妊娠期多种环境化合物暴露与出生体重的关联

曹秀丽; 王晶宇; 李媛媛; 徐顺清; 周远忠; 刘洪秀

doi:10.16462/j.cnki.zhjbkz.2025.02.002

妊娠期多种环境化合物暴露与出生体重的关联

doi: 10.16462/j.cnki.zhjbkz.2025.02.002

1.
华中科技大学同济医学院公共卫生学院环境医学研究所, 武汉 430030
2.
遵义医科大学公共卫生学院, 遵义 563006

基金项目:

国家自然科学基金 22006046

广西省环境暴露组学与全生命周期健康重点实验室开放课题 2023-GKLEH-02

贵州省科技计划 QKHPTRC-CXTD [2022] 014

贵州省教育厅科学研究项目 QJJ [2023] 019

详细信息

通讯作者:
刘洪秀, E-mail: lhx@hust.edu.cn

中图分类号: R181;R17
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出版历程
- 收稿日期: 2024-03-26
- 修回日期: 2025-01-02
- 网络出版日期: 2025-03-08
- 刊出日期: 2025-02-10

Association between prenatal exposure to multiple environmental chemicals and birth weight

1.
The Institute of Environmental Medicine, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2.
School of Public Health, Zunyi Medical University, Zunyi 563006, China

Funds:

National Natural Science Foundation of China 22006046

The Open Program of Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Heath 2023-GKLEH-02

The Science & Technology Program of Guizhou Province QKHPTRC-CXTD [2022] 014

Scientific Research Program of Guizhou Provincial Department of Education QJJ [2023] 019

More Information

Corresponding author: LIU Hongxiu, E-mail: lhx@hust.edu.cn

摘要

摘要: 目的探究孕妇妊娠期暴露于金属类、酚类、邻苯二甲酸酯类、对羟基苯甲酸酯类、苯并三唑类和苯并噻唑类组成的化学暴露组与出生体重之间的关联。方法选取2014―2015年加入武汉一项出生队列的829对母婴作为研究对象。在妊娠期指导孕妇填写基线调查表, 重复收集孕妇尿液样本, 通过检测尿样中33种金属类、8种酚类、8种邻苯二甲酸酯类、3种对羟基苯甲酸酯类、4种苯并三唑类和4种苯并噻唑(benzothiazole, BTH)类污染物的浓度, 来评估暴露水平。采用全暴露组关联分析(exposome-wide association study, ExWAS)独立检验每种暴露与出生体重的关联。随后采用弹性网络(elastic net, ENET)模型对ExWAS中的阳性变量进行筛选, 并将其纳入贝叶斯核机回归(Bayesian kernel machine regression, BKMR)模型, 以评估混合暴露的影响。结果 ExWAS结果显示, 双酚S(bisphenol S, BPS)、双酚F(bisphenol F, BPF)、铝(aluminum, Al)、镓(gallium, Ga)和BTH均与出生体重呈负相关, 其浓度升高1个四分位数间距(interquartile range, IQR), 出生体重的差异分别为-36.76(95% CI：-66.79~-6.73)g、-36.05(95% CI：-67.59~-4.51)g、-26.59(95% CI：-52.81~-0.37)g、-37.82(95% CI：-68.60~-7.04)g和-47.89(95% CI：-85.81~-9.96)g。ENET模型筛选得到BPS、Ga和BTH, BKMR模型发现这3种物质的混合暴露物与出生体重降低有关, 与处于P₅₀相比, 混合物浓度上升至P₇₅, 出生体重降低47.45(95% CI：19.21~75.69)g。性别分层分析显示, BPS、Ga和BTH仅对男婴的出生体重有影响。结论母亲妊娠期BPS、Ga和BTH暴露与婴儿出生体重的降低有关, 尤其是男婴的体重降低情况。
- 妊娠期暴露 /
- 出生体重 /
- 全暴露组关联分析 /
- 贝叶斯核机回归 /
- 队列
Abstract: Objective To investigate the association between maternal prenatal exposure to a chemical exposome consisting of metals, phenols, phthalates, hydroxybenzoates, benzotriazoles and benzothiazoles, and the birth weight of newborns. Methods A total of 829 mother-infant pairs who joined a birth cohort in Wuhan from 2014 to 2015 were selected as the study population. Pregnant women were guided to fill out baseline questionnaires, and their urine samples were collected repeatedly. The concentrations of 33 metals, 8 phenols, 8 phthalates, 3 hydroxybenzoates, 4 benzotriazoles, and 4 benzothiazoles metabolites in urine samples were measured. An exposome-wide association study (ExWAS) was applied to test the association of each exposure with birth weight. Subsequently, the elastic net (ENET) model was used to select significant variables from the ExWAS approach, and the selected variables were incorporated into the Bayesian kernel machine regression (BKMR) model to evaluate the effect of their mixture. Results The ExWAS results showed a negative correlation between bisphenol S (BPS), bisphenol F (BPF), aluminum (Al), gallium (Ga), and benzothiazole (BTH) with birth weight, and for each interquartile range (IQR) increase in the concentrations of these exposures, the differences in birth weight were -36.76 (95% CI: -66.79--6.73) g, -36.05 (95% CI: -67.59--4.51) g, -26.59 (95% CI: -52.81--0.37) g, -37.82 (95% CI: -68.60--7.04) g, and -47.89 (95% CI: -85.81--9.96) g, respectively. Besides, BPS, Ga, and BTH were selected by ENET model, then their mixture was significantly associated with reduced birth weight in BKMR model. Compared to the 50th percentile, increasing the concentration of the mixture to the 75th percentile resulted in a reduction in birth weight of 47.45 (95% CI: 19.21-75.69) g. Sex-stratified analysis revealed that BPS, Ga, and BTH only affected the birth weight of male infants. Conclusions Maternal exposure to BPS, Ga, and BTH during pregnancy is associated with a decrease in infant birth weight, particularly in male infants.
- Prenatal exposure /
- Birth weight /
- Exposome-wide association study /
- Bayesian kernel machine regression /
- Cohort

