Given its wide distribution in the environment and latent toxic effects, 1,3,6,8-tetrabromo-9H-carbazole (1368-BCZ) is an emerging concern that has gained increasing attention globally. 1368-BCZ exposure is reported to have potential cardiovascular toxicity. Although atherosclerosis is a cardiovascular disease and remains a primary cause of mortality worldwide, no evidence has been found regarding the impact of 1368-BCZ on atherosclerosis. Therefore, we aimed to explore the deleterious effects of 1368-BCZ on atherosclerosis and the underlying mechanisms. Serum samples from 1368-BCZ-treated atherosclerotic model mice were subjected to metabolomic profiling to investigate the adverse influence of the pollutant. Subsequently, the molecular mechanism associated with the metabolic pathway of atherosclerotic mice that was identified following 1368-BCZ exposure was validated Serum metabolomics analysis revealed that 1368-BCZ significantly altered the tricarboxylic acid cycle, causing a disturbance in energy metabolism. we further validated general markers of energy metabolism based on metabolome data: 1368-BCZ dampened adenosine triphosphate (ATP) synthesis and increased reactive oxygen species (ROS) production. Furthermore, blocking the aryl hydrocarbon receptor (AhR) reversed the high production of ROS induced by 1368-BCZ. It is concluded that 1368-BCZ decreased the ATP synthesis by disturbing the energy metabolism, thereby stimulating the AhR-mediated ROS production and presumably causing aggravated atherosclerosis. This is the first comprehensive study on the cardiovascular toxicity and mechanism of 1368-BCZ based on rodent models of atherosclerosis and integrated with models.

中文翻译：

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通过代谢组学分析与体外机制研究相结合，探讨 1,3,6,8-四溴-9H-咔唑对动脉粥样硬化模型小鼠的不良影响

鉴于其在环境中的广泛分布和潜在的毒性作用，1,3,6,8-四溴-9H-咔唑（1368-BCZ）成为一个新兴问题，在全球范围内受到越来越多的关注。据报道，1368-BCZ 暴露具有潜在的心血管毒性。尽管动脉粥样硬化是一种心血管疾病，并且仍然是全世界死亡的主要原因，但尚未发现有关 1368-BCZ 对动脉粥样硬化影响的证据。因此，我们旨在探讨1368-BCZ对动脉粥样硬化的有害作用及其潜在机制。对 1368-BCZ 治疗的动脉粥样硬化模型小鼠的血清样本进行代谢组学分析，以研究污染物的不利影响。随后，在暴露于 1368-BCZ 后确定的与动脉粥样硬化小鼠代谢途径相关的分子机制得到了验证。血清代谢组学分析显示，1368-BCZ 显着改变了三羧酸循环，导致能量代谢紊乱。我们根据代谢组数据进一步验证了能量代谢的一般标志物：1368-BCZ 抑制三磷酸腺苷 (ATP) 合成并增加活性氧 (ROS) 产生。此外，阻断芳烃受体（AhR）可逆转 1368-BCZ 诱导的 ROS 大量产生。结论是1368-BCZ通过扰乱能量代谢来减少ATP合成，从而刺激AhR介导的ROS产生并可能导致动脉粥样硬化加重。这是首次基于啮齿类动物动脉粥样硬化模型并与模型相结合，对1368-BCZ的心血管毒性及机制进行全面研究。