	605 (63.7%)
Yes	664 (35.5%)	319 (34.7%)	345 (36.3%)
Missing	1 (0.1%)	0 (0.0%)	1 (0.1%)
Fasting plasma glucose (mg/dL)	98.5 (93.0, 106.0)	97.0 (91.0, 103.0)	99.5 (93.0, 107.0)	<0.001
Missing	939 (50.2%)	460 (50.1%)	479 (50.4%)
Estimated pulse wave velocity (m/s)	7.4±1.6	7.4±1.6	7.4±1.6	0.654
Perfluorooctanoic acid (ng/mL)	1.8 (1.1, 2.6)	1.9 (1.3, 2.8)	1.6 (1.0, 2.4)	<0.001
Perfluorooctane sulfonate (ng/mL)	4.8 (2.8, 8.2)	5.1 (3.1, 8.5)	4.6 (2.7, 7.8)	0.004
Perfluorononanoic acid (ng/mL)	0.6 (0.4, 1.0)	0.7 (0.5, 1.0)	0.6 (0.4, 0.9)	<0.001
Perfluorohexane sulfonate (ng/mL)	1.2 (0.6, 2.1)	1.3 (0.7, 2.3)	1.1 (0.6, 1.9)	<0.001
Perfluorodecanoic acid (ng/mL)	0.2 (0.1, 0.3)	0.2 (0.1, 0.3)	0.1 (0.1, 0.3)	<0.001
Estradiol (pg/mL)	25.8 (16.0, 50.0)	26.1 (15.5, 50.6)	25.6 (16.4, 48.2)	0.676
Testosterone (ng/mL)	45.0 (19.9, 398.0)	46.1 (19.9, 395.0)	44.1 (20.0, 405.0)	0.860

Variable	Overall (n=1869)	2013-2014 (n=918)	2015-2016 (n=951)	P
Age (years)	42.4±15.5	42.5±15.4	42.2±-15.6	0.582
Gender				0.917
Male	864 (46.2%)	426 (46.4%)	438 (46.1%)
Female	1005 (53.8%)	492 (53.6%)	513 (53.9%)
Race/ethnicity				<0.001
Mexican american	289 (15.5%)	125 (13.6%)	164 (17.2%)
Other hispanic	219 (11.7%)	86 (9.4%)	133 (14.0%)
Non-hispanic white	675 (36.1%)	377 (41.1%)	298 (31.3%)
Non-hispanic black	373 (20.0%)	170 (18.5%)	203 (21.3%)
Other	313 (16.7%)	160 (17.4%)	153 (16.1%)
Education level				0.247
Low	364 (19.5%)	189 (20.6%)	175 (18.4%)
High	1503 (80.5%)	727 (79.4%)	776 (81.6%)
Missing	2	2	0
BMI category				0.459
Underweight	31 (1.7%)	17 (1.9%)	14 (1.5%)
Normal	558 (30.0%)	269 (29.5%)	289 (30.5%)
Overweight	616 (33.1%)	316 (34.6%)	300 (31.6%)
Obese	657 (35.3%)	311 (34.1%)	346 (36.5%)
Missing	7	5	2
Smoking status				0.919
Never	1158 (62.1%)	565(61.6%)	593 (62.5%)
Former	322 (17.3%)	161(17.6%)	161 (17.0%)
Current	386 (20.7%)	191(20.8%)	195 (20.5%)
Missing	3	1	2
Alcohol drinking				0.078
No	,043 (67.9%)	494 (65.7%)	549 (70.0%)
Yes	493 (32.1%)	258 (34.3%)	235 (30.0%)
Missing	333	166	167
Physical activity				0.168
Inactive	240 (16.7%)	127 (18.1%)	113 (15.3%)
Active	1199 (83.3%)	573 (81.9%)	626 (84.7%)
Missing	430	218	212
Menopausal status				0.560
Postmenopausal	304 (17.2%)	142 (16.3%)	162 (18.0%)
Premenopausal	602 (34.0%)	304 (34.9%)	298 (33.2%)
Missing	99 (5.3%)	46 (5.0%)	53 (5.6%)
Ever used female hormone therapy				0.978
No	798 (45.1%)	391 (44.9%)	407 (45.3%)
Yes	108 (6.1%)	54 (6.2%)	54 (6.0%)
Missing	99 (5.3%)	47 (5.1%)	52 (5.5%)
Dietary types				0.265
Normal	1532 (87.0%)	761 (88.2%)	771 (86.0%)
Low calorie diet	146 (8.3%)	66 (7.6%)	80 (8.9%)
Low fat diet	32 (1.8%)	12 (1.4%)	20 (2.2%)
Low salt diet	11 (0.6%)	3 (0.3%)	8 (0.9%)
Other special diet	39 (2.3%)	21 (2.4%)	18 (2.0%)
Missing	109 (5.8%)	55 (6.0%)	54 (5.7%)
Ever thyroid problem				0.711
No	1717 (92.0%)	846 (92.3%)	871 (91.7%)
Yes	150 (8.0%)	71 (7.7%)	79 (8.3%)
Missing	2 (0.1%)	1 (0.1%)	1 (0.1%)
Decreased kidney function or albuminuria				0.253
No	1712 (91.6%)	834 (90.8%)	878 (92.4%)
Yes	156 (8.4%)	84 (9.2%)	72 (7.6%)
Missing	1 (0.1%)	0 (0.0%)	1 (0.1%)
Elevated triglycerides				0.208
No	1686 (90.3%)	820 (89.3%)	866 (91.2%)
es	182 (9.7%)	98 (10.7%)	84 (8.8%)
Missing	1 (0.1%)	0 (0.0%)	1 (0.1%)
High total cholesterol				0.510
No	1204 (64.5%)	599 (65.3%)	605 (63.7%)
Yes	664 (35.5%)	319 (34.7%)	345 (36.3%)
Missing	1 (0.1%)	0 (0.0%)	1 (0.1%)
Fasting plasma glucose (mg/dL)	98.5 (93.0, 106.0)	97.0 (91.0, 103.0)	99.5 (93.0, 107.0)	<0.001
Missing	939 (50.2%)	460 (50.1%)	479 (50.4%)
Estimated pulse wave velocity (m/s)	7.4±1.6	7.4±1.6	7.4±1.6	0.654
Perfluorooctanoic acid (ng/mL)	1.8 (1.1, 2.6)	1.9 (1.3, 2.8)	1.6 (1.0, 2.4)	<0.001
Perfluorooctane sulfonate (ng/mL)	4.8 (2.8, 8.2)	5.1 (3.1, 8.5)	4.6 (2.7, 7.8)	0.004
Perfluorononanoic acid (ng/mL)	0.6 (0.4, 1.0)	0.7 (0.5, 1.0)	0.6 (0.4, 0.9)	<0.001
Perfluorohexane sulfonate (ng/mL)	1.2 (0.6, 2.1)	1.3 (0.7, 2.3)	1.1 (0.6, 1.9)	<0.001
Perfluorodecanoic acid (ng/mL)	0.2 (0.1, 0.3)	0.2 (0.1, 0.3)	0.1 (0.1, 0.3)	<0.001
Estradiol (pg/mL)	25.8 (16.0, 50.0)	26.1 (15.5, 50.6)	25.6 (16.4, 48.2)	0.676
Testosterone (ng/mL)	45.0 (19.9, 398.0)	46.1 (19.9, 395.0)	44.1 (20.0, 405.0)	0.860

