Temporal transcriptomic alterations of cadmium exposed human iPSC-derived renal proximal tubule-like cells. (October 2021)

• Record Type: Journal Article
• Authors: Singh, Pranika; Chandrasekaran, Vidya; Hardy, Barry; Wilmes, Anja; Jennings, Paul; Exner, Thomas E.
• Is Part Of: Toxicology in vitro. Volume 76(2021)
• Publication Date: 2021-10
• Subjects: HSPA6 -- Metallothionein -- iPSC -- In vitro -- Cadmium -- Metal responsive transcription factor-1 -- Temporal expression patterns -- Proximal tubules -- Nuclear factor erythroid-2-related factor 2; iPSC induced pluripotent stem cell -- Nrf2 Nuclear factor erythroid-2-related factor 2 -- MTF1 Metal-responsive transcription factor-1 -- AP-1 Activator Protein 1 -- PTL Proximal tubule-like cells -- LFC Log fold change -- ER Endoplasmic Reticulum Stress -- IPA Ingenuity Pathway Analysis -- RC Read count; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2021.105229
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Cadmium is a well-studied environmental pollutant where the kidney and particularly the proximal tubule cells are especially sensitive as they are exposed to higher concentrations of cadmium than other tissues. Here we investigated the temporal transcriptomic alterations (TempO-Seq) of human induced pluripotent stem cell (iPSC)-derived renal proximal tubule-like (PTL) cells exposed to 5 μM cadmium chloride for 1, 2, 4, 8, 12, 16, 20, 24, 72 and 168 h. There was an early activation (within 4 h) of the metal and oxidative stress responses (metal-responsive transcription factor-1 (MTF1) and nuclear factor erythroid-2-related factor 2 (Nrf2) genes). The Nrf2 response returned to baseline within 24 h. The Activator Protein 1 (AP-1) regulated genes HSPA6 and FOSL-1 followed the Nrf2 time course. While the MTF1 genes also spiked at 4 h, they remained strongly elevated over the entire exposure period. The data and cell culture model utilised will be useful in further research aimed at the refinement of safe human exposure limits for cadmium, other metals and their mixtures. Highlights: Human induced pluripotent stem cell (IPSC) derived renal proximal tubules for investigating stress response pathways. Temporal profiles investigate the early and sustained responses. MTF1 pathway is activated early and some genes reach log2 fold changes (LFCs) of up to 11 at 6 h and sustain until 168 h. Nrf2 induced oxidative stress pathway shows some genes reaching LFCs ofoup to 4 at 6 h but returns to baseline by 24 h.