Tissue-specific mutagenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine as the basis for urothelial carcinogenesis

Area of Science:

• Carcinogenesis
• Molecular Toxicology
• Urothelial Biology

Background:

• Bladder cancer is linked to environmental carcinogens and tobacco smoke.
• N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induces invasive bladder cancers in mice with high tissue-specificity.
• The molecular basis for BBN's tissue-specificity remains unexplored.

Purpose of the Study:

• To investigate the tissue-specificity of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) mutagenesis.
• To explore the role of urothelial cell mutagenesis in BBN-induced bladder carcinogenesis.

Main Methods:

• Utilized Big Blue™ transgenic mice and rats for mutagenesis studies.
• Administered BBN in drinking water to assess mutagenesis levels.
• Quantified mutagenesis in various tissues, including urothelial and smooth muscle cells of the urinary bladder, kidney, ureter, liver, and forestomach.

Main Results:

• BBN is a potent mutagen, causing significant mutagenesis specifically in mouse urothelial cells (two orders of magnitude above background).
• Mutagenesis in bladder smooth muscle cells was significantly lower than in urothelial cells.
• No substantial increase in mutagenesis was observed in other tested organs (kidney, ureter, liver, forestomach).
• BBN also elevated urothelial mutagenesis in rats, but to a lesser extent than in mice, correlating with lower susceptibility to aggressive BBN-induced bladder cancer.

Conclusions:

• The high susceptibility of urothelial cells to BBN-induced mutagenesis underlies the carcinogen's tissue-specificity.
• BBN-induced mutagenesis provides a novel model for studying the initiation of bladder carcinogenesis.
• Differences in BBN mutagenesis between mice and rats may explain their varying susceptibility to aggressive bladder cancer.