Aflatoxin B₁-Induced Hepatic Mutagenesis in Mice Expressing Gene-Edited Neil1.

Area of Science:

• Molecular biology and toxicology
• Cancer research
• DNA repair mechanisms

Background:

• Hepatocellular carcinoma (HCC) is a major cause of cancer mortality, linked to factors including aflatoxin B1 (AFB1) exposure.
• AFB1 induces mutagenic DNA lesions repaired by the base excision repair pathway, initiated by the DNA glycosylase NEIL1.
• NEIL1 deficiency exacerbates AFB1-induced mutagenesis and carcinogenesis in mice, and human NEIL1 variants (A51V, G83D) are known.

Purpose of the Study:

• To investigate the impact of specific human NEIL1 variants (A51V, G83D) on AFB1-induced mutagenesis in a murine model.
• To compare mutation frequencies and spectra in mice expressing these variants versus wild-type and NEIL1-deficient mice.

Main Methods:

• Homozygous Neil1^A51V and Neil1^G83D mice received a single dose of AFB1 at 6 days old.
• Liver genomes were analyzed 2.5 months post-exposure using duplex sequencing to assess mutation frequencies and spectra.
• Data were compared with existing data from wild-type (WT) and Neil1^-/- mice.

Main Results:

• Mice expressing Neil1^A51V and Neil1^G83D showed mutation frequencies comparable to WT mice after AFB1 exposure.
• However, both Neil1^A51V and Neil1^G83D models exhibited elevated proportions of base substitutions at A/T sites.
• This mutational signature is consistent with impaired NEIL1 function, similar to NEIL1 deficiency.

Conclusions:

• The A51V and G83D NEIL1 variants, while not increasing overall mutation frequency, alter the mutation spectrum in response to AFB1.
• These findings suggest that individuals carrying these NEIL1 variants may have an increased susceptibility to AFB1-induced HCC.
• Further research is warranted to elucidate the precise mechanisms and clinical implications of these NEIL1 variants in hepatocarcinogenesis.