During intestinal rotation, the developing gut tube lengthens and convolutes to correctly package the intestine. Intestinal malrotation is a prevalent birth anomaly, but its underlying causes are not well understood. Here, Nanette Nascone-Yoder and colleagues show that exposure of Xenopus embryos to atrazine, a widely-used herbicide, can disrupt cellular metabolism in the developing gut tube and lead to intestinal malrotation. First, the authors find that administering atrazine during later stages of gut development causes a dose-dependent inhibition of gut lengthening and malrotation. Then, investigating the phenotype at the cellular level, the authors find that atrazine inhibits intestinal cell mesenchymal-to-epithelial transition and proliferation. Transcriptome profiling analyses show that atrazine affects the expression of genes that regulate glycolysis and oxidative stress. Metabolomics analyses suggest that atrazine exposure perturbs central carbon metabolism, depleting key glycolytic and tricarboxylic acid cycle metabolites. Furthermore, atrazine-induced malrotations are phenocopied by rotenone, a mitochondrial electron transport chain complex I inhibitor. Finally, the authors find that atrazine-exposed embryos have elevated reactive oxygen species, and antioxidant supplementation can rescue the gut elongation and rotation phenotype, suggesting that malrotation may be partly due to redox imbalance. Overall, the findings reveal the role of metabolism in gut morphogenesis and the potential aetiology of intestinal malrotation.
