Table 2.
In vitro toxicity of emerging Fusarium and Alternaria mycotoxins.
| Cell Line | Mycotoxin | Exposure Time | Exposure Dose (µM) | Effect | Reference |
|---|---|---|---|---|---|
| Caco-2 a | BEA | 0 min | 1.5 | ROS b generation | [5,6,56,66,67] |
| 24–72 h | IC50: 20.6–3.2 µM (MTT c); IC50: 8.8–1.9 µM (NR d) | ||||
| 24–72 h | 1.5–3.0 | LPO e, ↓ GSH, ↑ GSSG, loss of mitochondrial membrane potential, cell cycle arrest in S and G2/M, apoptosis and necrosis | |||
| 24 h | 12 | DNA damage | |||
| ENN A | <1 h | 1.5–3.0 | ROS generation | ||
| 24–72 h | IC50: 9.3–0.46 µM | ||||
| 24–72 h | 1.5–3.0 | LPO, loss of mitochondrial membrane potential, cell cycle arrest in SubG0/G1 and (Sub)G2/M, DNA damage, apoptosis and necrosis | |||
| ENN A1 | 10 min | 1.5 | ROS generation | ||
| 24–72 h | IC50: 12.3–0.46 µM | ||||
| 24–72 h | 1.5–3.0 | LPO, loss of mitochondrial membrane potential, DNA damage, cell cycle arrest in (Sub)G0/G1 and G2/M, apoptosis, necrosis | |||
| ENN B | 10 min | 3.0 | ROS generation | ||
| 48–72 h | IC50: 10.7–1.4 µM | ||||
| 24–72 h | 1.5–3.0 | LPO, loss of mitochondrial membrane potential, cell cycle arrest in (Sub)G0/G1, and G2/M, apoptosis, necrosis | |||
| ENN B1 | 5–10 min | 1.5–3.0 | ROS generation | ||
| 48–72 h | IC50: 10.8–0.8 µM | ||||
| 24–74 h | 1.5–3.0 | LPO, loss of mitochondrial membrane potential, DNA damage, cell cycle arrest in (Sub) G0/G1, G2/M and S, apoptosis, necrosis | |||
| MON | 72 h | IC50: 30.9 µg/mL | |||
| AOH | 24 h | 15–30 | changes in MMP f, ↓ G1 phase, ↑ S and G2/M phase, apoptosis, necrosis | ||
| HT-29 g | ENN A | 24–48 h | IC50: 9.3–8.2 µM | [56] | |
| ENN A1 | 24–48 h | IC50: 9.1–1.4 µM | |||
| ENN B | 24–48 h | IC50: ≥2.8 µM | |||
| ENN B1 | 24–48 h | IC50: 16.8–3.7 µM | |||
| HCT116 g | AOH | IC50, 24h: 65 µM ↓ early apoptotic and late apoptotic/necrotic cells, ROS generation PTP h-dependent MMP caspase-cascade activation, activation of p53 protein expression |
[68,69] | ||
| AME | IC50, 24h: 120 µM apoptotic cell death, PTP-opening, induction of MMP, cytochrome c release caspase-cascade activation, ↑ p53 protein, ROS generation |
||||
| IPEC-J2 i | BEA | 24–72 h | 5–10 | TEERj reduction (between −59% and −80%), no reduction of cell viability | [59] |
| ENN A | 72 h | 5 | TEER reduction (−70%), no reduction of cell viability | ||
| ENN A1 | 24–72 h | 10 | TEER reduction (between −29% and −74%), no reduction of cell viability | ||
| ENN B | 48–72 h | 2.5 | TEER reduction (between −55% and −68%), no reduction of cell viability | ||
| ENN B1 | 48–72 h | 5 | TEER reduction (between −44% and −58%), no reduction of cell viability | ||
| ENN combinations | 1.5 | additive effect on TEER reduction | |||
| MON | 72 h | 5–10 | no effect on TEER or viability | [59] | |
| Hep-G2 k | ENN A | 24–48 h | IC50: 26.2–11.4 µM | [56,66] | |
| ENN A1 | 24–48 h | IC50: 11.6–2.6 µM | |||
| ENN B | 24–48 h | IC50: >30 µM | |||
| ENN B1 | 24–48 h | IC50: 24.3–8.5 µM | |||
| MON | 48–72 h | IC50: 39.5–24.1 µg/mL | |||
