Department of Pediatrics, Floating Hospital for Children/Tufts University School of Medicine, Boston, MA.
Mother Infant Research Institute, Tufts Medical Center, Boston, MA.
J Pediatr. 2019 Nov;214:60-65.e2. doi: 10.1016/j.jpeds.2019.07.032. Epub 2019 Aug 29.
To evaluate salivary biomarkers that elucidate the molecular mechanisms by which in utero opioid exposure exerts sex-specific effects on select hypothalamic and reward genes driving hyperphagia, a hallmark symptom of infants suffering from neonatal opioid withdrawal syndrome (NOWS).
We prospectively collected saliva from 50 newborns born at ≥34 weeks of gestational age with prenatal opioid exposure and 50 sex- and gestational age-matched infants without exposure. Saliva underwent transcriptomic analysis for 4 select genes involved in homeostatic and hedonic feeding regulation (neuropeptide Y2 receptor [NPY2R], proopiomelanocortin [POMC], leptin receptor [LEPR], dopamine type 2 receptor [DRD2]). Normalized gene expression data were stratified based on sex and correlated with feeding volume on day of life 7 and length of stay in infants with NOWS requiring pharmacotherapy.
Expression of DRD2, a hedonistic/reward regulator, was significantly higher in male newborns compared with female newborns with NOWS (Δ threshold cycle 10.8 ± 3.8 vs 13.9 ± 3.7, P = .01). In NOWS requiring pharmacotherapy expression of leptin receptor, an appetite suppressor, was higher in male subjects than female subjects (Δ threshold cycle 8.4 ± 2.5 vs 12.4 ± 5.1, P = .05), DRD2 expression significantly correlated with intake volume on day of life 7 (r = 0.58, P = .02), and expression of NPY2R, an appetite regulator, negatively correlated with length of stay (r = -0.24, P = .05).
Prenatal opioid exposure exerts sex-dependent effects on hypothalamic feeding regulatory genes with clinical correlations. Neonatal salivary gene expression analyses may predict hyperphagia, severity of withdrawal state, and length of stay in infants with NOWS.
评估唾液生物标志物，阐明宫内阿片类药物暴露通过选择性下丘脑和奖励基因发挥性别特异性作用的分子机制，这些基因驱动着过度进食，这是患有新生儿阿片类药物戒断综合征（NOWS）的婴儿的一个标志性症状。
我们前瞻性地收集了 50 名胎龄≥34 周、有产前阿片类药物暴露的新生儿和 50 名性别和胎龄匹配、无暴露的婴儿的唾液。对 4 种参与体内平衡和享乐性进食调节的选定基因（神经肽 Y2 受体[NPY2R]、前阿黑皮素原[POMC]、瘦素受体[LEPR]、多巴胺 D2 受体[DRD2]）的唾液进行了转录组分析。根据性别对正常化基因表达数据进行分层，并与需要药物治疗的 NOWS 婴儿第 7 天的喂养量和住院时间相关联。
在有 NOWS 的男性新生儿中，作为享乐/奖励调节剂的 DRD2 表达明显高于女性新生儿（Δ阈值循环 10.8±3.8 与 13.9±3.7，P=0.01）。在需要药物治疗的 NOWS 中，食欲抑制剂 LEPR 的表达在男性受试者中高于女性受试者（Δ阈值循环 8.4±2.5 与 12.4±5.1，P=0.05），DRD2 表达与第 7 天的摄入量显著相关（r=0.58，P=0.02），而 NPY2R 的表达与住院时间呈负相关（r=-0.24，P=0.05）。
产前阿片类药物暴露对下丘脑进食调节基因产生性别依赖性影响，并具有临床相关性。新生儿唾液基因表达分析可能预测过度进食、戒断状态的严重程度和 NOWS 婴儿的住院时间。
