Organoid-Based Strategy for Exploration of Cancer-Related Early Signatures of Low-Dose Methylmercury Exposure

Abstract Methylmercury (MeHg) compounds are classified as Group 2B agents, possibly carcinogenic to humans by the International Agency for Research on Cancer (IARC), and as Group C possible human carcinogens by the U.S. Environmental Protection Agency (U.S. EPA), but the carcinogenic implications of environmentally relevant low-dose exposure remain unclear. Here, we established a population-informed organoid-based strategy to explore the potential of low-dose MeHg exposure leading to cancer incidence. A National Health and Nutrition Examination Survey (NHANES)-based analysis revealed nonlinear associations of blood MeHg with overall cancer history with increased predicted cancer probability around 5.39 μg/L for MeHg. Liver organoid experiments showed that low-dose MeHg did not cause overt short-term cytotoxicity but induced DNA damage and stress-response signatures after prolonged exposure. Transcriptomic analysis further linked low-dose MeHg exposure to cancer-related stress pathways, including reactive oxygen species (ROS) associated chemical carcinogenesis, p53 signaling, DNA repair, mitochondrial stress, and cell-cycle regulation. These results indicate that low-dose MeHg exposure could trigger early biological responses related to cancer-associated processes before apparent cytotoxicity occurs. This study supports organoid models as a human-relevant strategy for linking population exposure signals with tissue-level toxicological evidence in MeHg research and provides a potentially adaptable framework for evaluating subtle health effects of low-dose environmental pollutants.