West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, 610041 Sichuan, PR China; Department of Cell and Molecular Biology, Tulane University, New Orleans, 70118 LA, USA.
Southern Center for Biomedical Research and Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Sciences, Fujian Normal University, Fuzhou, 350117 Fujian, PR China.
Br J Oral Maxillofac Surg. 2021 Jan;59(1):52-57. doi: 10.1016/j.bjoms.2020.07.009. Epub 2020 Jul 25.
Cleft palate is a common birth defect in mammals, which can be caused by genetic or environmental factors, or both. Decades have witnessed that many environmental exposures during gestation extremely increase the incidence of cleft palate. Tamoxifen (TAM), a widely-used drug in treating breast cancer, has been reported to be associated with craniofacial defects including micrognathia and cleft palate in humans. However, its exact effects on the developing palate remain unclear. Here we took advantage of a mouse model to explore how TAM affects palatal development at the molecular level. We showed that excess exposure of TAM in the early embryonic stages indeed leads to cleft palate in mice. RNA-sequencing results strongly suggest the involvement of mitogen-activated protein kinase (MAPK) signalling in TAM-induced cleft palate. Interestingly, in the anterior portion of the TAM-treated palatal shelf, phosphorylated (p)-AKT and p-ERK1/2 were activated but p-p38 was inhibited, while in the posterior palate, the p-AKT increased but the levels of p-p38 and p-JNK decreased. We conclude that excess TAM exposure causes cleft palate defects in mice by regulating MAPK pathways, which implicates the importance of tightly-regulated MAPK signalling in palatal development. This study provides a basis for further exploration of the molecular aetiology of cleft palate defects caused by environmental factors and, based on our results, we would give a serious warning regarding prescription of TAM and potential cleft palate defects in animal models involving the inducible Cre-LoxP system.
腭裂是哺乳动物中常见的出生缺陷，可由遗传或环境因素引起，也可由两者共同引起。数十年来的研究表明，妊娠期间的许多环境暴露会极大地增加腭裂的发病率。他莫昔芬（TAM）是一种广泛用于治疗乳腺癌的药物，据报道与包括小颌畸形和腭裂在内的颅面缺陷有关。然而，其对发育中的腭裂的确切影响尚不清楚。在这里，我们利用小鼠模型来探索 TAM 如何在分子水平上影响腭裂的发育。我们发现，TAM 在胚胎早期的过量暴露确实会导致小鼠出现腭裂。RNA 测序结果强烈表明丝裂原活化蛋白激酶（MAPK）信号通路参与了 TAM 诱导的腭裂。有趣的是，在 TAM 处理的腭突前部分，磷酸化（p）-AKT 和 p-ERK1/2 被激活，但 p-p38 被抑制，而在后腭突中，p-AKT 增加，但 p-p38 和 p-JNK 的水平下降。我们得出结论，过量的 TAM 暴露通过调节 MAPK 通路导致小鼠出现腭裂缺陷，这表明 MAPK 信号通路在腭突发育中的重要性。这项研究为进一步探索环境因素引起的腭裂缺陷的分子病因提供了基础，并且基于我们的结果，我们将对涉及诱导型 Cre-LoxP 系统的 TAM 处方和潜在的腭裂缺陷提出严重警告。
