PMID- 35026265 OWN - NLM STAT- MEDLINE DCOM- 20220304 LR - 20220304 IS - 1879-1026 (Electronic) IS - 0048-9697 (Linking) VI - 817 DP - 2022 Apr 15 TI - Identification of the hormetic dose-response and regulatory network of multiple metals co-exposure-related hypertension via integration of metallomics and adverse outcome pathways. PG - 153039 LID - S0048-9697(22)00129-2 [pii] LID - 10.1016/j.scitotenv.2022.153039 [doi] AB - Environmental stressors, including heavy metals, can be associated with hypertension development. However, little information regarding the dose-response relationship and toxicity mechanisms of metal mixtures with hypertension development is currently available. Therefore, we recruited 940 participants from six factories in northeastern China and measured the urinary concentrations of 19 metals. Then, we used Bayesian kernel machine regression (BKMR) to explore associations between metals co-exposure and hypertension. The BKMR model indicated a hermetic dose-response relationship between eight urinary metals (Co, Cr, Ni, Cd, As, Fe, Zn, and Pb) and hypertension risk. Moreover, heterogeneous and non-linear association patterns were detected across different metals/metalloids concentrations. Next, for the first time, we analyzed data of chemicals containing specific metal elements in the Comparative Toxicogenomics Database (CTD) from a disease perspective and provided insights from various biological levels to explain heavy metal co-exposure-related hypertension. On the molecular scale, 43 chemical components and 112 potential target genes were detected for metal exposure-related hypertension. Further, the network topology analysis indicated that target genes such as insulin (INS, degree = 78), albumin (ALB, degree = 74), renin (REN, degree = 71), interleukin-6 (IL6, degree = 70), endothelin 1 (EDN1, degree = 70), and endothelial nitric oxide synthase (NOS3, degree = 69) have a strong correlation with heavy metals co-exposure. Finally, we used integrative analyses in the adverse outcome pathway (AOP) wiki to analyze the co-exposure of heavy metals and hypertension and support an integrated metallomics approach. We selected the AOP 149 as the framework and found that the molecular initiating events (MIEs) of hypertension stems from the oxidation of AA residues on critical peptides of the NO pathway. The NOS3 was particularly promising since its subunit has three metal ion cross-linking domains with Zn(2+), Fe(2+), and Ga(3+), which might serve as a binding site for heavy metal ions. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Shi, Peng AU - Shi P AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Liu, Shengnan AU - Liu S AD - Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Xia, Xinyu AU - Xia X AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Qian, Jili AU - Qian J AD - Department of Health Statistics, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Jing, Hongmei AU - Jing H AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Yuan, Jiamei AU - Yuan J AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Zhao, Hanqing AU - Zhao H AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Wang, Fei AU - Wang F AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. FAU - Wang, Yue AU - Wang Y AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China; Key Laboratory of Environmental Health Damage Research and Assessment, China Medical University, Shenyang 110122, PR China. FAU - Wang, Xue AU - Wang X AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China; Key Laboratory of Environmental Health Damage Research and Assessment, China Medical University, Shenyang 110122, PR China. FAU - Wang, Xuan AU - Wang X AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China; Central Hospital, Shenyang Medical College, Shenyang 110122, PR China. FAU - He, Miao AU - He M AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China; Key Laboratory of Environmental Health Damage Research and Assessment, China Medical University, Shenyang 110122, PR China. FAU - Xi, Shuhua AU - Xi S AD - Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang 110122, PR China. Electronic address: shxi@cmu.edu.cn. LA - eng PT - Journal Article DEP - 20220110 PL - Netherlands TA - Sci Total Environ JT - The Science of the total environment JID - 0330500 RN - 0 (Metals, Heavy) SB - IM MH - *Adverse Outcome Pathways MH - Bayes Theorem MH - China MH - Environmental Monitoring MH - Hormesis MH - Humans MH - *Hypertension/chemically induced MH - *Metals, Heavy/toxicity OTO - NOTNLM OT - Adverse outcome pathways OT - Co-exposure OT - Hormesis OT - Hypertension OT - Metallomics OT - Regulatory network COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/01/14 06:00 MHDA- 2022/03/05 06:00 CRDT- 2022/01/13 20:16 PHST- 2021/09/29 00:00 [received] PHST- 2022/01/03 00:00 [revised] PHST- 2022/01/06 00:00 [accepted] PHST- 2022/01/14 06:00 [pubmed] PHST- 2022/03/05 06:00 [medline] PHST- 2022/01/13 20:16 [entrez] AID - S0048-9697(22)00129-2 [pii] AID - 10.1016/j.scitotenv.2022.153039 [doi] PST - ppublish SO - Sci Total Environ. 2022 Apr 15;817:153039. doi: 10.1016/j.scitotenv.2022.153039. Epub 2022 Jan 10.