基于出生队列研究孕期双酚A及替代物暴露对胎儿生长轨迹的影响与GH/IGF-1轴调控作用

It is indicated by animal studies that prenatal exposure to bisphenol A (BPA) may influence fetal intrauterine growth and cause irreversible health effects. In recent years, bisphenol S (BPS) and bisphenol F (BPF) are widely used as the substitutes of bisphenol A in industrial and consumer products. Recent toxicological studies have shown that these two chemicals have endocrine disrupting effects similar to bisphenol A. However, researches about the impact of intrauterine exposure to BPS and BPF on fetal development are limited, especially the epidemiological studies. This study is based on a birth cohort, in which the free and total concentrations of BPA, BPS and BPF will be detected in the maternal urine from three time points during pregnancy (first, second and third trimesters), as well as the umbilical cord blood. The ultrasound parameters of fetal growth will be measured at multiple time points during pregnancy and fetal body composition will be detected at birth, to analyze the impact of prenatal BPA/BPS/BPF exposure on dynamic fetal intrauterine growth. As previous studies have indicated that GH/IGF-1 axis plays a key role in fetal growth regulation, therefore, we will analyze the associations of prenatal BPA/BPS/BPF exposure and fetal GH/IGF-1 axis biomarkers, to explore the possible mechanism of the impact of prenatal BPA/BPS/BPF exposure on fetal growth. The results from this research will provide scientific basis for risk assessment of prenatal bisphenol analogous exposure and fetal growth.

动物研究表明，双酚A（BPA）可干扰子代宫内发育，造成不可逆的影响。近年来双酚S（BPS）和双酚F（BPF）被作为BPA主要替代物广泛使用，可能具有BPA类似毒性，但其宫内暴露对子代发育的影响研究不足，人群研究尤为缺乏。本项目拟基于前期建立的出生队列，动态监测孕早、中、晚期尿液和脐血中BPA、BPS、BPF总浓度及游离态浓度，采用B超对胎儿宫内发育进行多阶段连续监测，并分析出生体成分，以明确孕期BPA/BPS/BPF暴露与胎儿宫内发育指标的动态变化关系；鉴于GH/IGF-1轴在胎儿宫内发育中发挥关键的调控作用，本研究将分析各孕期BPA/BPS/BPF暴露对胎儿GH/IGF-1轴生物标志物的影响，以探索BPA/BPS/BPF宫内暴露干扰胎儿生长发育的可能机制。本研究结果将为BPA及主要替代物孕期暴露对胎儿发育的危害风险评估提供科学依据。

BPA是一种常见的环境内分泌干扰物，动物研究表明，孕期BPA暴露可干扰子代宫内发育，造成不可逆的影响。近年来BPS和BPF被作为BPA主要替代物广泛使用，可能具有BPA类似毒性，但其宫内暴露与子代发育的相关研究不足，人群研究尤为缺乏。孕期BPA及替代物暴露对子代生长轨迹的影响及作用机制尚不明确。本项目基于人群出生队列，对孕早、中、晚期尿液中BPA/BPS/BPF浓度进行检测，并追踪子代在胎儿期、出生及2岁内共12个时点的体格发育情况，拟合纵向生长轨迹，从而探索孕期BPA及替代物暴露对子代生长轨迹的影响及可能的激素介导作用。. 结果显示：1）各孕期BPA、BPS、BPF的检出率分别为74.73~78.27%、84.90~89.19%和98.50~98.93%；2）孕期BPA及替代物暴露与胎儿出生时体格发育指标呈负相关，如孕早期、孕晚期暴露于Q4浓度BPF，出生体重分别下降67.03g（95%CI=-132.59~-1.48）、94.15g (95%CI=-159.69~-28.62)。3）孕期BPA及替代物暴露可影响子代2岁时体格发育，如孕晚期BPA及BPS暴露与2岁儿童BMI水平呈正相关。4）孕期BPA及替代物暴露可影响胎儿期至2岁间生长轨迹，如孕中期BPA暴露（Q4：OR=2.20，95%CI=1.09~4.43）、孕晚期BPF暴露（Q4：OR=3.28，95%CI=1.55~6.95）可增加子代0~2岁间“低-增长”型BMI轨迹模式的风险；孕期BPS暴露可增加“胎儿至婴幼儿期持续高水平”及“胎儿期偏低-婴幼儿期追赶至中等水平”两种体重增长模式的风险；5）孕期BPA及替代物暴露与胎儿体格发育关联中可能存在激素介导作用，如雌二醇在孕早期、孕晚期BPF暴露与胎儿出生体重的负相关中可能存在中介效应（占比分别为11.52%和13.03%）。. 本研究为评估孕期BPA及替代物暴露对子代早期生长轨迹的影响及可能的机制提供了前瞻性人群队列研究依据。