Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, United States; Center for Behavioral and Preventive Medicine, The Miriam Hospital, United States.
Department of Psychology, The University of Tulsa, United States.
Psychoneuroendocrinology. 2023 Jul;153:106119. doi: 10.1016/j.psyneuen.2023.106119. Epub 2023 Apr 20.
The intrauterine environment and early life stress regulation are widely recognized as an early foundation for lifelong physical and mental health. Methylation of CpG sites in the placenta represents an epigenetic modification that can potentially affect placental function, influence fetal development, and ultimately impact the health of offspring by programming the hypothalamic-pituitary-adrenal (HPA) axis stress response during prenatal development. Leptin, an adipokine produced by the placenta, is essential for energy homeostasis. It is also epigenetically regulated by promoter DNA methylation. Mounting evidence suggests that leptin also affects the stress response system. Though heterogeneity in the early stress response system may influence life-long mental and physical health, few studies explicitly examine the heterogeneity in the newborn stress response system. Less is known about leptin's association with the human hypothalamic-pituitary-adrenocortical (HPA) axis early in life. This study sought to serve as a proof of concept study investigating the relationship between newborn cortisol output trajectories and placental leptin DNA methylation in 117 healthy newborns from socioeconomically and racially- and ethnically-diverse families. We characterized heterogeneity in newborn cortisol output during the NICU Network Neurobehavioral Scales exam in the first week of life with latent growth mixture models. We then evaluated whether leptin promoter (LEP) methylation in placental samples was associated with newborn cortisol trajectories. Our findings suggest that increased placental LEP methylation, which corresponds to decreased leptin production, is associated with infant cortisol trajectories marked by increased cortisol output in the NNNS exam. These results provide important insights into the role of placental leptin DNA methylation in human newborn HPA axis development and subsequent developmental origins of health and disease processes.
子宫内环境和早期生活应激调节被广泛认为是终身身心健康的早期基础。胎盘 CpG 位点的甲基化代表了一种表观遗传修饰，它可能通过编程产前发育过程中的下丘脑-垂体-肾上腺 (HPA) 轴应激反应，影响胎盘功能、影响胎儿发育，并最终影响后代的健康。瘦素是胎盘产生的一种脂肪细胞因子，对能量平衡至关重要。它也受到启动子 DNA 甲基化的表观遗传调控。越来越多的证据表明，瘦素也会影响应激反应系统。尽管早期应激反应系统的异质性可能会影响终生的心理和身体健康，但很少有研究明确检查新生儿应激反应系统的异质性。关于瘦素与人类下丘脑-垂体-肾上腺皮质 (HPA) 轴在生命早期的关系，人们知之甚少。本研究旨在通过对来自社会经济地位、种族和民族多样化的家庭的 117 名健康新生儿进行研究，证明新生儿皮质醇输出轨迹与胎盘瘦素 DNA 甲基化之间存在关联。我们使用潜在增长混合模型，对新生儿在生命的第一周接受 NICU 网络神经行为量表检查时的皮质醇输出轨迹进行了异质性描述。然后，我们评估了胎盘样本中瘦素启动子 (LEP) 甲基化是否与新生儿皮质醇轨迹相关。我们的研究结果表明，胎盘 LEP 甲基化增加，对应于瘦素产生减少，与新生儿皮质醇轨迹相关，NNNS 检查中皮质醇输出增加。这些结果为胎盘瘦素 DNA 甲基化在人类新生儿 HPA 轴发育以及随后的健康和疾病发展过程中的作用提供了重要的见解。
