Table 1.
The metabolic and immune shifts induced by mycotoxins (focusing on low concentrations).
| Mycotoxin | Effective dose, target | Effect | Major conclusion | References |
|---|---|---|---|---|
| AFB1 | ≤ 25 μg/kg, male F344 rat | ↑ Percentages of CD3+ and CD8+ T cells ↓ IL-4 |
5-week exposure modulates the cell-mediated immune responses | (6) |
| 30 μg/kg, murine | ↑ Protein and DNA synthesis in splenic lymphocytes, selectively affects helper T cells |
Alteration in host immunity by repeated treatment for 4 weeks | (7) | |
| 60, 300, and 600 μg, rat | ↓ DTH response (300 and 600) ↓ Proliferative response to PHA (60, 300, and 600) Inhibition of lymphocyte proliferation |
Continuous low levels suppress cell-mediated immunity and high susceptibility to infections and tumorigenesis | (8) | |
| 20 ng/mL, human microglia cell line | Overexpression of TLRs, MyD88, NF-κB, IKβ kinase, CXCR4, CCR4, and CCR8 Induction of intracellular ATP depletion Caspase-3/7 activation IFN-γ and GM-CSF secretion ↑ Apoptosis |
Alteration in key factors related to inflammation in vital immune-keeper cells | (9) | |
| 10 ng/mL, porcine monocyte-derived DCs | Dysregulation of the antigen-presenting capacity of DCs | Immunosuppressive effects on APCs and thus naïve T cells | (10) | |
| AFB1 (16.3–134 μg/kg feed) AFB2 (3.15–23.6 μg/kg feed), broiler | Disruption in cells cycle progression and apoptosis Histopathological lesions in thymus and bursa fabricius |
Disturbed T and B lymphocytes maturation | (11) | |
| 0.6 mg/kg, broilers chicken | Diffused intestinal epithelial cells Disappearance of microvilli, mitochondrial vacuolation, and mitochondrial cristae ↓ TLR-2/4/7 expression |
↓ Absorptive capacity of the small intestine (ultrastructural changes) Impairment of innate immunity of the small intestine | (12) | |
| 0.6 mg/kg, broilers chicken | ↓ Percentage of T-cell subsets ↓ mRNA expression levels of IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α in the small intestinal mucosa |
Intestinal mucosal immunity in the duodenum, jejunum and ileum | (13) | |
| 0.1 pg/mL, human monocyte | ↓ Phagocytosis and microbicidal activity of monocytes | Induction of depressed monocytes and high susceptibility to infections | (14) | |
| 5.10e-11 M or 0.05 μg/L, human NK cell | ↓ Cytotoxic and proliferative activities evaluated by a 51Cr release NK assay | Immunosuppressive effects on NK cells | (15) | |
| 0.11 to 0.21 mg/kg, duckling | ↓ Serum glucose, creatinine, albumin, total protein, globulin, Ca, P, and CPK ↑ Serum urea N, Cl, ALP, and AST levels ↓ L100 and L50 values (lysis titer) for rabbit, human, and horse erythrocytes ↓ Rabbit HA1 value (strong hemagglutination) ↓ PPARα expression level |
Liver damage Alteration of serum proteins and enzyme activity Impairment of innate immunity by reducing natural antibody and complement activities |
(16) | |
| 140 and 280 μg/L, weanling piglet | ↓ Total number of white blood cells ↑ Serum gamma-globulin ↓ IL-1β and TNF-α ↑ IL-10 mRNA expression |
Alteration of many aspects of humoral and cellular immunity | (17) | |
| 5–80 nM, BEAS-2B cell line human | ↑ C-PARP, C-caspase-3, and Bax expression ↓ Caspase-3, Bcl-2, and p-Bad expression ↑ DNA adduct and damage Activation of ATM, ATR, Chk2, p53, BRCA1, and H2AX proteins |
Cytotoxic and apoptotic effects on immortalized human bronchial epithelial cells mediated by cytochrome P450 2A13 | (18) | |
| AFM1 | 3.2 and 33 nM, Caco-2/TC7 cell | ↓ Value of trans-epithelial electrical resistance | Acceleration of AFs transport | (19) |
