Center for Human Health and the Environment, Department of Biological Sciences, North Carolina State University, 127 David Clark Labs Campus Box 7617, Raleigh, North Carolina 27695, USA.
Department of Entomology and Plant Pathology, North Carolina State University, Raleigh, North Carolina 27695, USA.
Toxicol Sci. 2022 May 26;187(2):254-266. doi: 10.1093/toxsci/kfac027.
In CD-1 mice, gestational-only exposure to cadmium (Cd) causes female-specific hepatic insulin resistance, metabolic disruption, and obesity. To evaluate whether sex differences in uptake and changes in essential metal concentrations contribute to metabolic outcomes, placental and liver Cd and essential metal concentrations were quantified in male and female offspring perinatally exposed to 500 ppb CdCl2. Exposure resulted in increased maternal liver Cd+2 concentrations (364 µg/kg) similar to concentrations found in non-occupationally exposed human liver. At gestational day (GD) 18, placental Cd and manganese concentrations were significantly increased in exposed males and females, and zinc was significantly decreased in females. Placental efficiency was significantly decreased in GD18-exposed males. Increases in hepatic Cd concentrations and a transient prenatal increase in zinc were observed in exposed female liver. Fetal and adult liver iron concentrations were decreased in both sexes, and decreases in hepatic zinc, iron, and manganese were observed in exposed females. Analysis of GD18 placental and liver metallothionein mRNA expression revealed significant Cd-induced upregulation of placental metallothionein in both sexes, and a significant decrease in fetal hepatic metallothionein in exposed females. In placenta, expression of metal ion transporters responsible for metal ion uptake was increased in exposed females. In liver of exposed adult female offspring, expression of the divalent cation importer (Slc39a14/Zip14) decreased, whereas expression of the primary exporter (Slc30a10/ZnT10) increased. These findings demonstrate that Cd can preferentially cross the female placenta, accumulate in the liver, and cause lifelong dysregulation of metal ion concentrations associated with metabolic disruption.
在 CD-1 小鼠中，妊娠期暴露于镉（Cd）会导致雌性特异性肝胰岛素抵抗、代谢紊乱和肥胖。为了评估摄取的性别差异和必需金属浓度的变化是否导致代谢结果，在雄性和雌性后代中定量评估了围产期暴露于 500 ppb CdCl2 的胎盘和肝脏中的 Cd 和必需金属浓度。暴露导致母体肝脏中的 Cd+2 浓度增加（364 µg/kg），类似于非职业暴露的人类肝脏中的浓度。在妊娠第 18 天（GD18），暴露组的胎盘和锰浓度在雄性和雌性中均显著增加，而雌性的锌浓度显著降低。GD18 暴露组的胎盘效率显著降低。在暴露组的雌性肝脏中观察到肝镉浓度增加和锌浓度的短暂产前增加。胎儿和成年肝脏铁浓度在两性中均降低，而暴露组的雌性肝脏锌、铁和锰浓度降低。GD18 胎盘和肝脏金属硫蛋白 mRNA 表达的分析显示，金属硫蛋白在两性中的表达均被 Cd 诱导上调，而暴露组的雌性胎儿肝脏金属硫蛋白表达显著降低。在胎盘，负责金属离子摄取的金属离子转运体的表达在暴露组的雌性中增加。在暴露的成年雌性后代的肝脏中，二价阳离子摄取体（Slc39a14/Zip14）的表达减少，而主要输出体（Slc30a10/ZnT10）的表达增加。这些发现表明，Cd 可以优先穿过雌性胎盘，在肝脏中积累，并导致与代谢紊乱相关的金属离子浓度的终身失调。
