Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China.
Department of Toxicology, School of Public Health, Anhui Medical University, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, China; Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People's Republic of China, China.
Chemosphere. 2023 Oct;338:139437. doi: 10.1016/j.chemosphere.2023.139437. Epub 2023 Jul 12.
Cadmium (Cd), is a well-known reproductive toxicant. The impacts of paternal Cd exposure on offspring glucose and lipid metabolism remain unclear, despite the abundance of adverse reports following early exposure from the mother. Here, we assessed paternally acquired metabolic derailment using a mouse model. LC-MS/MS, transcriptomics and molecular experimental techniques were subsequently applied in this study to explore the potential mechanism. We found that paternal Cd exposure caused glucose intolerance, lower insulin sensitivity and abnormal hepatic glycogen storage in adult female offspring, but not in males. LC-MS/MS data showed that hepatic phospholipids accumulation was also only observed in adult female offspring after paternal Cd exposure. Gene expression data showed that the level of insulin signaling and lipid transport-related genes was decreased in Cd-treated adult female offspring livers. Meanwhile, AHR, a transcription factor that combines with phospholipids to promote insulin resistance, was increased in Cd-treated adult female offspring livers. In addition, the escalation of the afore-mentioned lipid metabolites in the liver occurred as early as fetal stages in the female pups following paternal Cd exposure, suggesting the potential for these lipid species to be selected as early markers of disease for metabolic derailment later in life. Altogether, paternal Cd exposure causes offspring glucose metabolism disorder and phospholipids accumulation in a sex-dependent manner. This study provides a theoretical framework for future understanding of paternal-originated metabolic diseases.
镉（Cd）是一种众所周知的生殖毒性物质。尽管有大量早期母体暴露导致的不良报告，但父体镉暴露对子代葡萄糖和脂质代谢的影响仍不清楚。在这里，我们使用小鼠模型评估了亲代获得的代谢失调。随后，本研究应用 LC-MS/MS、转录组学和分子实验技术来探索潜在的机制。我们发现，父体镉暴露导致成年雌性后代出现葡萄糖不耐受、胰岛素敏感性降低和肝糖原储存异常，但对雄性没有影响。LC-MS/MS 数据显示，只有在父体镉暴露后，成年雌性后代的肝磷脂积累才会出现。基因表达数据显示，Cd 处理的成年雌性后代肝脏中胰岛素信号和脂质转运相关基因的水平降低。同时，AHR（一种与磷脂结合以促进胰岛素抵抗的转录因子）在 Cd 处理的成年雌性后代肝脏中增加。此外，在父体镉暴露的雌性幼仔中，这些脂质代谢物在胎儿期就已经在肝脏中上升，这表明这些脂质物种有可能成为以后生命中代谢失调的早期疾病标志物。总的来说，父体镉暴露以性别依赖的方式导致后代葡萄糖代谢紊乱和磷脂积累。本研究为未来理解源于亲代的代谢性疾病提供了理论框架。
