You are here:
Characterization of Microcystin-Induced Toxicity on Primary Human Hepatocytes
Citation:
Richardson, V., J. Strasser, AND E. Hilborn. Characterization of Microcystin-Induced Toxicity on Primary Human Hepatocytes. International Conference on Harmful Algae (ICHA), Virtual, NC, October 10 - 15, 2021. https://doi.org/10.23645/epacomptox.21095155
Impact/Purpose:
Presentation to the International Conference on Harmful Algae (ICHA) October 2021. This study investigates the cytotoxic effects of hydrophobic and hydrophilic microcystin congeners on primary human hepatocytes. The data show that hydrophobic microcystin congeners are more toxic than hydrophillic congeners. Although cell viability appears to correlate with the degree of hydrophobicity of the congener, protein phosphatase 2A (PP2A) inhibition appears to be independent of hydrophobicity. These results suggest PP2A inhibition plays an important role in microcystin-induced hepatotoxicity.
Description:
The amino acid composition of microcystins (MCs) can determine the structural, physical, and chemical characteristics including hydrophilicity and is thought to influence the toxicokinetic and toxicodynamic profiles of each congener. In this study, the effects of the more hydrophobic (LA, LF, LW, LY) and the more hydrophilic (LR, RR, WR, YR) congeners on cell viability, reactive oxygen species (ROS) production, glutathione (GSH) depletion, and protein phosphatase 2A (PP2A) inhibition were determined using primary human hepatocytes (HH). 24 hours after plating, HH were exposed to LR, LW, LA, LF, LY, WR, YR, or RR (0 to 20 µM) for up to 24 hours. EC50s from cell viability studies were used to determine the cytotoxic potency of each MC congener: the rank order for cytotoxic potency was LY>LW>LA>WR>LF>LR>YR>RR. HH were assayed for ROS, GSH or PP2A activity after exposure to each congener at their respective EC50 (≤0.2 µM) concentrations, as determined in the viability studies. ROS and GSH were unchanged; however, PP2A activity was inhibited by every congener. The decreased PP2A activity correlated with decreased cell viability (r2=0.83; p=0.002). This study shows that the more hydrophobic congeners caused a greater decrease in cell viability, compared to the more hydrophilic congeners. Correlations in cell viability and PP2A activity inhibition suggest that PP2A inhibition is an important marker of cytotoxicity in HH exposed to low concentrations of MCs. Coupled with kinetic data on MC uptake and distribution, our results provide an enhanced understanding of the potential toxic effects produced by these congeners in vivo. [This abstract does not represent EPA policy.]
URLs/Downloads:
DOI: Characterization of Microcystin-Induced Toxicity on Primary Human Hepatocytes
RICHARDSON_ICHA 2021_FINAL2.PDF (PDF, NA pp, 557.795 KB, about PDF)