Department of Surgery, Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California, USA.
Birth Defects Res. 2022 Feb;114(3-4):105-115. doi: 10.1002/bdr2.1968. Epub 2021 Dec 3.
Prenatal alcohol exposure (PAE) is associated with an increased incidence of congenital heart defects (CHD), in particular outflow tract (OFT) defects. However, the variability in the incidence of CHD following PAE has not been fully explored. We hypothesize that a concomitant, relevant genetic defect would potentiate the adverse effect of PAE and partially explain the variability of PAE-induced CHD incidence.
The OFT is formed by the second heart field (SHF). Our PAE model consisted of two intraperitoneal injections (3 g/kg, separated by 6 hr) of 30% ethanol on E6.5 during SHF specification. The impact of genetic defects was studied by SHF-specific loss of Delta-like ligand 4 (Dll4), fibroblast growth factor 8 (Fgf8) and Islet1.
Acute PAE alone significantly increased CHD incidence (4% vs. 26%, p = .015) with a particular increase in OFT alignment defects, viz., double outlet right ventricle (0 vs. 9%, p = .02). In embryos with a SHF genetic defect, acute PAE significantly increased CHD incidence (14 vs. 63%, p < .001), including double outlet right ventricle (6 vs. 50%, p < .001) compared to controls. PAE (p = .01) and heterozygous loss of Dll4 (p = .04) were found to independently contribute to CHD incidence, while neither Islet1 nor Fgf8 defects were found to be significant.
Our model recapitulates the increased incidence of OFT alignment defects seen in the clinic due to PAE. The presence of a concomitant SHF genetic mutation increases the incidence of PAE-related OFT defects. An apparent synergistic interaction between PAE and the loss of DLL4-mediated Notch signaling in OFT alignment requires further analysis.
产前酒精暴露（PAE）与先天性心脏病（CHD）的发病率增加有关，特别是流出道（OFT）缺陷。然而，PAE 后 CHD 的发病率变化尚未得到充分探讨。我们假设同时存在相关的遗传缺陷会增强 PAE 的不良影响，并部分解释 PAE 诱导的 CHD 发病率的变化。
OFT 由第二心脏场（SHF）形成。我们的 PAE 模型包括在 SHF 特化期间的 E6.5 时两次腹腔内注射 30%乙醇（3g/kg，间隔 6 小时）。通过 SHF 特异性缺失 Delta-like 配体 4（Dll4）、成纤维细胞生长因子 8（Fgf8）和胰岛 1 来研究遗传缺陷的影响。
单独急性 PAE 显著增加 CHD 发生率（4%对 26%，p=0.015），特别是 OFT 对齐缺陷增加，即双出口右心室（0 对 9%，p=0.02）。在具有 SHF 遗传缺陷的胚胎中，急性 PAE 显著增加 CHD 发生率（14%对 63%，p<0.001），包括双出口右心室（6%对 50%，p<0.001）与对照组相比。PAE（p=0.01）和 Dll4 杂合缺失（p=0.04）被发现独立导致 CHD 发生率增加，而胰岛 1 或 Fgf8 缺陷未被发现具有显著意义。
我们的模型再现了由于 PAE 导致的临床中 OFT 对齐缺陷发生率增加的情况。同时存在 SHF 遗传突变会增加 PAE 相关 OFT 缺陷的发生率。PAE 与 OFT 对齐中 DLL4 介导的 Notch 信号转导缺失之间的明显协同相互作用需要进一步分析。