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图 1 双酚S、镓和苯并噻唑混合暴露与出生体重的关联

Figure 1. Birth weight changed by the percentile concentrations of the mixture of BPS, Ga, and BTH based on the 50th percentile concentration

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表 1 本研究检测的化合物

Table 1. Chinese and English name and LOD of chemicals detected in the study

中文名称	英文名称	缩写	检出限/(μg·L^-1)	中文名称	英文名称	缩写	检出限/(μg·L^-1)
邻苯二甲酸乙酯	Mono-ethyl phthalate	MEP	0.10	硒	Selenium	Se	0.22
邻苯二甲酸单-2- 乙基-5-羧基戊酯	Mono-(2-ethyl-5- carboxypentyl) phthalate	MECPP	0.01	铷	Rubidium	Rb	0.01
邻苯二甲酸单-2- 乙基-5-羟基己酯	Mono-(2-ethyl-5- hydroxyhexyl) phthalate	MEHHP	0.05	锶	Strontium	Sr	0.01
邻苯二甲酸单-2- 乙基-5-氧代己酯	Mono-(2-ethyl-5- oxohexyl) phthalate	MEOHP	0.05	银	Silver	Ag	0.02
邻苯二甲酸单异丁酯	Mono-iso-butyl phthalate	MiBP	0.10	镉	Cadmium	Cd	< 0.01
邻苯二甲酸单正丁酯	Mono-n-butyl phthalate	MnBP	0.10	铯	Cesium	Cs	< 0.01
邻苯二甲酸单苄酯	Mono-benzyl phthalate	MBzP	0.10	钡	Barium	Ba	0.31
邻苯二甲酸单-2- 乙基己酯	Mono-(2- ethylhexyl) phthalate	MEHP	0.10	镧	Lanthanum	La	< 0.01
对羟基苯甲酸甲酯	Methyl paraben	MeP	0.05	铈	Cerium	Ce	< 0.01
对羟基苯甲酸乙酯	Ethyl paraben	EtP	0.01	镨	Praseodymium	Pr	< 0.01
对羟基苯甲酸丙酯	Propyl paraben	PrP	0.05	钕	Neodymium	Nd	< 0.01
4羟基苯甲酮	4-hydroxy-benzophenone	4-OH-BP	0.10	铕	Europium	Eu	< 0.01
双酚S	Bisphenol S	BPS	0.20	钆	Gadolinium	Gd	< 0.01
双酚A	Bisphenol A	BPA	0.20	镝	Dysprosium	Dy	< 0.01
二苯甲酮-1	Benzophenone-1	BP1	0.10	钬	Holmium	Ho	< 0.01
双酚AF	Bisphenol AF	BPAF	0.10	铒	Erbium	Er	< 0.01
二苯甲酮-3	Benzophenone-3	BP3	0.20	铥	Thulium	Tm	< 0.01
三氯生	Triclosan	TCS	0.10	镱	Ytterbium	Yb	< 0.01
双酚F	Bisphenol F	BPF	0.10	铊	Thallium	Tl	0.02
铝	Aluminum	Al	0.11	铅	Lead	Pb	0.01
钒	Vanadium	V	< 0.01	钍	Thorium	Th	< 0.01
铬	Chromium	Cr	0.01	铀	Uranium	U	< 0.01
锰	Manganese	Mn	0.05	1-H-苯并三唑	1-H-benzotriazol	1-H-BTR	0.01
铁	Iron	Fe	1.07	1-羟基苯并三唑	1-hydroxy-benzotriazole	1-OH-BTR	0.04
钴	Cobalt	Co	0.01	5, 6-二甲基-1-H-苯并三唑	5, 6-dimethyl-1-H-benzotriazole	XTR	0.01
镍	Nickel	Ni	0.02	甲基苯并三唑	Tolyltriazole	TTR	0.02
铜	Copper	Cu	0.13	苯并噻唑	Benzothiazole	BTH	0.02
锌	Zinc	Zn	0.02	2-羟基苯并噻唑	2-hydroxy-benzothiazole	2-OH-BTH	0.01
镓	Gallium	Ga	0.02	2-甲硫基苯并噻唑	2-methylthio-benzothiazole	2-MeS-BTH	0.02
砷	Arsenic	As	0.02	2-氨基苯并噻唑	2-amino-benzothiazole	2-amino-BTH	0.01

