Yao Lu1, Junru Wu2, Wenduo Gu3, Zhijun Huang1, Zhihao Shu1, Miao Huang1, Jingyuan Chen1, Mengli Zhou2, Yuanyuan Bai2, Xiang Chen4, Yi Xiao4, Minxue Shen5, Dan Luo5, Qihong Deng6, Liyuan Chai7, Meian He8, Jicheng Gong9, Hong Yuan2, Qingbo Xu10, Jingjing Cai11. 1. Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China. 2. 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. 3. Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom. 4. Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, China. 5. Department of Social Medicine and Health Management, Xiangya School of Public Health, Central South University, 110 Xiangya Road, Changsha 410008, China. 6. Xiangya School of Public Health/School of Public Health, Central South University, 110 Xiangya Road, Changsha 410008, China. 7. School of Metallurgical Science and Engineering, Central South University, 932 Lushannan Road, Changsha 410083, China. 8. Department of Occupational and Environmental Health, School of Public Health, Huazhong University of Science and Technology, 13 Aviation Road, Wuhan 430030, China. 9. College of Environmental Sciences and Engineering and Center for Environment and Health, Peking University, 5 Yiheyuan Road, Beijing 100871, China. 10. Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha 410013, China; Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, China. 11. 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. Electronic address: caijingjing83@hotmail.com.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: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. METHODS: 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 sepsismouse model. RESULTS: 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 sepsismouse 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. CONCLUSION: 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.