Microcystin Congener– and Concentration-Dependent Induction of Murine Neuron Apoptosis and Neurite Degeneration

Abstract

Cyanobacterial microcystins (MCs) represent a toxin group with > 100 variants, requiring active uptake into cells via organic anion-transporting polypeptides, in order to irreversibly inhibit serine/threonine-specific protein phosphatases. MCs are a human health hazard with repeated occurrences of severe poisonings. In the well-known human MC intoxication in Caruaru, Brazil (1996), patients developed signs of acute neurotoxicity, e.g., deafness, tinnitus, and intermittent blindness, as well as subsequent hepatotoxicity. The latter data, in conjunction with some animal studies, suggest that MCs are potent neurotoxins. However, there is little data to date demonstrating MC neuron-specific toxicity. MC exposure-induced cytotoxicity, caspase activity, chromatin condensation, and microtubule-associated Tau protein hyperphosphorylation (epitopes serine199/202 and serine396) were determined. Neurite degeneration was analyzed with confocal microscopy and neurite length determined using image analysis. MC-induced apoptosis was significantly increased by MC-LF and MC-LW, however, only at high concentrations (≥ 3μM), whereas significant neurite degeneration was already observed at 0.5μM MC-LF. Moreover, sustained hyperphosphorylation of Tau was observed with all MC congeners. The concentration- and congener-dependent mechanisms observed suggest that low concentrations of MC-LF and MC-LW can induce subtle neurodegenerative effects, reminiscent of Alzheimer's disease type human tauopathies, and thus should be taken more seriously with regard to potential human health effects than the apical cytotoxicity (apoptosis or necrosis) demonstrated at high MC concentrations.

The role of apoptosis in MCLR-induced developmental toxicity in zebrafish embryos

“…In the present study, the gene transcription and activity of caspase-3, caspase-8 and caspase-9 were greatly increased. Our results are consistent with earlier reports that the induction of caspases were detected in MCLR-induced apoptosis in rat testis, mouse liver and murine neuron Xiong et al, 2009;Feurstein et al, 2011). Taken together, we may speculate that these results indicate that that caspase-dependent apoptotic pathway may contribute greatly to the MCLR-induced apoptosis in the early-life stages of zebrafish.…”

A review of reproductive toxicity of microcystins

“…Different MC variants have varied biological affinities i.e., their potential to enter a certain tissue would be different depending on the affinity of the cell transporters for that MC variant [150][151][152]. Moreover, distinct properties of MC variants in terms of PP1 and PP2A inhibition, cytotoxicity, biotransformation, and detoxification have also been reported [152][153][154][155][156]. However, at present, the toxicological database for MCs is almost exclusively limited to data on a single variant, MC-LR, while data on the other variants is very lacking.…”

Mechanisms of Microcystin-induced Cytotoxicity and Apoptosis

“…Many of these cellular events ultimately lead to cell death. MCs were found to induce apoptosis in a variety of cell types, including hepatocytes [36], lymphocytes [37], neuron [38] and kidney epithelial cells [32].…”