Background: Genetic susceptibility to environmental mutagens and carcinogens plays a critical role in cancer development, particularly when cellular mechanisms that maintain genomic integrity are compromised. DNA repair pathways and telomere maintenance are crucial in preserving genome stability and modulating responses to toxic environmental exposures.
Objectives: To investigate how deficiencies in DNA repair pathways, specifically non-homologous end joining (NHEJ), nucleotide excision repair (NER) and telomere dysfunction influence cellular sensitivity to environmental toxicants. The broader aim is to evaluate their potential as mechanistic biomarkers for cancer risk assessment.
Methods: Mammalian cell models deficient in NHEJ and NER, as well as cells with telomere dysfunction, were exposed to environmental genotoxic agents, including sodium arsenite, silver nanoparticles (Ag-np), bisphenol A, ionising radiation, and oxidative stress. Cellular responses were assessed using DNA damage assays (g-H2AX foci, Comet), viability and cell cycle analyses, and gene expression profiling of stress and repair pathways.
Results: Cells with DNA repair deficiencies or telomere instability exhibited significantly increased DNA damage, genomic stability (chromosomal aberrations and telomere dysfunction), cell cycle arrest, and decreased viability upon exposure to toxicants. These effects were more pronounced in DNA-PKcs-deficient and NER-deficient cells, indicating a central role for repair pathways in mitigating both genotoxic and oxidative stress. Transcriptomic profiling further revealed upregulation of stress-response genes and suppression of key repair effectors.
Conclusions / Implications for Practice or Policy: Our findings underscore the importance of mechanistic toxicology in identifying genetically susceptible subpopulations. Understanding the role of DNA repair capacity and telomere maintenance in modulating responses to environmental exposures can inform cancer risk prediction models, guide biomarker development, and support targeted prevention strategies, particularly in environmentally or occupationally exposed populations.