Abstract
Microcystins (MC) are a group of cyanobacterial toxins that comprises MC-LF and other cyclic heptapeptides, best known as potent hepatotoxicants. Cell culture and epidemiological studies suggest that MC might also affect the nervous system when there is systemic exposure, e.g., via drinking water or food. We asked whether in vitro studies with human neurons could provide estimates on the neurotoxicity hazard of MC-LF. First, we used LUHMES neurons, a well-established test system for neurotoxicants and neuropathological processes. These central nervous system cells express OATP1A2, a presumed carrier of MC-LF, and we observed selective neurite toxicity in the μM range (EC20 = 3.3 μM ≈ 3.3 μg/mL). Transcriptome changes pointed towards attenuated cell maintenance and biosynthetic processes. Prolonged exposure for up to four days did not increase toxicity. As a second model, we used human dorsal root ganglia-like neurons. These peripheral nervous system cells represent parts of the nervous system not protected by the blood-brain barrier in humans. Toxicity was observed in a similar concentration range (EC20 = 7.4 μM). We conclude that MC-LF poses a potential neurotoxic hazard in humans. The adverse effect concentrations observed here were orders of magnitude higher than those presumed to be encountered after normal nutritional or environmental exposure. However, the low μM concentrations found to be toxic are close to levels that may be reached after very excessive algae supplement intake.
Highlights
While microcystins (MCs) are widely known for their acute hepatotoxicity (Carmichael, 1992; Nishiwaki-Matsushima et al, 1992), their potentially adverse effects on other target organs, such as the nervous system, are less clear
3.1 Neurotoxicity of MC-LF, assessed on LUHMES neurons LUHMES neurons differentiated for 4-6 days are fully post-mitotic (Scholz et al, 2011) but show many features of central nervous system cells (Tong et al, 2018; Gutbier et al, 2018; Matelski et al, 2020; Weng et al, 2012, 2014)
The cells were confirmed to be positive for OATP1A2, a transporter that accepts microcystins (MCs) as substrate (Fig. 1A) (Fischer et al, 2005; Chen and Xie, 2016)
Summary
While microcystins (MCs) are widely known for their acute hepatotoxicity (Carmichael, 1992; Nishiwaki-Matsushima et al, 1992), their potentially adverse effects on other target organs, such as the nervous system, are less clear. MCs are small cyclic heptapeptides comprised of 5 D- and 2 L-amino acids (cyclo-D-Ala1-X2-D-MeAsp3-Z4-Adda5-D-Glu6-Mdha). Structural variation of side-chains has been encountered in all seven positions, but the most variable amino acids (X and Z) are the L-amino acids in positions 2 and 4 (Botes et al, 1984; Daneshian et al, 2013). These variable L-amino acid residues are used for naming of the MC congeners, of which more than 248 different congeners are known to date (Altaner et al, 2019; Spoof and Catherine, 2016). A number of ubiquitously present cyanobacteria genera, e.g., Microcystis, Planktothrix, Anabaena and Dolichospermum, have been shown to produce MC (Svirčev et al, 2019)
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