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Published on: September 18, 2020
Effects of Methylglyoxal on Intestinal Cells: Insights on Epigenetic Regulatory Enzymes
Camilla Morresi1, Giulia Feliziani2,3, Luisa Bellachioma1
1Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy.
Abstract:
Methylglyoxal (MGO) is endogenously produced under physiological conditions as a by-product of glycolysis and by autooxidation of glucose and lipid peroxidation. The digestive system can also take up MGO from exogenous sources, especially from ultra-processed foods. MGO is a highly reactive molecule, able to react with macromolecules forming covalent adducts resulting in advanced glycation end-products formation. MGO can also enter the nucleus and react with nucleic acids with the formation of MGO-nucleic acid adducts. The intestinal epithelium is continuously exposed to dietary and endogenous stimuli, including MGO, but the potential harmful role of MGO at the intestinal level has been poorly investigated. Therefore, the aim of the study was to further investigate the effects of MGO in intestinal cells and the molecular mechanisms involved, with particular attention to epigenetic regulatory enzymes such as histone deacetylases (HDAC), ten-eleven translocation (TET) family enzymes, and DNA methyltransferases (DNMT). Our results demonstrate that MGO exposure induces alterations in intestinal barrier function in differentiated Caco-2 cells monolayers. Moreover, MGO treatment induces cell apoptosis associated with an increase in cytosolic and mitochondrial reactive oxygen species. MGO-induced oxidative stress was associated with activation of the NFκB pathway and increased levels of proinflammatory molecules such as TNF-α and antioxidant enzymes (superoxide dismutase 1 [SOD1] and catalase). The increased expression of γH2AX suggests damage to DNA in MGO-treated cells. A decrease in HDAC1/2 expression, consistent with the increase in acetylated histone H4 levels, and an inhibition of the expression of TET (TET1, TET2) proteins was observed in MGO-treated cells. These results suggest that MGO may also disrupt epigenetic homeostasis mechanisms, offering further insight into the pathways through which MGO causes cellular damage in intestinal cells.
Insights
Methylglyoxal (MGO), a reactive compound found in processed foods, damages intestinal cells by increasing oxidative stress and DNA damage. It also disrupts epigenetic regulators like histone deacetylases (HDAC) and ten-eleven translocation (TET) enzymes.
Area of Science:
- Cell Biology
- Molecular Biology
- Toxicology
Background:
- Methylglyoxal (MGO) is an endogenous and exogenous reactive compound implicated in cellular damage.
- The digestive system encounters MGO from metabolic byproducts and diet, particularly ultra-processed foods.
- The impact of MGO on intestinal cells and its underlying molecular mechanisms, including epigenetic alterations, remain poorly understood.
Purpose of the Study:
- To investigate the effects of MGO on intestinal cells.
- To elucidate the molecular mechanisms involved in MGO-induced intestinal cellular damage.
- To examine the influence of MGO on epigenetic regulatory enzymes (HDAC, TET, DNMT).
Main Methods:
- Exposure of differentiated Caco-2 cell monolayers to MGO.
- Assessment of intestinal barrier function.
- Measurement of reactive oxygen species (ROS), apoptosis, and DNA damage markers (γH2AX).
- Analysis of NFκB pathway activation, pro-inflammatory molecules (TNF-α), and antioxidant enzymes (SOD1, catalase).
- Evaluation of epigenetic enzyme expression (HDAC1/2, TET1/2) and histone acetylation levels.
Main Results:
- MGO exposure impaired intestinal barrier function in Caco-2 cells.
- MGO induced apoptosis and increased cytosolic and mitochondrial ROS.
- MGO-triggered oxidative stress activated the NFκB pathway, increasing TNF-α and antioxidant enzymes.
- Evidence of DNA damage (γH2AX) and disruption of epigenetic homeostasis, including decreased HDAC1/2 and TET protein expression, and increased histone H4 acetylation.
- MGO exposure led to increased levels of pro-inflammatory molecules and antioxidant enzymes.
Conclusions:
- MGO causes significant cellular damage in intestinal cells, characterized by barrier dysfunction, apoptosis, and oxidative stress.
- MGO exposure disrupts DNA integrity and epigenetic mechanisms, affecting key enzymes like HDACs and TETs.
- These findings highlight MGO as a potential contributor to intestinal pathologies via disruption of cellular homeostasis and epigenetic regulation.
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