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Development 2024 Feb 15;1514:. doi: 10.1242/dev.202020.
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Developmental regulation of cellular metabolism is required for intestinal elongation and rotation.

Grzymkowski JK , Chiu YC , Jima DD , Wyatt BH , Jayachandran S , Stutts WL , Nascone-Yoder NM .

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.

PubMed ID: 38369735
PMC ID: PMC10911142
Article link: Development
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: abcb1l abcg2 aff1 aldh1a1 angptl3 anln atosa atp1a1 atr bmp2 ccnb1.2 ccnb3 cdc20 crem crybg3 cyp2j2 ddit4 dnajb14 ephb2 errfi1 espn fabp2 fgf6l g6pc1 g6pc1.3 gckr gne herpud1 hspa5 igfbp1 inhbb irs4 klf9 lipe lpin2 micall2 mmp14 ndufa3 nfe2l2 nkapd1 nlrp1 pank1 pck1 pdk4 pfkfb1 plk1 plk3 plpp1 polr2a polr2k ppp1r3b pxk rnf157 rps24 runx1 septin6 sik2 slc22a2 slc23a2 slc38a2 slc38a3 stil ston1 suco tacc3 tcim tent5a thibz tmcc1 tnikl trap1 trib1 txnrd3 uap1 vdac1 zbtb16 znf534 znf706
GO keywords: foregut morphogenesis [+]
Antibodies: Casp3.2 Ab10 Cdh1 Ab1 Ctnnb1 Ab12 Fabp2 Ab1 H3f3a Ab9 Itgb1 Ab1 Tuba4b Ab2

Disease Ontology terms: visceral heterotaxy
Phenotypes: Xla Wt + Atrazine (Fig. 1 CDE) [+]

Article Images: [+] show captions