环境多溴联苯醚暴露对胎儿宫内发育迟缓及其追赶生长影响的出生队列研究

As one kind of persistent organic pollutants, polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in the manufacture of household furnishings, appliances, textiles, paints, and electronics including televisions, cell phones, and computers. A number of studies showed that in utero PBDEs exposure was associated with adverse fetal growth in humans and could decrease body weight gain of mammal animals during lactation. Intrauterine growth restriction (IUGR) is the main disease affecting children growth. The etiologies of IUGR include genetic and environmental factors. To explore the association between PBDEs exposure and IUGR in newborns, we conducted a case-control study in 2013 and found higher PBDE levels in IUGR newborns. However, PBDE levels were determined by using cord blood samples which were collected at delivery. We could not confirm PBDEs exposure occurred before IUGR. There’s no causal evidence in the relationship between PBDEs exposure and IUGR. Thus, we plan to design a birth cohort study in Wenzhou area to verify the exposure-effect relationship of in utero PBDEs exposure and IUGR in newborns. Subsequently, a follow-up study will be conducted to explore effects of PBDEs exposure on catch-up growth of IUGR infants and the potential biomarkers. In the development of IUGR, epigenetic modification of imprinted genes, such as IGF2-H19, may play an important role. Based on placental samples, we will explore whether PBDEs exposure could affect epigenetic modification of placental, which might be the potential mechanism of relationship between in utero PBDEs exposure and IUGR in newborns. The results will provide useful information to health-based risk assessment of PBDEs and control of PBDEs pollution, and contribute to the pathogenic interpretation of IUGR and the decrease of children disease burden.

多溴联苯醚(PBDEs)是一类广泛存在的持久性有机污染物，已有证据支持PBDEs宫内暴露可影响胎儿发育，且与动物出生后体重增长缓慢有关。作为影响儿童发育的主要疾病，胎儿宫内发育迟滞（IUGR）是一种受遗传和营养、环境等因素影响的多病因疾病。我们前期的研究发现，PBDEs宫内暴露与胎儿IUGR存在关联，但缺乏暴露-效应的时间先后及因果关联证据。因此，本研究拟用出生队列研究来确证宫内PBDEs暴露与IUGR间的因果关联及暴露-反应关系；运用追踪调查研究来探索哺乳期PBDEs暴露对IUGR患儿“追赶生长”的影响，并结合整体基因组和特定印迹基因区的表遗传修饰检测，进一步探索PBDEs宫内暴露诱导IUGR发生的可能作用机制。研究结果可为PBDEs的健康风险评估及其防控提供理论指导，并为阐明IUGR发病原因、降低IUGR所造成的疾病负担做出贡献。

本研究在出生队列基础上，采用巢式病例-对照研究设计探究环境PBDEs暴露对胎儿宫内发育迟缓（IUGR）的影响及其表观遗传学机制，并对IUGR病例及对照进行出生后一年的儿童随访，观察PBDEs暴露对IUGR患儿追赶生长的影响。.结果表明，IUGR病例组脐血血清中BDE-49、BDE-206、BDE-209、低溴联苯醚和∑19PBDEs浓度显著高于对照组；母血和脐血中PBDEs浓度与新生儿出生体重和克托莱指数呈负相关，随着脐血中BDE-206、低溴联苯醚、高溴联苯醚和∑19PBDEs浓度升高，新生儿发生IUGR的相对危险度也随之增加。IUGR病例组的胎盘形态指标显著小于对照组，且胎盘的重量、长宽和面积指标与新生儿出生体重和克托莱指数呈正相关，提示胎盘形态可能是新生儿发生IUGR的保护因素。.焦磷酸测序方法检测胎盘整体基因（LINE-1）和发育相关基因（IGF-2与HSD11B2）的DNA甲基化程度结果表明，IUGR病例组胎盘组织IGF-2基因DNA甲基化水平显著低于对照组，而病例组HSD11B2基因DNA甲基化水平显著高于对照组；IGF-2基因甲基化水平与新生儿出生体重和克托莱指数呈正相关，而HSD11B2基因甲基化水平与之呈负相关；PBDEs暴露可能使胎盘LINE-1和IGF-2基因甲基化程度降低，使胎盘HSD11B2基因甲基化程度升高，提示胎盘基因DNA甲基化程度改变可能影响胎儿在宫内的生长发育。.随访研究发现，哺乳期PBDEs暴露对IUGR和健康婴儿早期生长均有影响。与健康婴儿相比，IUGR婴儿在42天到6个月期间的PBDEs暴露水平更高，生长速度更快；IUGR男孩低溴联苯醚和BDE28~209的暴露与年龄别头围Z评分呈负相关；BDE153和BDE196与IUGR男童的体长Z评分显著相关，但PBDEs暴露与女童体格生长并未发现明显的关联。.综上所述，本研究发现孕期PBDEs暴露是影响胎盘组织形态和新生儿发生IUGR的危险因素；哺乳期PBDEs暴露影响IUGR婴儿的追赶生长，且存在性别差异及敏感窗口期；胎盘组织特定基因DNA甲基化改变与孕期PBDEs暴露水平和新生儿生长发育都有关联，可能是孕期PBDEs暴露影响新生儿发生IUGR的作用机制。本研究结果可为PBDEs污染防控、IUGR新生儿早期干预和治疗提供线索，并为降低IUGR对家庭和社会所造成的疾病负担做出贡献。