Gut turning disorders have been attributed to malfunctions in energy metabolism
The experiment of American scientists, in which they affected spurred frog embryos with atrazine, showed that this respiratory chain inhibitor specifically reduces the activity of cellular morphogenetic processes that are necessary for the elongation of the intestinal tube and, consequently, its proper turning. The expression of genes related to glycolysis and oxidative stress was impaired in intestinal tube cells, and depletion of key metabolites of glycolysis and the tricarboxylic acid cycle was observed. The work is published in the journal Development.
During embryonic development, the vertebrate digestive system undergoes a complex transformation in which the intestinal tube elongates and assumes a specific position in the abdominal cavity. In humans, this process is called intestinal turning, during which the entire mass of the intestinal tube is rotated 270 degrees relative to its original location in the embryo. At the same time, there are suggestions that the process of turning - rotation - may not involve a literal mass rotation of the entire intestine, but involves only a sequential looping of more limited sections of the elongating intestinal tube. And there is still no consensus among scientists about this process.
At the same time, about 1 in 500 newborns has an abnormality of intestinal development, in which the intestine does not take its normal place in the abdominal cavity due to incomplete rotation during intrauterine development - malrotation. Depending on the degree of intestinal malrotation, the course of malrotation can vary from asymptomatic to severe acute intestinal obstruction requiring surgical treatment. The lack of a comprehensive understanding of the etiology and pathogenesis of this congenital anomaly makes it impossible to develop preventive and therapeutic tactics.
A team of scientists led by Nanette Nascone-Yoder (Nanette Nascone-Yoder) from North Carolina State University investigated how the process of intestinal turning in spurred frog embryos (Xenopus) can be affected by external influences. Atrazine, a herbicide whose action is based on interruption of the photosystem II electron transfer chain at the quinone QB binding site, was chosen as the agent under study. Initially, such exposure resulted in the intestinal loops being in a different position - for example, more dorsally and at a different angle compared to control embryos.
The frequency of such malrotations increased with increasing atrazine concentrations and was associated with shortening of the intestinal tube, as indicated by its straighter (less curved) route through the abdomen and fewer intestinal loops (p < 0.01). Dichlorophenyldimethylurea, which also inhibits electron transport during photosynthesis, caused similar gut turning abnormalities. No other developmental abnormalities were observed in the embryos.
The scientists then examined how atrazine affected cells in the developing intestinal tube. It turned out that individual cells of the entoderm in such embryos were more rounded, as indicated by their reduced length-to-width ratio, although they become transversely elongated as the intestinal tube lengthens. Also found in these cells were misoriented and shorter microtubule bundles. At later stages, analysis of tissue architecture confirmed that the epithelial layer never acquired a normal morphology. Instead, a disorganized, abnormally polarized and poorly differentiated intestinal mucosa was observed. Atrazine also inhibited the completion of cell division, leading to mitotic arrest and eventual apoptosis.
Analysis of the intestinal tube cell transcriptome showed that atrazine exposure altered the expression of genes involved in the regulation of glycolysis and gluconeogenesis and decreased mitochondrial metabolism. Further investigation of the metabolome showed that atrazine blocked the switch from glycolytic ATP production to oxidative phosphorylation by decreasing the production of tricarboxylic acid cycle substrates and blocking complex I of the respiratory chain. Additional cellular damage was caused by the by-production of reactive oxygen species in this redox imbalance, which was alleviated by exposure to antioxidants.
Thus, this study provides the first experimentally validated hypotheses for the pathogenesis of the development of gut turning disorders during intrauterine development in vertebrates. In the future, additional experiments and studies are needed that will focus on other etiologic agents whose effects lead to malrotation. These will help in the development of prevention and treatment of this congenital anomaly.