Association between blood metals mixture and chronic kidney disease in adults: NHANES 2013-2016.

BACKGROUND: The association between single metal exposure and chronic kidney disease (CKD) has been established. However, there is limited research on the effects of multi-metal mixtures and their potential age-specific associations with kidney injury. This study aimed to examine the relationship between metal mixtures and kidney function in adults, while also exploring the modifying effects of age. METHODS: We included a subset (n = 4250) of a nationally representative adult population in the National Health and Nutrition Examination Survey (NHANES) 2013-2016. Kidney function was assessed using the glomerular filtration rate (eGFR) and creatinine albumin ratio (ACR). The individual and combined effects of lead (Pb), cadmium (Cd), mercury, and manganese on kidney injury and the risk of CKD were evaluated. RESULTS: Pb and Cd were found to be positively associated with decreased kidney function. For a one Ln-unit increase in lead and cadmium, the adjusted ORs of CKD were 1.60 (95% CI: 1.35, 1.90) and 1.41 (95% CI:1.12, 1.77), respectively. We also observed an interaction between lead and cadmium for ACR. We also observed the joint effect between Pb and Cd on eGFR, ACR and CKD. Stratified analysis found a higher risk of decreased kidney function among older individuals. The quantile-g calculation model further showed that metal mixture was associated with decreased kidney function and the risk of CKD (OR = 1.53, 95% CI: 1.22, 1.90). And lead and cadmium were the main contributors. And Pb and Cd were the major components that increased the risk of CKD. CONCLUSION: Co-exposure to metal mixture were associated with reduced kidney function in adults, especially in older. Our findings support co-exposure to lead and cadmium as risk factors of CKD in adults.

Herpesvirus activated NF-κB-mediated antigen processing and presentation to aggravate trichloroethylene-induced hypersensitivity dermatitis.

Trichloroethylene-induced hypersensitivity dermatitis (TIHD) is a delayed hypersensitivity response that is affected by genetic and environmental factors. Occupational exposure to trichloroethylene (TCE) enhances antigen presentation, leading to hypersensitivity in workers with the HLA-B* 13:01 allele. Several studies have observed the activation of herpesviruses, such as EpsteinBarr virus (EBV), in TIHD patients. However, the underlying mechanisms remain unclear. Toll-like receptors (TLRs) play a pivotal role in the pathogenesis of herpesvirus infection. This study aimed to explore whether TLRs serve as a shared mechanism for both herpesvirus and allergenic chemicals. In this study, HLA-B* 13:01-transfected Hmy2. A C1R cell model was constructed, and cells were treated with TCOH and EBV to explore the possible mechanisms. We established a mouse model of dermatitis and used a TLR4 agonist to verify the effect of herpesvirus on TIHD. The results showed that EBV and TCOH synergistically enhance antigen processing and presentation via the TLR2/NF-κB axis. Furthermore, TLR4 agonist further aggravated skin lesions and liver damage in TCE-sensitized mice through TLR4/NF-κB axis-mediated antigen processing and presentation. Together, this study indicates that viral infection further aggravates the inflammatory response in TIHD based on environment-gene interactions.

Effect of trichloroethanol on TLR2 and TLR4/NF-κB-mediated antigen processing and presentation in HLA-B* 13:01-transfected antigen-presenting cells.

Trichloroethanol (TCOH), as a metabolite of trichloroethylene, has sensitization in the pathogenesis of trichloroethylene-induced hypersensitivity dermatitis (TIHD) which the human leukocyte antigen (HLA)-B∗13:01 gene is strongly associated with it. However, it is still obscure how TCOH participates in the pathogenesis of TIHD. Here, we demonstrate that TLR2 and TLR4 signaling through MyD88 and TRAF6-dependent pathway could activate NF-κB by promoting degradation of the inhibitor IκB-α to stimulate the process of NF-κB nuclear translocation. Besides, the crucial molecules of antigen processing and presentation, including TAP1, LMP2, LMP7, and HLA-B* 13:01, were all enhanced and the abundance of HLA-B* 13:01 on the surface of CIR-B* 13:01 cells was also up-regulated with the TCOH concentration increasing. Notably, we used 50 µM pyrrolidinedithiocarbamate (ammonium) to effectively inhibit the activation of NF-κB, which could effectively reverse the stimulation of antigen processing and presentation in TCOH-treated CIR-B* 13:01 cells. Taken together, we speculated that TCOH could promote the abundance of HLA complex on the antigen-presenting cells via TLR2 and TLR4/NF-κB to induce the severe reactivation of T lymphocytes, leading to the extreme immune response.

Occupational health effect of TCE exposure: Experiment evidence of gene-environment interaction in hypersensitivity reaction.

BACKGROUND: Recently, Trichloroethylene (TCE) induced TCE hypersensitivity syndrome (THS) has attracted the attention of many researchers in the field of environmental and occupational health. Studies have revealed that Human leukocyte antigen (HLA) polymorphisms were the important genetic determinants of the diseases, but the potential molecular mechanism remains unclear. OBJECTIVE: This study aimed to investigate the association between THS and HLA at the molecular level. METHOD: We chose the human B-lymphoblastoid cell line Hmy2.C1R transfected with cDNA of HLA-B*13:01 and HLA-B*13:02 to analyze the characteristics of HLA-B-binding peptides and investigate the effect of TCE on the binding affinity of peptides to the HLA-B molecules. Further, the mathematical model was used to identify the possible interaction between TCE and HLA-B*13:01 or HLA-B*13:02 molecule. RESULTS: 54 HLA-B*13:01-binding peptides and 85 HLA-B*13:02-binding peptides were identified. Comparing the protein sequences of HLA-B*13:01 and HLA-B*13:02, amino acids were different at positions 94, 95 and 97. The results of the binding affinity of self-peptides to HLA molecules in the presence of TCE showed that TCE significantly decreased the binding affinity of peptides to HLA-B*13:01 only, but did not affect that of HLA-B*13:02. Molecular docking model showed that there was a unique high-affinity binding mode between TCE and HLA-B*13:01 (but not HLA-B*13:02), and the binding site located in the region of F pocket, suggesting that the unique structure of the F pocket of HLA-B*13:01 might provide the possibility of binding TCE. The pathogenesis of interaction between HLA-B*13:01 and TCE might belong to the model of the alteration of the HLA-presented self-peptide repertoire. DISCUSSION: This study explored the molecular mechanism of the association between THS and HLA-B*13:01, and had important implications for understanding the role of gene-environment interaction in the development of complex environment-related diseases.