Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha 410013, China.
Ecotoxicol Environ Saf. 2021 Mar 15;211:111881. doi: 10.1016/j.ecoenv.2020.111881. Epub 2021 Jan 11.
Cadmium is the most prevalent form of heavy metal contaminant globally and its exposure rises serious health concern. Chronic exposure to cadmium causes immune disturbances. However, few studies have addressed how it affects circulating immune cells, one of the most essential elements for the host defense system, at both population and molecular level. Therefore, this is the first single-cell transcriptomic analysis of the response of the human circulating immune system to plasma cadmium level.
We conducted a cross-sectional study in Hunan province, which has the highest level of cadmium land contamination in China. A total of 3283 individuals were eligible for analyzing the association between plasma cadmium levels and the monocyte counts and its subgroups. Another 780 individuals were assigned for validation. Thirty propensity-matched individuals without chronic disease from the lowest- and highest-quartile groups according to serum cadmium levels were selected for single-cell RNA sequencing (scRNA-seq) and flow cytometry analyses. Moreover, the monocyte phenotypic alterations in the heavy metal-exposed population were validated with a cecal ligation and puncture sepsis mouse model.
From August 2016 to July 2017, we conducted a cross-sectional study to identify phenotypic alterations in peripheral immune cells in cadmium polluted areas in China. Monocyte percentages were negatively associated with plasma cadmium levels in multivariable linear regression analysis. Peripheral blood mononuclear cell scRNA-seq revealed that the CD14 monocyte subset was dramatically reduced in the highest-quartile cadmium-exposed group. Moreover, we assessed different hallmarks of immune cell dysfunction-such as host defense capability, apoptotic signaling, cellular diversity and malignant gene expression in monocytes. Importantly, cadmium induced phenotypic alterations in the immune system were validated in the cecal ligation and puncture sepsis mouse model, in which chronic exposure to cadmium not only increased the death rate but also decreased monocyte numbers and the ability to clear bacterial infections.
This transcriptomic analysis provides molecular information about how the most important hallmarks of immune cell dysfunction are affected by plasma cadmium level. The significant phenotypic alterations in monocytes serving as early indicators of increased susceptibility to infectious and malignant diseases.
镉是全球最普遍的重金属污染物形式，其暴露引发了严重的健康问题。慢性镉暴露会导致免疫紊乱。然而，很少有研究探讨它如何在人群和分子水平上影响循环免疫细胞，这是宿主防御系统最重要的元素之一。因此，这是首次对人类循环免疫系统对血浆镉水平的反应进行单细胞转录组分析。
我们在中国镉土地污染最严重的湖南省进行了一项横断面研究。共有 3283 人符合分析血浆镉水平与单核细胞计数及其亚群之间关联的条件。另外 780 人被分配用于验证。根据血清镉水平，从最低和最高四分位数组中选择 30 名无慢性病的倾向匹配个体进行单细胞 RNA 测序（scRNA-seq）和流式细胞术分析。此外，还使用盲肠结扎和穿刺脓毒症小鼠模型验证了重金属暴露人群中单核细胞表型的改变。
从 2016 年 8 月到 2017 年 7 月，我们在中国镉污染地区进行了一项横断面研究，以确定外周免疫细胞的表型改变。多元线性回归分析显示，单核细胞百分比与血浆镉水平呈负相关。外周血单核细胞 scRNA-seq 显示，最高四分位数镉暴露组中 CD14 单核细胞亚群显著减少。此外，我们评估了免疫细胞功能障碍的不同特征，如宿主防御能力、凋亡信号、细胞多样性和恶性基因表达在单核细胞中的作用。重要的是，在盲肠结扎和穿刺脓毒症小鼠模型中验证了镉诱导的免疫系统表型改变，在该模型中，慢性暴露于镉不仅增加了死亡率，还降低了单核细胞数量和清除细菌感染的能力。
这项转录组分析提供了关于血浆镉水平如何影响免疫细胞功能障碍的最重要特征的分子信息。单核细胞的显著表型改变可作为易感性增加的早期指标，易患感染性和恶性疾病。