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表 2 研究对象的基线信息

Table 2. Baseline informations of 829 pairs of women and their infants, including maternal age, parity, maternal education, pre-pregnancy BMI, annual household income, passive smoking during pregnancy, gestational duration, season of conception, child gender, and birth weight

特征	x±s/人数(占比%)	特征	x±s/人数(占比%)
孕妇年龄/岁		孕期被动吸烟
< 29	461(55.61)	否	549(66.22)
≥29	368(44.39)	是	280(33.78)
产次		孕龄/周	39.46±1.00
初产	713(86.01)	受孕季节
经产	116(13.99)	春(3―5月)	173(20.87)
受教育水平		夏(6―8月)	227(27.38)
高中及以下	181(21.83)	秋(9―11月)	266(32.09)
大专及以上	648(78.17)	冬(12―次年2月)	163(19.66)
孕前BMI/(kg·m^-2)		新生儿性别
< 18.5	154(18.58)	男	432(52.11)
18.5 ~ < 24.0	567(68.40)	女	397(47.89)
≥24.0	108(13.03)	出生体重/g	3 332.26±392.45
家庭年均收入/元
< 100 000	475(57.30)
≥100 000	354(42.70)

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表 3 暴露的分布及单个暴露与出生体重的关联

Table 3. The concentrations of 33 metals, 8 phenols, 8 phthalates, 3 hydroxybenzoates, 4 benzothiazoles, and 4 benzotriazoles in urine and their respective associations with birth weight