| H295R l | ENN B | 72 h | 10–100 | ↓ viability by 37%, ↑ S-phase, ↓ G0/G1phase, ↑ apoptosis ↓ HMGR, STAR, CYP11A, HSD3B2, CYP17A1 ↑ CYP1A1, MC2R, NR0B1, CYP21A2, CYP11B1, CYP19 ↓ progesterone, testosterone and cortisol; estradiol unaffected |
[63,70,71] |
| AOH | 3.87 | no influence on viability ↑ 7 proteins (FDX1, HSD3B, CYP21A2, SCAMP3, SOAT1, ARF6, RRP15) ↓ 15 proteins (ACTBL2, NUCKS1, EIF2B5, COX2, CRMP1, ABHD14A-ACY1, ATP5J, ACSF2, HN1, ETHE1, HIST1H1E, ACBD5, NPC1, NR5A1, TOMM7) upregulation mRNA for CYP21A2 and HSD3B ↑ G0/G1 and ↑ G2/M phase |
|||
| H29R l | AOH | no effect on testosterone and cortisol levels ↑ progesterone and estradiol levels ↓ NR0B1 gene ↑ CYP1A1, MC2R, HSD3B2, CYP17, CYP21, CYP11B2, CYP19 |
[72] | ||
| neonatal Leydig cells | ENN B | 10–100 | ↓ viability by 20%, ↓ estradiol in unstimulated cells ↓ estradiol and testosterone in LH stimulated cells, probably due to cytotoxicity |
[63] | |
| human breast adenocarcinoma RGA cell line | AOH | agonistic estrogen response, relative estrogenic potential: 0.0004% and equivalent estrogenic quantity of 17β-estradiol: 2.9 fg/mL | [72] | ||
| cell free buffer | AOH | binding affinity to ERα: 10,000× lower compared to 17β-estradiol binding affinity to ERβ: 2500× lower compared to 17β-estradiol similar EC50 |
[73] | ||
| Ishikawa human endometrial adenocarcinoma cell line | AOH | 2.5–10 | ↑ alkaline phosphatase mRNA and activity ↓ G1 phase and ↑ S and G2/M phase ↓ cell number due to inhibition of proliferation |
[73] | |
| porcine oocytes and embryos | BEA | >0.5 | ↓ rate of development of maturing oocyte and 2–4 cell stage embryo, activated oocytes and 2–4 cell stage embryos more sensitive than maturing oocytes, compromised cytoplasmic maturation and abnormal meiosis in oocytes, ↓ cumulus viability and progesterone synthesis, cumulus cells control intracellular BEA through MDR1 activity, in oocytes mitochondrial function was altered, altered gene expression in cumulus cells and oocytes, altered MDR1 activity in activated oocytes, ↓ viability embryo | [61] | |
| pig granulosa cells | AOH | 0.8–1.6 | ↓ cell viability, ↓ progesterone levels, ↓ P450scc ↓ α-tubulin, actin and EIF4a |
[71] | |
| AME | 0.8–1.6 | ↓ cell viability, ↓ progesterone levels, ↓ P450scc | |||
| TeA | 6.4–100 | no influence on viability no influence on progesterone concentrations |
|||
| bovine granulosa cells | BEA | 3 | ↓ estradiol and progesterone production ↓ CYP11A1 and CYP19A1 mRNA |
[62] | |
| 6–10 | ↓ (fetal calf serum-induced) proliferation | ||||
| CHO-K1 m | BEA | 24–72 h | IC50: 10.7–2.2 µM combination of BEA + PAT n, BEA + STG o, BEA + PAT + STG: synergistic effect at low (IC < 1), additive effect at higher (IC 0.6–5.9) doses |
[52,66,74] | |
| ENN A | 24–72 h | >7.5–2.83 µM | |||
| ENN A1 | 24–72 h | 8.8–1.65 µM | |||
| ENN B | 24–72 h | 11.0–2.44 µM | |||
| ENN B1 | 24–72 h | 4.53–2.47 µM | |||
| ENN combinations | 24 h | additive effects: A + B1, A1 + B, B + B1 synergistic effects: A + A1, A + B, A1 + B1, A1 + B1, A + A1 + B, A + A1 + B1, A1 + B + B1 (higher concentrations) antagonistic effects: A + A1 + B1, A1 + B +B1 (lower concentrations) |
|||
| MON | IC50: >100 µg/mL | ||||
