Zhang Yaxin, Xu Dongliang, Song Shuaixing, Wang Guoxu, Su Hexin, Wu Yang, Zhang Yuwei, Liu Hongyan, Li Qingfu, Wang Xiangdong, Yu Zengli, Liu Xiaozhuan
Center for Clinical Single-Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China; Department of Nutrition and Food Hygiene, Public Health College, Zhengzhou University, Henan 450001, China.
Center for Clinical Single-Cell Biomedicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, China; Department of Prosthodontics, Henan Provincial People's Hospital, Zhengzhou 450003, China.
Reprod Toxicol. 2024 Dec;130:108731. doi: 10.1016/j.reprotox.2024.108731. Epub 2024 Oct 12.
In utero exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can contribute to high rates of cleft palate (CP) formation, but the mechanistic basis for these effects remains uncertain. Here, multi-omics-based metabolomic and transcriptomic analyses were employed to characterize the etiological basis for TCDD-induced CP on gestational day 14.5 (GD14.5). These analyses revealed that TCDD-induced CP formation is associated with calcium, MAPK, PI3K-Akt, and mTOR pathway signaling. PI3K-Akt and mTOR signaling activity is closely linked with the maintenance of cellular proliferation and survival. Moreover, mTOR-mediated regulation of autophagic activity is essential for ensuring an appropriate balance between metabolic activity and growth. Murine embryonic palatal mesenchymal (MEPM) cell proliferation was thus characterized, autophagic activity in these cells was evaluated through electron microscopy and western immunoblotting was used to compare the levels of autophagy- and AKT/mTOR-related protein between the control and TCDD groups on GD14.5. These analyses indicated that MEPM cell proliferative and autophagic activity was inhibited in response to TCDD exposure with the concomitant activation of AKT/mTOR signaling, in line with the multi-omics data. Together, these findings suggested that following TCDD exposure, the activation of AKT/mTOR-related autophagic signaling may play a role in the loss of appropriate palatal cell homeostasis, culminating in the incidence of CP.
子宫内暴露于环境污染物2,3,7,8-四氯二苯并对二恶英（TCDD）会导致高腭裂（CP）发生率，但这些影响的机制基础仍不确定。在此，采用基于多组学的代谢组学和转录组学分析来表征TCDD在妊娠第14.5天（GD14.5）诱导CP的病因基础。这些分析表明，TCDD诱导的CP形成与钙、丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）和哺乳动物雷帕霉素靶蛋白（mTOR）信号通路相关。PI3K-Akt和mTOR信号活性与细胞增殖和存活的维持密切相关。此外，mTOR介导的自噬活性调节对于确保代谢活性和生长之间的适当平衡至关重要。因此，对小鼠胚胎腭间充质（MEPM）细胞增殖进行了表征，通过电子显微镜评估这些细胞中的自噬活性，并使用蛋白质免疫印迹法比较了对照组和TCDD组在GD14.5时自噬相关蛋白和AKT/mTOR相关蛋白的水平。这些分析表明，与多组学数据一致，TCDD暴露会抑制MEPM细胞的增殖和自噬活性，并伴随AKT/mTOR信号的激活。总之，这些发现表明，TCDD暴露后，AKT/mTOR相关自噬信号的激活可能在腭细胞稳态失衡中起作用，最终导致CP的发生。
