Heterogeneous Biological Responses to Low-Level Sodium Saccharin Exposure: An Integrated Computational Toxicology and...

The long-term biological effects of low-level exposure to artificial sweeteners remain debated. We integrated computational toxicology and Mendelian randomization (MR) to explore potential biological responses associated with sodium saccharin across multiple cancer outcomes.

Public databases were screened to identify saccharin-related targets, followed by protein-protein interaction network construction and enrichment analyses. Molecular docking assessed binding potential. Two-sample MR analyses were conducted using European genome-wide association study (GWAS) summary statistics to evaluate potential causal associations.

Among 191 identified targets, 160 overlapped with genes implicated across 36 cancer types. Hub genes included TP53, IL6, and MAPK3, with docking indicating moderate binding affinity. Enrichment analyses highlighted inflammatory pathways including interleukin-17 signaling. MR analyses suggested inverse associations with non-melanoma skin cancer (odds ratio [OR] = 0.38, P = 0.006) and colon cancer (OR = 0.56, P < 0.001), while a preliminary positive signal was observed for Kaposi sarcoma (OR = 3.73, P = 0.044). No significant associations were detected for most other cancers.

Sodium saccharin may interact with cancer-related molecular networks; however, population-level evidence indicates heterogeneous and context-dependent associations rather than a generalized carcinogenic effect under low-level exposure conditions.