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Table 2 Overview of microcystin effects on the gastrointestinal tract and/or the (gut-associated) immune system

From: Effects of cyanobacterial toxins on the human gastrointestinal tract and the mucosal innate immune system

Experimental Model Assays performed, endpoint Exposure conditions, concentration ranges Affected tissue(s) of interest Main results References
In vivo
Mouse (ICR, female) Radionuclide recovery 3H-dihydro MC-LR, 70-µg/kg bw (i.p.); detection after 3–90 min Stomach, small intestine, large intestine, gastrointestinal tract Detection of exposure-linked radioactivity in the gastrointestinal tract (≈37.6% of the total administered dose), especially in small intestine (6.4%) [5, 115]
Mouse (aged Balb/C, ICR) Immunohistochemistry MC-LR, 500-µg/kg bw (p.o.); 1–13 weeks Stomach, small intestine, caecum Especially small intestine (villi and lamina propria) stained highly immunopositive; erosion of small intestine [89]
Mouse (Balb/C, s.p.f., 7-week-old female) Histology, immunohistochemistry 75% of MC-LR LD50 (i.p.), 8–32 h Small intestine Apoptotic indices after 32-h exposure: 4.25 ± 0.125% (duodenum), 2.5 ± 0.125% (jejunum), 1.75 ± 0.125% (ileum) [93]
Mouse (N:NIH-S, male) Phosphatase inhibition assay MC-LR, 50-µg/kg bw (p.o.) every 48 h, 30 days Gut-associated lymphoid tissue Decrease of intraepithelial lymphocytes by 28.7% ± 5.0% [95]
Mouse (Swiss albino, female) Comet assay (single-cell gel electrophoresis; DNA damage) 10 mL/kg bw (p.o. or i.p.), 3–24 h. oral doses: 2–4-mg MC-LR/kg bw; i.p. doses: 10–50 µg MC-LR/kg bw. Blood, liver, kidney, small intestine (ileum), large intestine (colon) DNA damage induced in intestinal tissues (ileum and colon) may contribute to increased cancer risk [92]
Rat (Wistar) Determination of MC-LR toxicokinetics by histopathology and LC–MS detection MC-LRequivalent, 80 µg/kg bw (i.v.); 1–24 h Stomach Detection of MC in different tissues upon intravenous gavage; 0.010–0.058-μg/g dry weight MC-LRequivalent in the stomach [116]
Fish (medaka) Immunohistochemistry 5-µg/g MC-LR bw (p.o., direct administration to the fish stomach), 2 h Gut-associated lymphoid tissue, intestine (submucosa) MC-positive staining of submucosa (penetration through the epithelium); disrupted cellular cohesion; MC-positive stained macrophages [108]
Human (fishermen) Epidemiology, cohort study, risk assessment MC-LRequivalent Whole organism Estimated daily intake: 2.2–3.9 µg;
LOEL, tolerated daily intake: 0.28 µg/kg bw/day
[41, 94]
In vitro
Human (CaCo-2) Apparent permeability of the pseudoepithelial cell layer to MC-LR 1–75 µM MC-LR; 0.5–24 h Intestine (colon) Apical-to-basolateral transport: 24–40% decrease in apical compartment/0.3–1.3% increase in basolateral compartment; low efflux from cellular to basolateral compartment. basolateral-to-apical transport: slow concentration decrease (basolateral, fast increase (apical); better efflux in basolateral-to-apical direction [100]
Human (CaCo-2) Immunolocalization (microcystin uptake) 1–50-µM MC-LR, -RR, 0.5–24 h Intestine (colon) Rapid uptake in less than 1 h of both variants (no difference in uptake profile); nuclear localization of MCs upon uptake; facilitated uptake (probably via OATPs) and active excretion [103]
