邻苯二甲酸酯(PAEs)具有内分泌干扰特性。人类研究表明,子宫内邻苯二甲酸盐暴露会影响母体甲状腺激素,对胎儿的生长发育至关重要。然而,这些研究还报道了邻苯二甲酸酯与甲状腺激素之间关系的不一致结果.这项前瞻性队列研究旨在评估妊娠三个月的邻苯二甲酸盐暴露及其与甲状腺激素水平的关系。从2019年到2022年,我们招募了672名孕妇,在怀孕期间,从每个参与者收集了两个尿液样本和一个血液样本。我们首先检查了663、335和294名女性的尿液样本,第二,妊娠晚期,分别,对于以下7种邻苯二甲酸酯代谢物:来自邻苯二甲酸二乙酯(DEP)的邻苯二甲酸单乙酯(MEP);来自邻苯二甲酸二丁酯(DBP)的邻苯二甲酸单正丁酯(MnBP)和邻苯二甲酸单异丁酯(MiBP);来自邻苯二甲酸丁基苄酯的邻苯二甲酸单苄基酯(MBzP);和三种邻苯二甲酸二(2-乙基己基)(DEHP)代谢物,邻苯二甲酸单(2-乙基-5-羟基己基)酯(MEHHP),邻苯二甲酸单(2-乙基-5-氧代己基)酯(MEOHP),和单-(2-乙基-5-羧基戊基)邻苯二甲酸酯(MECPP)。此外,我们检查了游离甲状腺素(FT4)的水平,促甲状腺激素(TSH),以下参与者的血清样本中的总三碘甲状腺原氨酸(TT3):妊娠早期596、627和576;妊娠中期292、293和282;妊娠中期250、250和248,分别。除了MBZP,在25%-33%的样本中检测到,在>86%的尿液样本中检测到其他代谢物,表明广泛接触DEP,DBP,DEHP。我们队列中检测到的邻苯二甲酸盐暴露水平明显高于其他国家。代谢物水平在三个月内各不相同,暗示整个怀孕期间暴露和新陈代谢的变化。观察到的邻苯二甲酸酯代谢物尿浓度的变异性,从贫穷到中等,强调了在怀孕期间进行多次测量以进行精确暴露评估的重要性。使用线性混合模型,我们分析了邻苯二甲酸酯反复暴露对甲状腺激素水平的影响,同时校正了潜在的混杂因素.我们观察到FT4、TSH、and,在较小程度上,TT3跨越特定邻苯二甲酸酯代谢物的四分位数。比较最高和最低的四分位数,我们发现FT4水平显著增加,从2%到3.7%不等,与MEP相关;MECPP;MEHHP;和七个代谢物的总和(∑7PAE),三种DEHP代谢物(∑3DEHP),两种DBP代谢物(∑DBP),以及低分子量(∑LMW)和高分子量代谢物。观察到所有邻苯二甲酸酯代谢物(MEHHP除外)的TSH水平增加(5%-16%)及其摩尔总和,包括∑7PAE。对于TT3,用MEP观察到显著增加(2.2%),用ΣDBP观察到降低(-2.7%)。在几种邻苯二甲酸酯代谢物的最高四分位数(第三或第四)中,观察到较高的TSH/FT4比率:MEP(8.8%),MiBP(8.7%),MnBP(22.2%),∑7PAE(15.3%),∑DBP(16.4%),和∑LMW(18.6%)。这些荷尔蒙的改变,最值得注意的是在第二和第三个三个月,提示邻苯二甲酸盐暴露可能通过影响母体甲状腺功能而影响胎儿生长发育。
Phthalate esters (PAEs) possess endocrine-disrupting properties. Studies in humans have indicated that in utero phthalate exposure affects maternal thyroid hormones, which are essential for fetal growth and development. However, these studies also reported inconsistent results on the relationship between phthalates and thyroid hormones. This prospective cohort
study aimed to assess phthalate exposure across the three trimesters of pregnancy and its association with thyroid hormone levels. From 2019 to 2022, we recruited 672 pregnant women, and two urine samples and one blood sample were collected from each participant during the pregnancy. We examined the urine samples from 663, 335, and 294 women in the first, second, and third trimester, respectively, for the following seven phthalate metabolites: monoethyl phthalate (MEP) from diethyl phthalate (DEP); mono-n-butyl phthalate (MnBP) and mono-iso-butyl phthalate (MiBP) from dibutyl phthalate (DBP); monobenzyl phthalate (MBzP) from butyl benzyl phthalate; and three di(2-ethylhexyl) phthalate (DEHP) metabolites, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP). Additionally, we examined the levels of free
thyroxine (FT4), thyroid-stimulating hormone (TSH), and total triiodothyronine (TT3) in the serum samples of the following participants: 596, 627, and 576 in the first trimester; 292, 293, and 282 in the second trimester; and 250, 250, and 248 in the third trimester, respectively. Other than MBzP, which was detected in 25%-33% of the samples, other metabolites were detectable in >86% of urine samples, indicating widespread exposure to DEP, DBP, and DEHP. The detected phthalate exposure levels in our cohort were significantly higher than those reported in other countries. Metabolite levels varied across the trimesters, implying changes in exposure and metabolism throughout pregnancy. The observed variability in urinary concentrations of phthalate metabolites, which ranged from poor to moderate, underscores the importance of taking multiple measurements during pregnancy for precise exposure assessment. Using a linear mixed model, we analyzed the effects of repeated phthalate exposure on thyroid hormone levels while adjusting for potential confounders. We observed significant linear trends in FT4, TSH, and, to a lesser extent, TT3 across quartiles of specific phthalate metabolites. Comparing the highest to the lowest quartiles, we found a significant increase in FT4 levels, ranging from 2 to 3.7%, associated with MEP; MECPP; MEHHP; and the sum of seven metabolites (∑7PAE), three DEHP metabolites (∑3DEHP), two DBP metabolites (∑DBP), and both low molecular weight (∑LMW) and high molecular weight metabolites. Increased TSH levels (5%-16%) were observed for all phthalate metabolites (except MEHHP) and their molar sums, including ∑7PAE. For TT3, a significant increase was observed with MEP (2.2%) and a decrease was observed with ∑DBP (-2.7%). A higher TSH/FT4 ratio was observed with the highest quartiles (third or fourth) of several phthalate metabolites: MEP (8.8%), MiBP (8.7%), MnBP (22.2%), ∑7PAE (15.3%), ∑DBP (16.4%), and ∑LMW (18.6%). These hormonal alterations, most notably in the second and third trimesters, suggest that phthalate exposure may impact fetal growth and development by affecting maternal thyroid function.