| 25 or 50 μg/kg, murine (Predicted no observable effect level (NOAEL) is estimated to be 2.5 μg/kg) | ↓ Spleen and thymus mass ↓ Hemagglutination titer ↓ Spleen cellularity ↓ Proliferation response to LPS and PHA ↓ CH50 ↓ DTH response ↓ Spleen cell subtypes ↓ Serum IgG level and ↓ IFN-ɤ ↑ IL-10 |
Suppression of innate and acquired immunity | (20) | |
| OTA | 3 μM, macrophagic cell line, J774A.1 | ↑ COX-2 and iNOS expression ↓ COX-2 and iNOS expression, co-stimulated with LPS ↑ PGE2 release and ↓ PGE2 release (LPS) ↑ NO production and ↓ NO production (LPS) ↓ cytosolic IκBα level (time-dependent) ↑ p65 NF-κB expression (time-dependent) |
Interfering with inflammatory responses against LPS-containing pathogens | (21) |
| 1 μg/mL, blood lymphocytes of broiler chickens | ↑ MDA levels ↑ Acetylcholinesterase enzymatic activity |
↑ Cellular oxidative stress levels Disturbing lymphocytes activation and differentiation | (22) | |
| FB1 | 8 mg/kg, weanling piglet | In males, ↓ mycoplasma-specific antibody levels and T helper2 cytokines (IL-10) mRNA expression level after vaccination | Sex-related immunosuppressive effects | (23) |
| T-2 Satratoxin |
200 μg/kg, porcine ileal Peyer's patches | ↓ IL-10 production ↓ IL-4 and IFN-γ (not significant) ↑ Percentage of CD8+ T lymphocytes (days 14 and 42) ↓ Percentage of CD8+ T lymphocytes (day 28) ↓ Percentage of CD21+ B cells ↓ Percentages of CD4+ and CD8+ T lymphocytes (days 14 and 28) |
Chronic exposure to low doses affects lymphocytes-mediated humoral immune responses | (24) |
| ≤ 10 ng/mL RAW 264.7 murine macrophage and U937 human leukemic cells | Induction of apoptosis ERK1/2, p38MAPK, and SAPK/ JNK activation in myeloid models |
Alteration in leukocytes viability and function | (25) | |
| DON | 1 mg/L and 0.2 mg/L, mice | ↓ Specific IgM titer and lower DTH reaction Inhibition of a cell-mediated immune response |
↓ Resistance against Salmonella infections through toxic effects on cellular and humoral immunity | (26) |
| Up to 500 ng/mL, human B (RPMI1788) and T (Jurkat E6.1) lymphocyte cell lines | ↓ Cells viability (at 250 and 500 ng/mL) Alteration of phosphorylation state in proteins: ↑C1-THF synthase, ↑eEF2, ↓GRB2, ↑eIF3i, ↑NDKA, and ↓HSC70, (involved in immune functions with metabolism regulation, protein biosynthesis, co-chaperoning, and signaling transduction) |
Phosphoproteomic changes in human T and B lymphocytes | (27) | |
| 2.2–2.5 mg/kg, pig | ↑ Total IgA plasmatic levels (47% increase) ↑Specific IgA production (160% increase) Biphasic effects, increase and decrease in lymphocyte proliferation ↓IFN-ɤ and TGF-β mRNA expression in mesenteric lymph nodes |
Disruption in vaccine immune response | (28) | |
| 1.2–2 mg/kg, pig | ↓ IL-1β, IL-8, and TNF-α in blood and ileum | Chronic exposure induces down-regulation of immune-related factors | (29) | |
| 1 and 2 mg/kg, BALB/c mice | lymphoid inhibition ↓ Relative number of mononuclear cells ↓ Percentage of B cells (CD19+) in blood Inhibition of CD19+ progenitor or newly B cells in bone marrow |
Lower humoral and innate immunity (with a reduction in B cells and monocytes), especially in infectious conditions | (30) | |
| ↓ Monocytes in blood and spleen in BALB/c female mice Delay in monocyte or macrophage maturation |
||||
| ≤ 10 μmol/L, human epithelial cell line (HT-29-D4) | ↓ Human intestinal epithelial cells proliferation ↓ D-glucose/D-galactose sodium-dependent transporter SGLT1, sugar transporters: GLUT5, and L-serine transporter ↑ water absorption in the intestinal lumen |
Induction of apoptosis in intestinal epithelial cells | (31) | |
