Like father, like daughter:Paternal cadmium exposure causes hepatic glucose metabolic disorder and phospholipids accumulation in adult female offspring

Authors：Lu-Lu Tan , Yong-Wei Xiong , Jin Zhang , Dai-Xin Li , Yichao Huang , Hua Wang

Source：Chemosphere. 2023 Oct;338:139437

DOI: 10.1016/j.chemosphere.2023.139437

Abstract：

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.

摘要：

镉（Cd）是一种众所周知的生殖毒性物质。尽管有大量关于母亲早期接触镉后的不良报道，但父亲接触镉对后代葡萄糖和脂质代谢的影响仍不清楚。在这里，我们利用小鼠模型评估了父亲获得性代谢失调。随后，本研究采用了 LC-MS/MS、转录组学和分子实验技术来探索其潜在机制。我们发现，父代镉暴露会导致成年雌性后代葡萄糖不耐受、胰岛素敏感性降低和肝糖原储存异常，而雄性后代则不会。LC-MS/MS 数据显示，只有成年雌性后代在父代接触镉后才会出现肝磷脂积累。基因表达数据显示，镉处理的成年雌性后代肝脏中胰岛素信号转导和脂质转运相关基因的水平降低。同时，镉处理的成年雌性子代肝脏中与磷脂结合促进胰岛素抵抗的转录因子AHR水平升高。此外，雌性幼崽在父代接触镉后，其肝脏中上述脂质代谢物的增加早在胎儿期就已出现，这表明这些脂质种类有可能被选为疾病的早期标志物，在以后的生活中导致代谢失调。总之，父代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。这项研究为今后了解父代代谢性疾病提供了一个理论框架。