Prolonged Exposure to Environmental Levels of Haloacetamides Exacerbates Cellular Senescence: Phenotypic and Mechanistic Insights

Disinfection byproducts (DBPs), such as haloacetamides (HAMs), have been associated with adverse health outcomes, including bladder cancer. The potential for DBPs to exacerbate cellular senescence, thereby linking exposure to health impacts, remains underexplored. In this study, MRC-5 cells were exposed to HAMs at concentrations of 2, 5, and 8 μg/L for 30 days to simulate long-term exposure to levels found in drinking water. All six tested HAMs significantly increased the cellular senescence degree and enriched the cellular senescence pathway at the proteomic-wide level. Specifically, HAMs upregulated microRNA-24 expression, which increased p16 mRNA levels and decreased p16 protein levels, thereby activating oncogene-induced senescence pathways. Additionally, HAMs were found to covalently bind to TNRC6A, activating the p53/p21 pathway. Principal component analysis highlighted the critical role of functional groups in activating senescence, and the interaction between HAMs and TNRC6A could extend to at least 27 other amide-containing DBPs. Prolonged exposure to HAMs at environmentally relevant levels notably exacerbates cellular senescence, shedding light on a commonly overlooked phenomenon. Given the widespread presence of DBPs in drinking water and their continuous exposure in humans, their role in cellular senescence represents an ongoing public health concern.