Human (CaCo-2) Gene expression, transcriptomics 10–100 µM MC-LR, 4–24 h Intestine (colon) Major effects on oxidative stress, ERK/MAPK, and cell cycle pathways [102]
Human (CaCo-2) Bradford assay (cell number, protein content), neutral red uptake, MTS reduction (viability) MC-LR, -RR, -YR; 50–200 µM, 24–48 h Intestine (colon) EC50: reduction of total protein content: 111.1 ± 3-µM MC-LR (24 h), ˃200 µM MC-RR (48 h); neutral red uptake: 57.3-µM MC-YR (48 h) [97, 117]
Human (CaCo-2) MTT assay, Comet assay 0.2–10.1 µM MC-LR, 4–48 h Intestine (colon) 40% reduced cell viability upon 48-h exposure to 10-µM MC-LR (MTT assay), 19.6% damaged DNA after 4-h exposure to 0.2 µM MC-LR [98]
Human (CaCo-2) Lactate dehydrogenase (LDH) leakage (cytotoxicity), cell proliferation and morphology, protein phosphatase (PP) inhibition 1–50 µM MC-LR, -LF, LW, 22–48 h Intestine (colon) EC50: LDH leakage: 25% (50-µM MC-LR, control), 36% (MC-LW), 51% (MC-LF); PP inhibition: 3.0-nM MC-LF, 3.8-nM MC-LW, 1.0-nM MC-LR; apoptosis and morphological changes: membrane blebbing, cell shrinkage, chromatin condensation, cytoskeletal reorganization [91]
Human (IEC-6) CCK-8 (cell viability), apoptosis, trans-epithelial electric resistance (TEER), PP2A activity, western blot 0–50-µM MC-LR, 6–24 h Intestine (colon) LOEC/TEER: 50 µM (12 h), 12.5 µM (24 h); viability: 12.5 µM (24 h); apoptosis: 25 µM (24 h); western blot: 12.5 µM (24 h; occludin), 25 µM (24 h; ZO-1); PP2A activity: 12.5 µM (24 h) [118]
Human (NCC) Gene chip analysis, western blot, kinase activity assays, proliferation 0.1–1005-µM MC-LR, 28 d Intestine (colon) Neoplastic transformation; constitutive upregulation of signaling pathways (PI3K, APK2, Akt, cyclin D1 and D3), of Ras GTP/GDP proteins (IQGAP-2, RabGTPase, Rap1GAP, RasGAP, R-Ras, Krev-1, TC21) and Ras/MAPK pathway (A-Raf, B-Raf, PAK); decreased proliferation of MC-LR-transformed colorectal crypt cells [77]
Human (DLD-1, HT29) Western blot, RT-qPCR, gene knockdown by siRNA, cell migration 0.1–50-nM MC-LR, 24 h Intestine (colon) Motility acquired by epithelial-mesenchymal transition through exposure to 25-nM MC-LR (LOEC) in both colorectal cancer cell lines; MC-LR is likely to aggravate (colorectal) cancer development [75]
Mouse (Balb/C, isolated peritoneal macrophages) mRNA expression 1–1000-nM MC-LR + 100 µg/L LPS; 6 h Innate immune system Reduction/alleviation of LPS-induced inflammation [112]
Mouse (RAW 264.7, blood macrophages) Western blot, ELISA 1–1000 nM MC-LR, 0.5–24 h Innate immune system LOECs upon 24-h exposure to MC-LR for: MAPK (ERK1/2) activation (100 nM), NF-κB activation (1000 nM), TNF-α production (1 nM) [69]
Human (predominantly) Case study meta-analysis, review Various Various References to human intoxication cases, relation between esophagus cancer and human contact with cyanotoxins through the food chain requires further investigation [12]
  1. CYN: Cylindrospermopsin; EC50: half-maximal effective concentration; ERK: extracellular signal-regulated kinase; LD50: half-maximal lethal dose; LOAEL/NOAEL: lowest/no-observed adverse effect level; LOEC/NOEC: lowest/no-observed effect concentration; MAPK: mitogen-activated protein kinase; MC: microcystin; OATP: organic anion transporting polypeptide; NF-κB: nuclear factor κB; PP2A: protein phosphatase 2A; s.p.f.: special pathogen-free; TEER: trans-epithelial electrical resistance