1. Academic Validation
  2. Transcriptomics-based analysis of co-exposure of cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) indicates mitochondrial dysfunction induces NLRP3 inflammasome and inflammatory cell death in renal tubular epithelial cells

Transcriptomics-based analysis of co-exposure of cadmium (Cd) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) indicates mitochondrial dysfunction induces NLRP3 inflammasome and inflammatory cell death in renal tubular epithelial cells

  • Ecotoxicol Environ Saf. 2022 Aug;241:113790. doi: 10.1016/j.ecoenv.2022.113790.
Yi Zhang 1 Bo Hu 1 Xiaolan Qian 1 Guangtao Xu 2 Xin Jin 2 Deqing Chen 2 Jie Tang 3 Long Xu 4
Affiliations

Affiliations

  • 1 Department of Pathology and Key-Innovative Discipline Molecular Diagnostics, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China.
  • 2 Forensic and Pathology Laboratory, Department of Public Health, Department of Pathology, Institute of Forensic Science, Jiaxing University, Jiaxing 314001, Zhejiang, China.
  • 3 Department of Pathology and Key-Innovative Discipline Molecular Diagnostics, Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China. Electronic address: tjie1993@163.com.
  • 4 Forensic and Pathology Laboratory, Department of Public Health, Department of Pathology, Institute of Forensic Science, Jiaxing University, Jiaxing 314001, Zhejiang, China. Electronic address: xulong@zjxu.edu.cn.
Abstract

Environmental pollution often releases multiple contaminants resulting in as yet largely uncharacterized additive toxicities. Cadmium (Cd) is a widespread pollutant that induces nephrotoxicity in animal models and humans. However, the combined effect of Cd in causing nephrotoxicity with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a typical congener of polybrominated diphenyl ethers (PBDEs), has not been evaluated and mechanisms are not completely clear. Here, we applied transcriptome Sequencing analysis to investigate the combined toxicity of Cd and BDE-47 in the renal tubular epithelial cell lines HKCs. Cd or BDE-47 exposure decreased cell viability in a dose-dependent manner, and exhibited cell swelling and rounding similar to necrosis, which was exacerbated by co-exposure. Transcriptomic analysis revealed 2191, 1331 and 3787 differentially-expressed genes following treatment with Cd, BDE-47 and co-exposure, respectively. Interestingly, functional annotation and enrichment analyses showed involvement of pathways for oxidative stress, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammatory cell death for all three treatments. Examination of indices of mitochondrial function and oxidative stress in HKC cells showed that the levels of Reactive Oxygen Species (ROS), malondialdehyde (MDA) and intracellular calcium ion concentration [CA2+]i were elevated, while superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) were decreased. The ratio of apoptotic and necrotic cells and intracellular Lactate Dehydrogenase (LDH) release were increased by Cd or BDE-47 exposure, and was aggravated by co-exposure, and was attenuated by ROS scavenger N-Acetyl-L-cysteine (NAC). NLRP3 inflammasome and Pyroptosis pathway-related genes of NLRP3, adaptor molecule apoptosis-associated speck-like protein (ASC), Caspase-1, interleukin-18 (IL-18) and IL-1β were elevated, while gasdermin D (GSDMD) was down-regulated, and protein levels of NLRP3, cleaved Caspase-1 and cleaved GSDMD were increased, most of which were relieved by NAC. Our data demonstrate that exposure to Cd and BDE-47 induces mitochondrial dysfunction and triggers NLRP3 inflammasome and GSDMD-dependent Pyroptosis leading to nephrotoxicity, and co-exposure exacerbates this effect, which could be attenuated by inhibiting ROS. This study provides a further mechanistic understanding of kidney damage, and co-exposure impact is worthy of concern and should be considered to improve the accuracy of environmental health assessment.

Keywords

BDE-47; Cadmium; Inflammatory cell death; Mitochondrial dysfunction; Renal tubular epithelial cells; Transcriptomics.

Figures
Products