Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS UMR7104), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Université de Strasbourg, Illkirch, France.
Environ Health Perspect. 2011 Nov;119(11):1590-5. doi: 10.1289/ehp.1003075. Epub 2011 Aug 1.
Palate development depends on complex events and is very sensitive to disruption. Accordingly, clefts are the most common congenital malformations worldwide, and a connection is proposed with fetal exposure to toxic factors or environmental contaminants, such as dioxins. There is increasing evidence that dioxin interferes with all-trans-retinoic acid (atRA), a hormone-like signal derived from vitamin A, which plays an essential role during embryonic development. Although similarities have been described between dioxin-induced toxicity and the outcome of altered atRA signaling during palate development, their relationship needs to be clarified.
We used a genetic approach to understand the interaction between atRA and dioxin and to identify the cell type targeted by dioxin toxicity during secondary palate formation in mice.
We analyzed the phenotype of mouse embryos harboring an atRA-sensitive reporter transgene or bearing null mutations for atRA-synthesizing enzymes (RALDH) or atRA receptors (RAR) and maternally exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at gestation day 10.5.
We found that an intact atRA signal was required to enable TCDD to induce cleft palate. This mandatory atRA signal was generated through the activity of RALDH3 in the nasal epithelium and was transduced by RARγ (RARG) in the nasal mesenchyme, where it notably controlled aryl hydrocarbon receptor (Ahr) transcript levels. TCDD also did not alter the developmental pattern of atRA signaling during palate formation.
TCDD-induced alteration of secondary palate development in the mouse appears to depend on atRA signaling, which controls AHR expression. This mechanism is likely conserved throughout vertebrate evolution and may therefore be relevant in humans.
腭的发育依赖于复杂的事件，并且对干扰非常敏感。因此，腭裂是全球最常见的先天性畸形，并且有人提出与胎儿暴露于有毒因素或环境污染物（如二恶英）有关。越来越多的证据表明，二恶英会干扰全反式视黄酸（atRA），一种源自维生素 A 的激素样信号，它在胚胎发育中起着至关重要的作用。尽管已经描述了二恶英诱导的毒性与腭发育过程中 atRA 信号改变的结果之间的相似性，但它们之间的关系仍需澄清。
我们使用遗传方法来了解 atRA 和二恶英之间的相互作用，并确定在小鼠二次腭形成过程中二恶英毒性靶向的细胞类型。
我们分析了携带 atRA 敏感报告基因转座子或具有 atRA 合成酶（RALDH）或 atRA 受体（RAR）缺失突变的小鼠胚胎的表型，并在妊娠第 10.5 天母体暴露于 2,3,7,8-四氯二苯并对二恶英（TCDD）。
我们发现，完整的 atRA 信号是 TCDD 诱导腭裂所必需的。这种必需的 atRA 信号是通过鼻上皮中的 RALDH3 活性产生的，并通过鼻间充质中的 RARγ（RARG）转导，它显著控制芳烃受体（Ahr）转录物水平。TCDD 也不会改变腭形成过程中 atRA 信号的发育模式。
TCDD 诱导的小鼠二次腭发育异常似乎依赖于控制 AHR 表达的 atRA 信号。这种机制可能在整个脊椎动物进化中保守，因此可能与人类有关。
