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Mutagenicity and Carcinogenicity01:25

Mutagenicity and Carcinogenicity

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Mutagenicity and carcinogenicity refer to the ability of drugs to cause genetic defects and induce cancer, respectively. The International Agency for Research on Cancer (IARC) classifies agents into four groups based on their carcinogenic potential. Group 1 agents are known human carcinogens; group 2A agents are probably carcinogenic to humans; group 3 agents lack data to support their role in carcinogenesis; and group 4 includes agents for which data support that they are not likely to be...
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Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).
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Microtubules are dynamic structures and can be regulated by microtubule targeting agents (MTAs). Microtubule destabilizing drugs are a class of MTAs that destabilize and prevent microtubules' polymerization. Both natural and synthetic chemicals can be found under this class of drugs. Vincristine and vinblastine, two vinca alkaloids, and colchicine were among the first to be discovered. These drugs can affect cells in various ways, either by inducing a change in cell morphology, preventing...
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Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
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To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.
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Quantification of Colonic Stem Cell Mutations
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Microbiota-derived genotoxin tilimycin generates colonic stem cell mutations.

Lisa Pöltl1, Maksym Kitsera1, Sandra Raffl1

  • 1Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.

Cell Reports
|March 4, 2023
PubMed
Summary

Genotoxic bacteria like Klebsiella can cause DNA damage in intestinal stem cells, leading to mutations and increased disease risk. This study reveals how tilimycin, a bacterial toxin, impacts colon health.

Keywords:
CP: Microbiologyantibioticsbacterial metabolitecolorectal epitheliumgenotoxingut microbiotaintestinal stem cellnecrotizing enterocolitissomatic mutation frequency

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Area of Science:

  • Microbiology
  • Genetics
  • Gastroenterology

Background:

  • The gut microbiome plays a crucial role in intestinal health.
  • Certain bacteria produce genotoxins that can harm host cells.
  • Intestinal stem cells are vital for tissue repair and regeneration.

Purpose of the Study:

  • To investigate the effects of the DNA-alkylating genotoxin tilimycin on intestinal stem cells.
  • To understand the link between tilimycin-producing Klebsiella and colorectal stem cell mutations.
  • To assess the impact of genotoxic bacteria on somatic genetic changes in the colon.

Main Methods:

  • Spatial distribution and quantification of tilimycin metabolites in colonized mice.
  • Analysis of genetic aberrations in colorectal stem cells using marker gene G6pd.
  • Comparison of mutation frequencies in mice colonized with tilimycin-producing versus non-producing Klebsiella.

Main Results:

  • Tilimycin accumulation was observed in Klebsiella-colonized mice.
  • Loss of G6pd function indicated genetic damage in colorectal stem cells, forming monoclonal mutant crypts.
  • Mice with tilimycin-producing Klebsiella showed significantly higher frequencies and burdens of somatic mutations.

Conclusions:

  • Genotoxic Klebsiella species can induce somatic genetic alterations in the colon.
  • Tilimycin-induced DNA damage to stem cells may contribute to disease susceptibility.
  • Understanding these microbial genotoxic effects is crucial for human gut health.