暴露	M(P₂₅, P₇₅)	四分位数间距^①	β值(95% CI)^②	P值
邻苯二甲酸酯类/(μg·L^-1)
MEP	8.42 (4.90, 16.32)	1.20	-5.69(-33.68~22.30)	0.690
MECPP	8.73 (5.71, 12.58)	0.79	12.90(-11.02~36.82)	0.291
MEHHP	5.61 (3.67, 8.15)	0.80	11.19(-15.67~38.05)	0.414
MEOHP	4.43 (2.88, 6.56)	0.82	22.49(-4.28~49.26)	0.100
MiBP	14.70 (7.55, 24.61)	1.18	-3.60(-21.73~14.53)	0.697
MnBP	48.08 (24.03, 88.86)	1.31	-3.50(-29.83~22.82)	0.794
MBzP	0.07 (0.04, 0.13)	1.09	-22.07(-53.06~8.92)	0.163
MEHP	2.02 (0.79, 3.81)	1.57	27.29(-0.89~55.47)	0.058
对羟基苯甲酸酯类/(μg·L^-1)
MEPA	15.03 (4.98, 47.50)	2.26	-8.61(-43.21~25.99)	0.626
ETPA	0.53 (0.23, 1.43)	1.82	-24.86(-50.97~1.24)	0.062
PrP	0.77 (0.22, 2.87)	2.57	-24.53(-60.89~11.83)	0.186
酚类/(μg·L^-1)
4-OH-BP	0.15 (0.08, 0.28)	1.26	-22.16(-53.74~9.42)	0.169
BPS	0.37 (0.18, 0.86)	1.58	-36.76(-66.79~-6.73)	0.017^③
酚类/(μg·L^-1)
BPA	1.01(0.28, 2.52)	2.18	-12.90(-45.49~19.69)	0.438
BP	0.24(0.11, 0.56)	1.59	-17.85(-46.00~10.29)	0.214
BPAF	0.03(0.02, 0.05)	1.14	6.44(-19.48~32.36)	0.626
BP3	0.40(0.11, 1.20)	2.38	-25.67(-60.52~9.19)	0.149
TCS	0.39(0.12, 1.31)	2.40	2.53(-32.34~37.40)	0.887
BPF	0.66(0.37, 1.34)	1.28	-36.05(-67.59~-4.51)	0.025^③
金属类/(μg·L^-1)
Al	18.39(9.58, 37.05)	1.35	-26.59(-52.81~-0.37)	0.047 ^③
V	0.86(0.33, 1.14)	1.25	-20.6(-53.25~12.06)	0.217
Cr	0.60(0.36, 0.91)	0.94	-15.78(-43.24~11.69)	0.261
Mn	1.04(0.61, 1.85)	1.11	-17.39(-46.83~12.04)	0.247
Fe	24.54(14.45, 41.92)	1.06	-20.67(-51.17~9.83)	0.185
Co	0.37(0.22, 0.55)	0.93	-1.7(-33.08~29.68)	0.916
Ni	1.81(0.92, 2.98)	1.18	-15.25(-45.41~14.92)	0.322
Cu	8.11(4.19, 10.92)	0.96	-5.21(-30.35~19.93)	0.685
Zn	168.00(91.90, 244.21)	0.98	-10.72(-29.51~8.06)	0.264
Ga	0.03(0.02, 0.05)	0.71	-37.82(-68.60~-7.04)	0.016 ^③
As	14.63(9.23, 19.99)	0.77	-9.18(-28.53~10.17)	0.353
Se	10.69(7.22, 13.80)	0.65	-15.64(-41.35~10.07)	0.234
Rb	1 158.23(820.89, 1 435.89)	0.56	-5.17(-13.61~3.26)	0.230
Sr	119.25(67.35, 176.09)	0.96	-5.02(-23.09~13.05)	0.586
Ag	0.04(0.02, 0.08)	1.35	-3.11(-45.21~39.00)	0.885
Cd	0.42(0.23, 0.60)	0.97	-15.32(-40.34~9.69)	0.230
Cs	6.23(4.53, 7.57)	0.51	-6.03(-16.72~4.66)	0.269
Ba	5.17(2.68, 8.40)	1.14	-11.16(-42.96~20.64)	0.492
La	0.04(0.01, 0.08)	2.04	-0.16(-36.37~36.04)	0.993
Ce	0.04(0.01, 0.09)	2.11	-0.63(-36.84~35.57)	0.973
Pr	0.01(< 0.01, 0.02)	2.26	-3.33(-40.95~34.29)	0.862
Nd	0.02(0.01, 0.04)	1.71	-6.62(-43.05~29.81)	0.722
Eu	0.01(< 0.01, 0.02)	1.52	-12.48(-53.93~28.97)	0.555
Gd	0.01(< 0.01, 0.02)	1.55	-16.02(-52.98~20.95)	0.396
Dy	0.01(< 0.01, 0.01)	2.02	-8.12(-50.15~33.91)	0.705
Ho	0.01(< 0.01, 0.02)	2.10	-14.96(-59.18~29.26)	0.507
Er	0.01(0.01, 0.02)	1.76	-12.97(-52.99~27.06)	0.526
Tm	0.01(< 0.01, 0.02)	1.91	-11.19(-52.16~29.77)	0.592
Yb	0.01(< 0.01, 0.01)	1.43	-15.23(-55.57~25.11)	0.460
Tl	0.30(0.20, 0.38)	0.64	-16.03(-46.94~14.88)	0.310
Pb	1.91(1.21, 2.74)	0.81	-10.40(-32.85~12.06)	0.364
Th	0.04(0.01, 0.10)	2.06	4.30(-34.43~43.04)	0.828
U	0.03(0.01, 0.05)	2.11	-29.04(-66.48~8.41)	0.129
苯并三唑类/(μg·L^-1)
1-H-BTR	0.07(0.02, 0.26)	2.67	10.83(-30.74~52.40)	0.610
1-OH-BTR	0.25(0.06, 0.77)	2.50	8.45(-34.17~51.08)	0.698
XTR	0.05(0.02, 0.11)	1.89	26.58(-9.82~62.99)	0.153
TTR	0.04(0.03, 0.10)	1.36	2.01(-32.11~36.14)	0.908
苯并噻唑类/(μg·L^-1)
BTH	1.11(0.29, 2.69)	2.24	-47.89(-85.81~-9.96)	0.014^③
2-OH-BTH	0.20(0.06, 0.71)	2.51	-8.08(-48.00~31.84)	0.692
2-MeS-BTH	0.30(0.13, 0.58)	1.51	5.04(-26.35~36.43)	0.753
2-amino-BTH	0.02(0.01, 0.05)	1.48	8.00(-28.75~44.75)	0.670
注：①四分位数间距在经自然对数转换后的暴露浓度中计算; ②模型调整了孕妇年龄、产次、受教育水平、孕前BMI、家庭年均收入、孕期被动吸烟、孕龄、受孕季节和新生儿性别因素; ③ P < 0.05。

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