Tobacco consumption remains one of the leading causes of preventable diseases and deaths worldwide. Among its major constituents, nicotine (NIC) and tobacco-specific nitrosamines (TSNAs) stand out attributed to their toxicological and carcinogenic potential. While NIC is primarily recognized for its addictive properties, TSNAs such as N '-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are well-established procarcinogens derived from nicotine metabolism. Although the genotoxic and mutagenic effects of NNN and NNK have been extensively documented, the impact of their combined exposure with NIC remains poorly understood. This study investigated the mutagenic and recombinogenic activities of NIC in association with NNN and NNK in vivo using the Drosophila melanogaster wing somatic mutation and recombination test (SMART). Two experimental designs were applied: the standard cross, with basal levels of cytochrome P450-dependent metabolic activity, and the high bioactivation cross, characterized by elevated P450 levels essential for metabolic activation of procarcinogens and promutagens. Data demonstrated that NIC, NNN, and NNK tested individually did not significantly alter mutant clone frequencies. However, combined treatment of NNN 0.001 mg/ml and NNK 0.001 mg/ml in the high bioactivation cross induced a significant rise in total frequency of mutant spots. Further analysis revealed that 73.5% of induced genetic alterations were attributable to somatic recombination events. These findings demonstrate the genotoxic potential of combined TSNAs, suggesting that simultaneous exposure may potentiate genetic damage primarily through recombination mechanisms, emphasizing an important risk factor for tobacco-related health outcomes.
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