Postnatal Complications and Interventions against Halogenated Organics during Pregnancy

项目总结 在过去的40年里，儿童肥胖率增加了两倍多，18.5%的儿童和青少年 他们现在都很肥胖。干扰内分泌的化学物质，特别是多氯联苯等致肥胖物 多氯联苯、全氟烷基物质和多氟烷基物质是导致肥胖率迅速上升的原因。 最近的研究表明，产前暴露于多氯联苯和全氟辛烷磺酸会导致特定性别的肥胖。 儿童的发展。这两组污染物都有一个共同的潜在机制途径，即 氧化应激，它们的作用源于转录因子之间相当大的串扰 包括核因子(红系衍生的2)样2(NRF2)和芳香烃受体。其他人则有 发现直接用多氯联苯或全氟辛烷磺酸[全氟辛烷磺酸(PFOS)和 全氟辛酸(全氟辛酸)]利用人类和小鼠细胞影响脂肪生成。重要的是，全氟辛烷磺酸 通过Nrf2的作用诱导脂肪生成和葡萄糖摄取。使用鼠标模型作为 在前一轮资助中，在围产期接触多氯联苯的后代中也有类似的观察结果 与车辆处理过的水坝所生的后代相比，脂肪和瘦肉的质量分布要差得多。此外， 暴露于多氯联苯的水坝所生的成熟后代与来自 车辆处理过的水坝。重要的是，健康的行为干预，产妇自愿锻炼期间 怀孕，与子宫内接触多氯联苯相关的后代疾病风险改善。拟议的项目将 继续使用活体小鼠模型以及过渡到人类样本以检查 在一个狭窄的敏感性窗口期间环境污染物毒性的分子影响。AIM 1将测试 无论是怀孕期间的自愿锻炼还是后代本身的自愿锻炼都可以作为一种干预 预防与子宫内接触多氯联苯相关的长期代谢损害的战略。目标2 将阐明出生的婴儿糖耐量受损和身体成分改变的机制 暴露于多氯联苯的水坝(包括使用Nrf2基因敲除小鼠)，并将决定母亲锻炼的程度 保护后代免受这些损伤。目标3将使用人类细胞来识别特定的生物标记物 与宫内卤化有机污染物暴露相关的危害并阐明其潜在的 暴露在空气中的婴儿肥胖和糖尿病风险增加的机制。我们的工作将衡量 孕妇和脐带血中的实际污染物暴露水平，并直接量化脂肪细胞分化 在从同一新生儿身上分离出来的细胞中。预期结果尤其重要，因为它们突出了 早期发育阶段是持续性肥胖和 有毒环境侮辱对糖尿病的影响。

PROJECT SUMMARY Childhood obesity rates have more than tripled over the last 40 years with 18.5% of children and adolescents who are now obese. Endocrine-disrupting chemicals, particularly obesogens such as polychlorinated biphenyls (PCBs) and per- and polyfluoroalkyl substances (PFAS), are contributing to the rapid increases in obesity. Recent studies indicate that prenatal exposures to PCBs and PFAS contribute to gender-specific obesity development in children. Both groups of contaminants share a common underlying mechanistic pathway, that of oxidative stress, and their actions arise from the considerable crosstalk between transcription factors including nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the aryl hydrocarbon receptor. Others have found that treating cells in culture directly with PCBs or PFAS [perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA)] influences adipogenesis using human and mouse cells. Importantly, PFOS induced adipogenesis and glucose uptake by acting through Nrf2. Using a mouse model as part of the previous round of funding, similar observations were made in that offspring exposed perinatally to PCBs had significantly worse fat and lean mass profiles compared to offspring born to vehicle-treated dams. Further, mature offspring born to PCB-exposed dams had impaired glucose tolerance compared to offspring from vehicle-treated dams. Importantly, a healthy behavioral intervention, maternal voluntary exercise during pregnancy, improved offspring disease risk associated with in utero PCB exposure. The proposed project will continue to use an in vivo mouse model as well as transition to human samples in order to examine the molecular impact of environmental contaminant toxicity during a narrow window of susceptibility. Aim 1 will test whether voluntary exercise during pregnancy or in the offspring themselves can be used as an intervention strategy to protect against the long-term metabolic detriments associated with in utero PCB exposure. Aim 2 will elucidate the mechanism of impaired glucose tolerance and altered body composition in offspring born to PCB-exposed dams (including the use of Nrf2 knockout mice), and will determine how maternal exercise is protecting offspring from these impairments. Aim 3 will use human cells to identify biomarkers of the specific harm associated with in utero halogenated organic pollutant exposures and to elucidate the potential mechanisms that contribute to increased obesity and diabetes risk in exposed infants. Our work will measure actual contaminant exposure levels in maternal and cord serum, and quantify adipocyte differentiation directly in cells isolated from the same neonates. Anticipated results are particularly significant in that they highlight early developmental stages as potential periods of particular vulnerability to program lasting obesity and diabetes effects of toxic environmental insults.