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论文摘要: The Yangtze River, a critical drinking water source for over 500 million people, faces escalating contamination from pharmaceuticals and antibiotic resistance genes (ARGs). This study systematically investigated 11 water sources and 39 tap water sites in the Mid-Yangtze River, quantifying 10 pharmaceuticals and 384 ARGs via ultra-trace analysis (UPLC-MS/MS) and HT-qPCR. Pharmaceuticals occurred at low total concentrations (1.45-6.41 ng/L), with tap water levels reduced by 1-2 orders of magnitude post-treatment. Notably, we observed decoupling between pharmaceutical exposure and ARGs proliferation-while pharmaceuticals posed minimal human health risks (RQ(h) <10(-4)) and moderate ecological risks (MRQ(e) = 0.84), environmental factors (nitrogen, phosphorus, organic matter) explained 51.2% of ARGs variation, far exceeding pharmaceutical contributions (2.9%). Dissolved organic carbon, nitrate nitrogen, and total phosphorus emerged as primary environmental drivers of ARGs/MGEs proliferation, with mobile genetic elements (MGEs, e.g., tnpA-2, intI1) serving as central hubs for horizontal transfer. Network analysis revealed anti-inflammatories (ibuprofen/naproxen) unexpectedly co-occurred with resistance determinants despite their low selective pressure. This decoupling mechanism demonstrates that nutrient-driven gene transfer supersedes pharmaceutical selection in sustaining ARGs persistence, even under low exposure conditions. The findings necessitate paradigm shifts in risk management: controlling nutrient loads and targeting MGEs may prove more effective than solely regulating pharmaceuticals for mitigating antimicrobial resistance in drinking water systems.