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Heterogeneous Biological Responses to Low-Level Sodium Saccharin Exposure: An Integrated Computational Toxicology and
Zhao Xin1,2, Wang Yanchun1,2,3, Chen Xinwang1
1Acupuncture and Moxibustion and Massage College, Henan University of Chinese Medicine, Zhengzhou, Henan, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Low-level exposure to sodium saccharin shows mixed associations with cancer risk. Computational and genetic analyses suggest interactions with cancer pathways but not a generalized carcinogenic effect.
Area of Science:
- Computational toxicology
- Genetics
- Cancer research
Background:
- The biological impact of long-term, low-level artificial sweetener exposure is debated.
- Sodium saccharin's effects on various cancer types require further investigation.
Purpose of the Study:
- To investigate potential biological responses to sodium saccharin exposure.
- To explore associations with multiple cancer outcomes using computational and genetic methods.
Main Methods:
- Screened public databases for saccharin targets and constructed protein-protein interaction networks.
- Performed molecular docking and two-sample Mendelian randomization (MR) analyses using GWAS data.
- Evaluated potential causal associations between genetic variants and cancer risk.
Main Results:
- Identified 191 saccharin targets, with 160 overlapping genes across 36 cancer types, including hub genes TP53, IL6, and MAPK3.
- Enrichment analyses revealed involvement of inflammatory pathways like interleukin-17 signaling.
- MR analyses indicated inverse associations with non-melanoma skin and colon cancers, and a potential positive association with Kaposi sarcoma.
Conclusions:
- Sodium saccharin may interact with cancer-related molecular networks.
- Population-level evidence suggests heterogeneous, context-dependent associations, not a generalized carcinogenic effect at low exposure levels.
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