Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada ; Developmental Neurosciences and Child Health, Child & Family Research Institute, Vancouver, BC, Canada.
PLoS One. 2013 Sep 16;8(9):e73926. doi: 10.1371/journal.pone.0073926. eCollection 2013.
Neonatal pain-related stress is associated with elevated salivary cortisol levels to age 18 months in children born very preterm, compared to full-term, suggesting early programming effects. Importantly, interactions between immune/inflammatory and neuroendocrine systems may underlie programming effects. We examined whether cortisol changes persist to school age, and if common genetic variants in the promoter region of the NFKBIA gene involved in regulation of immune and inflammatory responses, modify the association between early experience and later life stress as indexed by hair cortisol levels, which provide an integrated index of endogenous HPA axis activity. Cortisol was assayed in hair samples from 128 children (83 born preterm ≤ 32 weeks gestation and 45 born full-term) without major sensory, motor or cognitive impairments at age 7 years. We found that hair cortisol levels were lower in preterm compared to term-born children. Downregulation of the HPA axis in preterm children without major impairment, seen years after neonatal stress terminated, suggests persistent alteration of stress system programming. Importantly, the etiology was gender-specific such that in preterm boys but not girls, specifically those with the minor allele for NFKBIA rs2233409, lower hair cortisol was associated with greater neonatal pain (number of skin-breaking procedures from birth to term), independent of medical confounders. Moreover, the minor allele (CT or TT) of NFKBIA rs2233409 was associated with higher secretion of inflammatory cytokines, supporting the hypothesis that neonatal pain-related stress may act as a proinflammatory stimulus that induces long-term immune cell activation. These findings are the first evidence that a long-term association between early pain-related stress and cortisol may be mediated by a genetic variants that regulate the activity of NF-κB, suggesting possible involvement of stress/inflammatory mechanisms in HPA programming in boys born very preterm.
新生儿疼痛相关应激与儿童出生时非常早产（相比足月产）至 18 个月时唾液皮质醇水平升高相关，提示存在早期编程效应。重要的是，免疫/炎症和神经内分泌系统之间的相互作用可能是编程效应的基础。我们研究了皮质醇变化是否持续到学龄期，以及 NFKBIA 基因启动子区域的常见遗传变异是否会改变早期经历与后来生活应激之间的关联，后者以头发皮质醇水平来衡量，头发皮质醇提供了内源性 HPA 轴活动的综合指数。在 7 岁时，我们对 128 名儿童（83 名出生时早产≤32 周，45 名足月产）的头发样本进行了皮质醇检测，这些儿童没有重大感觉、运动或认知障碍。我们发现，与足月产儿童相比，早产儿的头发皮质醇水平较低。在新生儿应激结束多年后，早产儿的 HPA 轴下调，表明应激系统编程发生持续改变。重要的是，病因是性别特异性的，即仅在早产男孩（而非女孩）中，特别是那些 NFKBIA rs2233409 次要等位基因的男孩中，较低的头发皮质醇与新生儿疼痛（从出生到足月的皮肤破损程序数量）之间存在关联，这与医学混杂因素无关。此外，NFKBIA rs2233409 的次要等位基因（CT 或 TT）与炎症细胞因子的分泌增加有关，支持了新生儿疼痛相关应激可能作为促炎刺激物，诱导长期免疫细胞激活的假说。这些发现是早期疼痛相关应激与皮质醇之间存在长期关联的第一个证据，这可能是由调节 NF-κB 活性的遗传变异介导的，提示非常早产出生的男孩的 HPA 编程中可能涉及应激/炎症机制。
