Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, Chemistry Department, Meritorious Autonomous University of Puebla, 14 South, FCQ1, Ciudad Universitaria, C.P. 72560, Puebla, Mexico.
Department of Pharmacy, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, 22 South, FCQ9, Ciudad Universitaria, C.P. 72560, Puebla, Mexico.
Biol Trace Elem Res. 2023 Aug;201(8):3903-3918. doi: 10.1007/s12011-022-03471-5. Epub 2022 Nov 8.
Cadmium is a critical toxic agent in occupational and non-occupational settings and acute and chronic environmental exposure situations that have recently been associated with metabolic disease development. Until now, the no observed adverse effect level (NOAEL) of cadmium has not been studied regarding insulin resistance development. Therefore, we aimed to monitor whether chronic oral exposure to cadmium NOAEL dose induces insulin resistance in Wistar rats and investigate if oxidative stress and/or inflammation are related. Male Wistar rats were separated into control (standard normocalorie diet + water free of cadmium) and cadmium groups (standard normocalorie diet + drinking water with 15 ppm CdCl). At 15, 30, and 60 days, oral glucose tolerance, insulin response, and insulin resistance were analyzed using mathematical models. In the liver glycogen, triglyceride, pro- and anti-inflammatory cytokines, cadmium, zinc, metallothioneins, and redox balance were quantified. Immunoreactivity analysis of proteins involved in metabolic and mitogenic insulin signaling was performed. The results showed that a cadmium NOAEL dose after 15 days of exposure causes ROS and mitogenic arm of insulin signaling to increase while hepatic glycogen diminishes. At 30 days, Cd accumulation accentuated ROS production, hepatic triglyceride overaccumulation, and mitogenic signals that develop insulin resistance. Finally, inflammation and lipid peroxidation appear after 60 days of Cd exposure, while lipids and carbohydrate homeostasis deteriorate. In conclusion, environmental exposure to cadmium NAOEL dose causes hepatic Cd accumulation and ROS overproduction that chronically declines the antioxidant defense, deteriorates metabolic homeostasis associated with the mitogenic pathway of insulin signaling, and induces insulin resistance.
镉是职业和非职业环境以及急性和慢性环境暴露情况下的一种关键毒性物质，最近与代谢性疾病的发展有关。到目前为止，尚未研究镉的无观察到不良效应水平 (NOAEL) 对胰岛素抵抗发展的影响。因此，我们旨在监测慢性口服暴露于镉 NOAEL 剂量是否会导致 Wistar 大鼠产生胰岛素抵抗，并研究氧化应激和/或炎症是否与之相关。雄性 Wistar 大鼠分为对照组（标准正常热量饮食+不含镉的水）和镉组（标准正常热量饮食+含 15 ppm CdCl 的饮用水）。在第 15、30 和 60 天，使用数学模型分析口服葡萄糖耐量、胰岛素反应和胰岛素抵抗。在肝糖原、甘油三酯、促炎和抗炎细胞因子、镉、锌、金属硫蛋白和氧化还原平衡中进行定量分析。还进行了参与代谢和促胰岛素信号的蛋白质的免疫反应性分析。结果表明，暴露 15 天后的镉 NOAEL 剂量会导致 ROS 和促胰岛素信号通路增加，而肝糖原减少。在第 30 天，Cd 积累会加剧 ROS 产生、肝甘油三酯过度积累以及导致胰岛素抵抗的促有丝分裂信号。最后，在暴露于 Cd 60 天后会出现炎症和脂质过氧化，同时脂质和碳水化合物的稳态会恶化。总之，环境暴露于镉的 NOAEL 剂量会导致肝内 Cd 积累和 ROS 过度产生，从而导致抗氧化防御能力慢性下降，与胰岛素信号的促有丝分裂途径相关的代谢稳态恶化，并导致胰岛素抵抗。
