Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607, USA.
Molecular Education, Technology and Research Innovation Center (METRIC), Raleigh, NC 27695, USA.
Development. 2024 Feb 15;151(4). doi: 10.1242/dev.202020. Epub 2024 Feb 19.
Malrotation of the intestine is a prevalent birth anomaly, the etiology of which remains poorly understood. Here, we show that late-stage exposure of Xenopus embryos to atrazine, a widely used herbicide that targets electron transport chain (ETC) reactions, elicits intestinal malrotation at high frequency. Interestingly, atrazine specifically inhibits the cellular morphogenetic events required for gut tube elongation, including cell rearrangement, differentiation and proliferation; insufficient gut lengthening consequently reorients the direction of intestine rotation. Transcriptome analyses of atrazine-exposed intestines reveal misexpression of genes associated with glycolysis and oxidative stress, and metabolomics shows that atrazine depletes key glycolytic and tricarboxylic acid cycle metabolites. Moreover, cellular bioenergetics assays indicate that atrazine blocks a crucial developmental transition from glycolytic ATP production toward oxidative phosphorylation. Atrazine-induced defects are phenocopied by rotenone, a known ETC Complex I inhibitor, accompanied by elevated reactive oxygen species, and rescued by antioxidant supplementation, suggesting that malrotation may be at least partly attributable to redox imbalance. These studies reveal roles for metabolism in gut morphogenesis and implicate defective gut tube elongation and/or metabolic perturbations in the etiology of intestinal malrotation.
肠旋转不良是一种常见的出生缺陷，其病因尚不清楚。在这里，我们表明，晚期暴露于莠去津的非洲爪蟾胚胎（一种广泛用于靶向电子传递链（ETC）反应的除草剂）会以高频率引发肠旋转不良。有趣的是，莠去津特异性抑制了肠道管伸长所必需的细胞形态发生事件，包括细胞重排、分化和增殖；因此，肠道伸长不足会重新定向肠道旋转的方向。莠去津暴露的肠道转录组分析显示与糖酵解和氧化应激相关的基因表达异常，代谢组学表明莠去津耗尽了关键的糖酵解和三羧酸循环代谢物。此外，细胞生物能学分析表明，莠去津阻止了从糖酵解 ATP 产生到氧化磷酸化的关键发育转变。鱼藤酮（一种已知的 ETC 复合物 I 抑制剂）可模拟莠去津诱导的缺陷，同时伴随着活性氧的增加，抗氧化剂补充可挽救这些缺陷，这表明旋转不良可能至少部分归因于氧化还原失衡。这些研究揭示了代谢在肠道形态发生中的作用，并提示肠道管伸长缺陷和/或代谢紊乱与肠旋转不良的病因有关。