| THP-1 p monocyte | AOH | 24–48 h | 7.5–15 | cell cycle arrest in S- and G2/M-phase | [55] |
| ↓ CD14 and CD11b upregulation during macrophage differentiation | |||||
| ↓ downregulation of CD71 during macrophage differentiation, ↓ TNF-α secretion due to ↓ gene expression |
|||||
| +DON: additive effect +ZEA: synergistic effect on macrophage differentiation |
|||||
| CCRF-CEM q | BEA | 24 h | 1 | cytotoxicity, apoptosis | [54] |
| human lymphocytes | MON | 48 h | 10–25 15–25 |
chromosome breaks, chromatid breaks and exchanges, polyploidy, increase in sister chromatid exchanges and micronuclei frequency all effects were dose-dependent |
[8] |
| human immature dendritic cells | BEA | IC50: 1.0 µM | [53] | ||
| ENN B | IC50: 1.6 µM | ||||
| MON | 80 | 20% mortality, ↓ endocytosis, ↓ CD1a expression | |||
| human mature dendritic cells | BEA | IC50: 2.9 µM, ↓ CCR7 expression, ↑ IL-10 concentration | [53] | ||
| ENN B | IC50: 2.6 µM, ↓ CD80, CD86 and CCR7 expression, ↑ IL-10 | ||||
| MON | 80 | 20% mortality | |||
| human macrophages | BEA | ≥0.5 | IC50: 2.5 µM, ↓ endocytosis | [53,75] | |
| ENN B | IC50: 2.5 µM, ↓ endocytosis, ↑ CD71 | ||||
| MON | ↓ endocytosis, ↓ CD71, ↓ HLA-DR | ||||
| AOH | 24 h | 30 | changed morphology: from round to elongated with dendrite-like protrusions ↑ CD83 and CD86 ↓ HLA-DR and CD68 ↑ secretion of TNFα and IL-6 ↓ endocytosis and ↓ autophagy double DNA strand breaks |
||
| RAW 2654.7 mouse macrophage | AOH | 24–48 h | 30 | changed morphology: from round to flattened, star-shaped or elongated spindle-shaped cells micronuclei, polyploidy, ↑ CD86, CD80, MHCII (T cell activation), ↑ CD11b ↑ mRNA of TNFα and IL-6, but only ↑ TNFα secretion, ↑ endocytosis |
[75] |
| mouse hemidiaphragm preparation | BEA | 5 | inhibition (in) directly elicited tetanic muscle contraction; inhibition nerve-evoked and directly elicited muscle twitches, reduction amplitude and frequency of miniature endplate potentials | [60] | |
| 1 h | 7.5 | inhibition directly elicited twitches, induction contracture, decrease resting membrane potential | |||
| 1 h | 10 | complete block of (in) directly elicited isometric muscle contraction, amplitude reduction of directly elicited muscle twitch, decrease resting membrane potential | |||
| C5-O r | MON | 72 h | IC50: 34.2 µg/mL | [66] | |
| V79 s | MON | 72 h | IC50: >100 µg/mL | [62,66,73] | |
| AOH | 5–50 | induction of micronuclei cell cycle arrest in G2 and S phase |
↓ decrease; ↑ increase; a human adenocarcinoma colon cells; b reactive oxygen species; c tetrazolium salt reduction assay; d Neutral Red assay; e lipid peroxidation; f mitochondrial membrane permeabilization; g human colon carcinoma cells; h permeability transition pore; i intestinal porcine epithelial cells from the jejunum; j transepithelial electrical resistance; k human hepatocellular carcinoma cells; l human adrenocortical carcinoma cells; m Chinese hamster ovary cells; n patulin; o sterigmatocystin; p human acute monocyte leukemia cell line; q human leukemia cells; r Balb/c mice keratinocyte cells; s Chinese hamster lung fibroblast.