DNA hypomethylation induced by non-genotoxic carcinogens in mouse and rat colon

Area of Science:

• Epigenetics and Carcinogenesis
• Molecular Toxicology
• Gastrointestinal Oncology

Background:

• DNA methylation patterns are crucial for regulating gene expression and maintaining genomic stability.
• Alterations in DNA methylation, particularly hypomethylation, are implicated in the development of various cancers, including colon cancer.
• Non-genotoxic carcinogens represent a significant class of environmental agents that can promote cancer through mechanisms independent of direct DNA damage.

Purpose of the Study:

• To investigate the association between non-genotoxic colon carcinogens and DNA hypomethylation.
• To determine if specific compounds known to influence colon cancer risk induce changes in DNA methylation.
• To correlate the DNA hypomethylation potential of these agents with their established carcinogenic activity in the colon.

Main Methods:

• Administration of 5-aza-2'-deoxycytidine, a known hypomethylating agent, to female mice to establish a dose-response relationship for DNA hypomethylation in colon tissue.
• Dietary administration of rutin and various bile acids (deoxycholic acid, chenodeoxycholic acid, cholic acid, lithocholic acid, ursodeoxycholic acid) to male F344 rats.
• Gavage or drinking water administration of bromodichloromethane (BDCM) to male F344 rats and B6C3F1 mice.
• Quantification of 5-methylcytosine levels in colon DNA following exposure to the test compounds.

Main Results:

• 5-aza-2'-deoxycytidine induced a dose-related decrease in colon DNA 5-methylcytosine in mice.
• Rutin and four pro-carcinogenic bile acids (deoxycholic acid, chenodeoxycholic acid, cholic acid, lithocholic acid) significantly reduced DNA methylation in rat colon, while cancer-preventive ursodeoxycholic acid did not.
• Bromodichloromethane (BDCM) decreased DNA methylation in rats, with greater effect via gavage, correlating with its higher carcinogenic potency by this route.
• BDCM did not affect DNA methylation in mice, consistent with its lack of colon carcinogenicity in this species.

Conclusions:

• The ability of non-genotoxic compounds to induce DNA hypomethylation in the colon is strongly correlated with their carcinogenic activity in this tissue.
• These findings suggest that epigenetic modifications, specifically DNA hypomethylation, are a key mechanism by which certain non-genotoxic agents promote colon carcinogenesis.
• Understanding the link between chemical exposure, DNA methylation changes, and cancer development can inform strategies for cancer prevention and risk assessment.