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Biales AD, Bencic DC, Flick RW, et al. Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG). Toxicon X. 2020;8:100060doi: 10.1016/j.toxcx.2020.100060.
Biales, A. D., Bencic, D. C., Flick, R. W., Delacruz, A., Gordon, D. A., & Huang, W. (2020). Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG). Toxicon: X, 8100060. https://doi.org/10.1016/j.toxcx.2020.100060
Biales, Adam D, et al. "Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG)." Toxicon: X vol. 8 (2020): 100060. doi: https://doi.org/10.1016/j.toxcx.2020.100060
Biales AD, Bencic DC, Flick RW, Delacruz A, Gordon DA, Huang W. Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG). Toxicon X. 2020 Oct 07;8:100060. doi: 10.1016/j.toxcx.2020.100060. eCollection 2020 Dec. PMID: 33235993; PMCID: PMC7670210.
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Toxicon X. 2020 Oct 07;8:100060. doi: 10.1016/j.toxcx.2020.100060. eCollection 2020 Dec.

Global transcriptomic profiling of microcystin-LR or -RR treated hepatocytes (HepaRG).

Toxicon: X

Adam D Biales, David C Bencic, Robert W Flick, Armah Delacruz, Denise A Gordon, Weichun Huang

Affiliations

  1. U.S. Environmental Protection Agency, Office of Research and Development, Cincinnati, OH, 45268, USA.
  2. U.S. Environmental Protection Agency, Office of Research and Development, Research Triangle Park, NC, 27709, USA.

PMID: 33235993 PMCID: PMC7670210 DOI: 10.1016/j.toxcx.2020.100060

Abstract

The canonical mode of action (MOA) of microcystins (MC) is the inhibition of protein phosphatases, but complete characterization of toxicity pathways is lacking. The existence of over 200 MC congeners complicates risk estimates worldwide. 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 for 2 h. Significant reduction in cell survival was observed in LR1000 and LR100 treatments whereas no acute toxicity was observed in any MR-RR treatment. RNA-seq was performed on all treatments of MC-LR and -RR. Differentially expressed genes and pathways associated with oxidative and endoplasmic reticulum (ER) stress, and the unfolded protein response (UPR) were highly enriched by both congeners as were inflammatory pathways. Genes associated with both apoptotic and inflammatory pathways were enriched in LR1000. We present a model of MC toxicity that immediately causes oxidative stress and leads to ER stress and the activation of the UPR. Differential activation of the three arms of the UPR and the kinetics of JNK activation ultimately determine whether cell survival or apoptosis is favored. Extracellular exosomes were enrichment of by both congeners, suggesting a previously unidentified mechanism for MC-dependent extracellular signaling. The complement system was enriched only in MC-RR treatments, suggesting congener-specific differences in cellular effects. This study provided an unbiased snapshot of the early systemic hepatocyte response to MC-LR and MC-RR congeners and may explain differences in toxicity among MC congeners.

© 2020 Published by Elsevier Ltd.

Keywords: ER stress; Gene expression; Hepatocytes; MC-LR; MC-RR; Microcystin-LR; Microcystin-RR; Oxidative stress; RNA-seq; Transcriptomics

Conflict of interest statement

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.

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