Abstract
The epithelium's barrier function is crucial for maintaining homeostasis and preventing the passage of food antigens and luminal bacteria. This function is essentially subserved by tight junctions (TJs), multiprotein complexes located in the most apical part of the lateral membrane. Some gastrointestinal disease states are associated with elevated intestinal permeability to macromolecules. In a study on rats, we determined the influence of chronic, daily ingestion of chlorpyrifos (CPF, a pesticide that crosses the placental barrier) during pre- and postnatal periods on intestinal permeability and TJ characteristics in the pups. Fluorescein isothiocyanate (FITC)-dextran was used as a marker of paracellular transport and mucosal barrier dysfunction. Pups were gavaged with FITC-dextran solution and blood samples were collected every 30 min for 400 min and analyzed spectrofluorimetrically. At sacrifice, different intestinal segments were resected and prepared for analysis of the transcripts (qPCR) and localization (using immunofluorescence) of ZO-1, occludin and claudins (scaffolding proteins that have a role in the constitution of TJs). In rats that had been exposed to CPF in utero and after birth, we observed a progressive increase in FITC-dextran passage across the epithelial barrier from 210 to 325 min at day 21 after birth (weaning) but not at day 60 (adulthood). At both ages, there were significant changes in intestinal TJ gene expression, with downregulation of ZO-1 and occludin and upregulation of claudins 1 and 4. In some intestinal segments, there were changes in the cellular localization of ZO-1 and claudin 4 immunostaining. Lastly, bacterial translocation to the spleen was also observed. The presence of CPF residues in food may disturb epithelial homeostasis in rats. Changes in TJ protein expression and localization may be involved in gut barrier dysfunction in this model. Uncontrolled passage of macromolecules and bacteria across the intestinal epithelium may be a risk factor for digestive inflammatory diseases.
Highlights
The intestinal epithelium constitutes the host’s first line of defense against exogenous agents such as food antigens, live bacteria, bacterial products and other exogenous agents present in the intestinal lumen.At birth, the epithelial barrier becomes more selective: nutrients are absorbed but potentially harmful intraluminal bacteria, microbial products and exogenous chemical substances are excluded [1].Excessive intestinal permeability to macromolecules may favor the uncontrolled passage of antigens and the onset of intestinal inflammation or gastrointestinal disease [2].The integrity of the protective epithelial cell layer is primarily maintained by intercellular junctional complexes (such as tight junctions (TJs) [3], adherens junctions and desmosomes), whereas gap junctions provide channels for intercellular communication
Occludin and claudins family are linked to cytoskeletal components by the zona occludens (ZO) family of proteins (ZO-1, ZO-2 and ZO-3); which connects the TJs to other cell-cell and cell-substratum adhesion sites
We focused our investigation on gut epithelial permeability, TJ protein expression and bacterial translocation
Summary
The intestinal epithelium constitutes the host’s first line of defense against exogenous agents such as food antigens, live bacteria, bacterial products and other exogenous agents present in the intestinal lumen. The interplay between gut bacterial colonization, the epithelial barrier and the immune system has a crucial role in the development of intestinal function and maturation of gut-associated lymphoid tissue (GALT) during the first months of life in human neonates and the first weeks of life in rodents. It has been shown that bacterial translocation is required to achieve GALT maturation in the neonate [4] This interaction can be modulated by other factors, such as food components and food contaminants. CPF’s impact on intestinal permeability after chronic in utero and postnatal exposure has not previously been studied. This topic is of particular interest because CPF is known to cross the placental barrier. We focused our investigation on gut epithelial permeability, TJ protein expression and bacterial translocation
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