Hormone	Hormone level	β (95% CI)	P interaction
Estradiol	Low	0.891 (0.751, 1.032)	<0.01
	Moderate	0.670 (0.558, 0.783)
	High	0.428 (0.291, 0.565)
Testosterone	Low	0.814 (0.659, 0.970)	<0.001
	Moderate	0.432 (0.335, 0.529)
	High	0.193 (0.099, 0.287)

Hormone	Hormone level	β (95% CI)	P interaction
Estradiol	Low	0.891 (0.751, 1.032)	<0.01
	Moderate	0.670 (0.558, 0.783)
	High	0.428 (0.291, 0.565)
Testosterone	Low	0.814 (0.659, 0.970)	<0.001
	Moderate	0.432 (0.335, 0.529)
	High	0.193 (0.099, 0.287)

E2				T
PFAS	Hormone level	β (95% CI)	P interaction	PFAS	Hormone level	β (95% CI)	P interaction
PFOA			0.134	PFOA			<0.001
	Low	0.59 (0.36, 0.82)			Low	0.87 (0.68, 1.07)
	Moderate	0.29 (0.14, 0.44)			Moderate	0.57 (0.43, 0.71)
	High	0.21 (0.10, 0.32)			High	0.19 (-0.06, 0.41)
PFOS			<0.001	PFOS			0.092
	Low	0.81 (0.63, 0.99)			Low	0.79 (0.63, 0.95)
	Moderate	0.53 (0.41, 0.65)			Moderate	0.63 (0.52, 0.74)
	High	0.14 (0.05, 0.23)			High	0.50 (0.31, 0.69)
PFNA			<0.01	PFNA			0.278
	Low	0.75 (0.52, 0.98)			Low	0.79 (0.59, 0.98)
	Moderate	0.45 (0.32, 0.59)			Moderate	0.62 (0.48, 0.76)
	High	0.19 (0.09, 0.30)			High	0.50 (0.28, 0.71)
PFHS			<0.001	PFHS			<0.001
	Low	0.69 (0.50, 0.88)			Low	0.85 (0.70, 1.01)
	Moderate	0.24 (0.12, 0.35)			Moderate	0.42 (0.31, 0.53)
	High	0.10 (0.01, 0.19)			High	0.23 (0.04, 0.42)
PFDA			0.780	PFDA			0.884
	Low	0.38 (0.18, 0.59)			Low	0.44 (0.24, 0.63)
	Moderate	0.28 (0.17, 0.40)			Moderate	0.36 (0.24, 0.48)
	High	0.20 (0.11, 0.30)			High	0.28 (0.10, 0.46)