Maternal Smoking: HPA and Epigenetic Pathways to Infant Neurobehavioral Deficits

描述（由申请人提供）：孕妇在怀孕期间吸烟与婴儿发病率和死亡率以及大龄儿童的行为缺陷有关。尽管普遍禁止吸烟，但仍有13-30%的妇女继续吸烟，导致超过十分之一的婴儿暴露于吸烟。鉴于产妇吸烟率持续居高不下，需要采取新的方法来保护婴儿免受吸烟的影响。本研究为孕妇吸烟的不良行为提供了一种全新的、潜在可逆的生物学途径。具体来说，我们提供了第一个严格的测试，类似于母亲的压力，母亲吸烟“程序”后代下丘脑垂体肾上腺皮质（HPA）轴导致持续的神经行为缺陷。我们进一步提出，母体吸烟导致的HPA编程将通过母体-胎盘神经内分泌环境的改变来调节。本小组的初步研究表明，母亲吸烟对母体-胎盘HPA失调标志物（母体皮质醇、胎盘112羟类固醇脱氢酶2型（112 HSD 2）基因表达）的影响，以及这些标志物与婴儿神经行为缺陷之间的关系。在动物模型中，糖皮质激素受体（GR）基因的表观遗传调控已成为母亲应激代际传递的另一个关键媒介，但很少有人类研究。表观遗传机制涉及表型的遗传变化，而不涉及DNA序列的改变，因此为新的治疗靶点提供了前所未有的修饰潜力。我们的初步工作揭示了暴露于母亲吸烟后胎盘GR的表观遗传调控的第一个证据。这项拟议的研究是对母亲吸烟导致婴儿神经行为缺陷途径的深入调查。该研究包括对吸烟者和孕期控制者进行前瞻性检查，随后在1个月和6个月时对婴儿神经行为和皮质醇反应性进行发育敏感测量，并测量母体-胎盘HPA和表观遗传调节的新标志物。我们的目标是：1)研究母亲吸烟对1个月和6个月婴儿神经行为和皮质醇反应的影响；2)检验母亲吸烟通过调节母亲糖皮质激素和胎盘112 HSD2调控HPA轴的可能性，以及这些变化影响婴儿神经行为/皮质醇反应的可能性；3)检验母亲-胎盘HPA调节由GR的表观遗传调节介导的假设；4)探索所提途径的性别差异。据我们所知，我们的研究是第一个调查人类母亲吸烟不良后果的HPA和表观遗传途径的研究。我们的研究以我们团队开创的新途径和创新方法为重点。该研究的结果将阐明母亲吸烟风险的最早生物标志物，并可能导致开发新的治疗靶点，以保护母亲继续吸烟的婴儿。

DESCRIPTION (provided by applicant): Maternal smoking during pregnancy is associated with infant morbidity and mortality and behavioral deficits in older children. Despite pervasive sanctions against smoking, 13-30% of women continue to smoke leading to greater than one in ten infants exposed. Given continued high rates of maternal smoking, novel approaches are needed to protect infants from the consequences of exposure. The proposed study offers a paradigm shift in approaches to maternal smoking by defining novel and potentially reversible biological pathways to adverse behavioral outcomes from maternal smoking. Specifically, we provide the first rigorous test of the proposal that, similar to maternal stress, maternal smoking "programs" the offspring hypothalamic pituitary adrenocortical (HPA) axis leading to persistent neurobehavioral deficits. We further propose that HPA programming by maternal smoking will be mediated by alterations in the maternal-placental neuroendocrine milieu. Preliminary work by our group has shown effects of maternal smoking on markers of maternal-placental HPA dysregulation (maternal cortisol, placental 112 hydroxysteroid dehydrogenase type 2 (112 HSD 2) gene expression), and between these markers and infant neurobehavioral deficits. Epigenetic regulation of the glucocorticoid receptor (GR) gene has emerged as an additional critical mediator of intergenerational transmission of maternal stress in animal models, but little human research. Epigenetic mechanisms involve inherited changes in phenotype that do not involve alterations in DNA sequence, thus offering unprecedented potential for modification with novel therapeutic targets. Our preliminary work revealed the first evidence of epigenetic regulation of placental GR following exposure to maternal smoking. The proposed study is an intensive investigation of pathways to infant neurobehavioral deficits from maternal smoking. The study involves prospective examination of smokers and controls over pregnancy followed by developmentally-sensitive measures of infant neurobehavior and cortisol reactivity at 1 and 6 months and measurement of novel markers of maternal-placental HPA and epigenetic regulation. Our goals are: 1) to characterize effects of maternal smoking on infant neurobehavior and cortisol reactivity at 1 and 6 months, 2) to test the possibility that maternal smoking programs the HPA axis via regulation of maternal glucocorticoids and placental 112 HSD2 and that these changes influence infant neurobehavior/cortisol reactivity, 3) to test the hypothesis that maternal-placental HPA regulation is mediated by epigenetic regulation of GR, and 4) to explore sex differences in proposed pathways. To our knowledge, our study is the first to investigate HPA and epigenetic pathways to adverse outcomes from maternal smoking in humans. Our study is distinguished by its focus on novel pathways and innovative methods pioneered by our group. Results from the proposed study will elucidate the earliest biomarkers of risk from maternal smoking and may lead to the development of novel therapeutic targets to protect infants whose mothers continue to smoke.