Progestins, such as norethindrone (NET), have been increasingly detected in aquatic environments due to their extensive use for medical applications. While NET is notorious for its endocrine disrupting effects, it has been recently shown to cause cellular damage, suggesting its potential impacts on the body defence of organisms. Hence, we examined the histological features and antioxidant defence of zebrafish (Danio rerio) after exposing to NET (50 ng/L and 500 ng/L) for 72 days, followed by analysing its metabolome to explore whether NET disturbs the metabolic processes responsible for antioxidant defence. While acute mortality was not triggered, we found that antioxidant defence was substantially weakened by NET at 500 ng/L (i.e. reduced SOD and GSH levels) and hence liver injury was inflicted (i.e. elevated ALT and MDA levels), as manifested by vacuolization of liver tissues and reduced number of normal cells in the liver. Metabolomic analysis showed that the metabolic processes responsible for antioxidant defence were disrupted by NET (e.g. upregulation of nervonyl carnitine and chenodeoxycholic acid 3-sulfate; downregulation of homolanthionine and acevaltrate) and these changes can undermine antioxidant defence by suppressing Nrf2-ARE and NF-κB pathways that contribute to the synthesis of SOD and GSH. This study demonstrates how NET can compromise the body defence of aquatic organisms via metabolic disruption, suggesting that the impacts of progestins on their fitness are more detrimental than previously thought.

由于其在医疗应用中的广泛应用，在水生环境中越来越多地检测到诸如炔诺酮（NET）等孕激素。尽管NET因其内分泌干扰作用而臭名昭著，但最近已证明它会引起细胞损伤，表明其对生物体的身体防御能力有潜在的影响。因此，我们检查了斑马鱼的组织学特征和抗氧化防御能力（Danio rerio）暴露于NET（50 ng / L和500 ng / L）中72天后，随后分析其代谢组以研究NET是否会干扰负责抗氧化防御的代谢过程。虽然未触发急性死亡，但我们发现NET在500 ng / L时抗氧化防御能力显着减弱（即SOD和GSH含量降低），因此造成了肝损伤（例如ALT和MDA含量升高），表现为空泡化肝脏组织和肝脏中正常细胞的数量减少。代谢组学分析表明，NET破坏了负责抗氧化防御的代谢过程（例如，神经氨酸肉碱和3-硫酸鹅脱氧胆酸的上调；降低了高硫氨酸和乙酰丙酸酯的含量），这些变化可以通过抑制有助于合成SOD和GSH的Nrf2-ARE和NF-κB途径来破坏抗氧化防御能力。这项研究证明了NET如何通过代谢破坏来损害水生生物的机体防御能力，这表明孕激素对其适应性的影响比以前认为的更为有害。