Acetaldehyde and defective mismatch repair increase colonic tumours in a Lynch Syndrome model with Aldh1b1 inactivation

Guia Cerretelli, Ying Zhou, Mike F Mueller, David J Adams, Mark J Arends

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Defective mismatch repair (dMMR) interacts with acetaldehyde, in a gene/environment interaction, enhancing dMMR-driven colonic tumour formation in a Lynch Syndrome murine model of Msh2 conditional inactivation combined with either conditional or constitutive Aldh1b1 inactivation. ALDH1B1 expressed in intestinal epithelium, metabolises acetaldehyde to acetate, protecting against acetaldehyde-induced DNA damage. MSH2 is a key component of the DNA mismatch repair pathway (MMR), involved in Lynch Syndrome (LS)-associated colorectal cancers. Either conditional-Aldh1b1 (Aldh1b1flox/flox) or constitutive-Aldh1b1 (Aldh1b1-/-) knockout alleles combined with conditional Msh2flox/- intestinal knockout mouse model of LS (Msh2-LS), received either ethanol that is metabolised to acetaldehyde or water. We demonstrated that 41.7% ethanol-treated Aldh1b1flox/flox Msh2-LS mice and 66.7% Aldh1b1-/- Msh2-LS mice developed colonic epithelial hyperproliferation and adenoma formation, in 4.5 and 6 months respectively, significantly greater than 0% in water-treated controls. Significantly higher numbers of dMMR colonic crypt foci precursors and increased plasma acetaldehyde levels were observed in ethanol-treated Aldh1b1flox/flox Msh2-LS and Aldh1b1-/- Msh2-LS mice compared with water-treated controls. Hence, ALDH1B1 loss increases acetaldehyde levels and DNA damage that interacts with defective MMR to accelerate colonic, but not small intestinal, tumour formation.
Original languageEnglish
JournalDisease Models and Mechanisms
Early online date3 Jul 2023
DOIs
Publication statusE-pub ahead of print - 3 Jul 2023

Keywords / Materials (for Non-textual outputs)

  • Lynch Syndrome
  • mismatch repair
  • Msh2
  • ALDH1B1
  • ethanol
  • acetaldehyde
  • colorectal
  • ADENOMA RESISTANCE LOCUS

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