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Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG).
Citation:
Biales, A., D. Bencic, R. Flick, A. Delacruz, D. Gordon, AND W. Huang. Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG). Toxicon: X. Elsevier B.V., Amsterdam, Netherlands, 8:100060, (2020). https://doi.org/10.1016/j.toxcx.2020.100060
Impact/Purpose:
The article describes the molecular response of hepatocytes treated with two congeners of microcystins. The article presents new information and provides a more complete picture of the response
Description:
Microcystins (MC) are toxins found in harmful algal blooms. The canonical MC mode of action (MOA) is the inhibition of protein phosphatases, but complete characterization of its toxicity pathway has yet to be identified. The existence of 100s of MC structural congeners further complicates risk estimates. This work employed RNA-seq to provide an unbiased and comprehensive characterization of cellular targets and impacted cellular processes of hepatocytes exposed to either MC-LR or MC-RR congeners. The human hepatocyte cell line, HepaRG, was treated with three concentrations of MC-LR or -RR (1000, 100, 10 μg/L) for two hours. Significant reduction in cell survival was observed in the LR1000 and 100 treatments. RNA-seq was performed on controls and all concentrations of MC-LR and -RR and differentially expressed genes (DEGs) were identified. Genes and pathways associated with oxidative and endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) were highly enriched by both congeners. Enrichment of inflammatory pathways was also evident. In the cytotoxic LR1000 treatment, apoptotic pathways and related genes were identified, suggesting cells pursue both inflammation and apoptosis simultaneously and that cellular fate may be determined by the activation kinetics of Jun N-terminal kinase (JNK). We present a model of MC toxicity where MCs cause the production of reactive oxygen species (ROS) and oxidative stress leading to ER stress and activation of the UPR. Under non-cytotoxic conditions this leads to an inflammatory and pro-survival cellular response mediated through up-regulation and activation of NF-κΒ and its inhibition of JNK. With acute MC exposure, increased ER stress results in the cellular program switching to favor apoptosis by inhibiting NF-κΒ resulting in sustained JNK activation and through the activation of C/EBP homologous protein (CHOP) via the protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the UPR.
URLs/Downloads:
DOI: Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG).