Carbamazepine is one of the most abundant pharmaceutical active compounds detected in aquatic systems. Based on laboratory exposures, carbamazepine has been proven to adversely affect aquatic organisms. However, the underlying molecular events remain poorly understood. This study aims to investigate the molecular mechanisms potentially associated with toxicological effects of carbamazepine on the mussel Mytilus galloprovincialis exposed for 3 days at realistic concentrations encountered in coastal environments (80 ng/L and 8 μg/L). An integrated metabolomics and proteogenomics approach, including data fusion strategy, was applied to gain more insight in molecular events and cellular processes triggered by carbamazepine exposure. Consistent metabolic and protein signatures revealed a metabolic rewiring and cellular stress at both concentrations (e.g. intensification of protein synthesis, transport and catabolism processes, disruption of lipid and amino acid metabolisms). These highlighted molecular signatures point to the induction of autophagy, closely related with carbamazepine mechanism of action, as well as a destabilization of the lysosomal membranes and an enzymatic overactivity of the peroxisomes. Induction of programmed cell death was highlighted by the modulation of apoptotic cognate proteins. The proposed integrative omics data analysis was shown to be highly relevant to identify the modulations of the two molecular levels, i.e. metabolites and proteins. Multi-omics approach is able to explain the resulting complex biological system, and document stronger toxicological pieces of evidence on pharmaceutical active compounds at environmental concentrations in sentinel organisms.

卡马西平是在水生系统中检测到的最丰富的药物活性化合物之一。根据实验室暴露情况，卡马西平已被证明对水生生物有不利影响。然而，潜在的分子事件仍然知之甚少。本研究旨在探讨卡马西平对贻贝Mytilus galloprovincialis 的毒理学作用可能相关的分子机制。在沿海环境中遇到的实际浓度（80 ng/L 和 8 μg/L）下暴露 3 天。应用综合代谢组学和蛋白质基因组学方法，包括数据融合策略，以更深入地了解卡马西平暴露引发的分子事件和细胞过程。一致的代谢和蛋白质特征揭示了两种浓度下的代谢重新布线和细胞应激（例如蛋白质合成、运输和分解代谢过程的强化、脂质和氨基酸代谢的破坏）。这些突出的分子特征表明自噬的诱导，与卡马西平的作用机制密切相关，以及溶酶体膜的不稳定和过氧化物酶体的酶活性过度。凋亡同源蛋白的调节突出了程序性细胞死亡的诱导。所提议的综合组学数据分析被证明与鉴定两个分子水平，即代谢物和蛋白质的调节高度相关。多组学方法能够解释由此产生的复杂生物系统，并记录前哨生物中环境浓度下药物活性化合物的更强毒理学证据。