Mutagenicity of Helicobacter hepaticus infection in the lower bowel mucosa of 129/SvEv Rag2^−/‐Il10^−/−gpt delta mice is influenced by sex

Abstract

Inflammatory bowel disease and colonic tumors induced by Helicobacter hepaticus (Hh) infection in susceptible mouse strains are utilized to dissect the mechanisms underlying similar human diseases. In our study, infection with genotoxic cytolethal distending toxin-producing Hh in 129/SvEv Rag2−/−Il10−/− gpt delta (RagIl10gpt) mice of both sexes for 21 weeks induced significantly more severe cecal and colonic pathology compared to uninfected controls. The mutation frequencies in the infected RagIl10gpt males were 2.1-fold higher for the cecum and 1.7-fold higher for the colon than male RagIl10gpt controls. In addition, there was a 12.5-fold increase of G:C-to-T:A transversions in the colon of Hh-infected males compared to controls. In contrast, there was no statistical significance in mutation frequencies between infected female Rag2Il10gpt mice and controls. Moreover, Hh infection in RagIl10gpt males significantly up-regulated transcription of Tnfα and iNos, and decreased mRNA levels of cecal Atm compared to the infected females; there was no significant difference in mRNA levels of Il-22, Il-17A, Ifnγ and Atr between the infected males and females. Significantly higher levels of cecal and colonic iNos expression and γH2AX-positive epithelial cells (a biomarker for double-strand DNA breaks [DSB]) in Hh-infected Rag2Il10gpt males vs. Hh-infected females were noted. Finally, Hh infection and associated inflammation increased levels of intestinal mucosa-associated genotoxic colibactin-producing pks+ Escherichia coli. Elevated Tnfα and iNos responses and bacterial genotoxins, in concert with suppression of the DSB repair responses, may have promoted mutagenesis in the lower bowel mucosa of Hh-infected male RagIl10gpt mice.

Male-Dependent Promotion of Colitis in 129 Rag2−/− Mice Co-Infected with Helicobacter pylori and Helicobacter hepaticus

“…This premise is supported by our previous work illustrating that Hh infection induced more invasive cancer in the lower bowel of Rag2-deficient male mice receiving Il10-deficient regulatory T cells compared to their female counterparts [ 29 ]. In addition, our recent study reported that Hh infection increased genomic mutation frequencies in male but not female Il10-deficient RAG2 gpt mice compared with their respective controls, suggesting that males are more susceptible to genomic mutations promoted by Hh infection [ 30 ].…”

Cytolethal Distending Toxin Subunit B: A Review of Structure–Function Relationship

“…Mutations of the three catalytic residues mentioned above were widely used in the literature to abolish the catalytic activity of CdtB. First of all, proliferating cells exposed to a toxin bearing a CdtB mutated in the corresponding DNase I H134 catalytic residue do not suffer DNA damage, cell cycle block or apoptosis, as shown with EcolCDT-I and-II [25,27,51,73,88,89], CjejCDT [12,93], AactCDT [40,64,77] and HparCDT [94]. However, this AactCDT mutant still induces apoptosis in non-proliferating blood cells [40], suggesting that CdtB catalytic activity may not be involved in the observed toxicity.…”