| 1, 2.5, and 25 mg/kg, mice | Systemic increase in plasma IL-1β concentration Modulation of peripheral organ inflammation biomarkers in brain, liver, duodenum, and adipose tissues ↑ TNF-α, IL-1β, and mPGES-1 mRNA expression level ↓ mPGES-1 mRNA expression level |
Sub-chronic exposure to low doses makes a central and peripheral low grade inflammation | (32) | |
| 200 ng/mL, human lymphocyte | 50% inhibition of lymphocytes proliferation ↑ IL-2, IFN-γ, and ↓ IL-6 cytokines production by lymphocytes |
Considerable effects on human lymphocyte cytokine production | (33) | |
| 1 mg/kg, mice | First, rapidly induction of three MAPK families; JNK1/2, ERK1/2, and p38 phosphorylation in murine spleen Second, AP-1, C/EBP activation Third, prolonged activation of AP-1, CREB, and NF-κB Down-regulation and or up-regulation of TNF-α, IL-1β, and IL-6 |
Time-dependent dysfunctional effects on immune pathways; kinase signaling pathways and transcription factors | (34) | |
| ≤ 5 μg/mL, Caco-2 cell | ↑ IκB phosphorylation and NF-κB activation ↑ IL-1β-induced IL-8 secretion by human intestinal epithelial cells depending on PKR, NF-κB, and MAPK p38 activation |
Exacerbating intestinal inflammation | (35, 36) | |
| ZON | 8 μg/kg, porcine ileal Peyer's patches | ↓ IL-2 and IFN-γ secretion ↑ IL-4 and IL-10 secretion Shifting Th1/Th2 balance toward humoral immune response ↑ B1 cell populations ↓ NK cells proliferation and IFN-γ secretion |
Changing lymphocyte phenotypes and impairment of T cell-dependent humoral immune responses | (37) |
| 8 μg/kg, porcine ileal Peyer's patches | ↑ IL-4 and IL-10 concentrations Shifting polarization toward Th2 cells and stimulation of B cells ↑ IL-2 and IFN-γ cytokine levels (not significant) |
Changes in Th1/Th2 immune responses and susceptibility to autoimmune (development of allergies) and infectious diseases | (38) |
AFB1, aflatoxin B1; CD3, cluster of differentiation 3; IL-4, interleukin 4; DTH, delayed type of hypersensitivity; PHA, phytohemagglutinin; TLR, toll-like receptor; MyD88, myeloid differentiation primary response 88; NF-κB, Nuclear Factor-Kappa B; CXCR4, C-X-C chemokine receptor type 4; CCR4, C-C chemokine receptor type 4; ATP, adenosine triphosphate; IFN-γ, interferon gamma; GM-CSF, granulocyte-macrophage colony-stimulating factor; DCs, dendritic cells; APCs, antigen-presenting cells; TNF-α, tumor necrosis factor alpha; NK cell, natural killer cell; Ca, calcium; P, phosphor; CPK, creatine phosphokinase; ALP, alkaline phosphatase; AST, aspartate transaminase; HA1, strong hemagglutination; PPARα, peroxisome proliferator-activated receptor alpha; C-PARP, cleaved poly-ADP-ribose polymerases; Bax, Bcl-2-associated X; Bcl-2, B-cell lymphoma 2; ATM, ataxia-telangiectasia-mutated; ATR, ataxia telangiectasia and Rad3-related; Chk2, checkpoint kinase 2; BRCA1, breast cancer type 1; H2AX, H2A histone family member X; LPS, lipopolysaccharides; CH50, hemolytic complement; IgG, immunoglobulin G; OTA, ochratoxin A; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase; PGE2, prostaglandin E2; NO, nitric oxide; IκBα, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; MDA, malondialdehyde; FB1, fumonisin B1; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; SAPK, stress-activated kinase; JNK, c-Jun N-terminal kinase; DON, deoxynivalenol; C1-THF, C1-tetrahydrofolate; eEF2, eukaryotic elongation factor 2; GRB2, growth factor receptor-bound protein 2; eIF3i, eukaryotic translation initiation factor 3 subunit I; NDKA, nucleoside diphosphate kinase A; HSC70, heat shock cognate 71 kDa protein; TGF-β, transforming growth factor beta; SGLT1, sodium/glucose cotransporter 1; mPGES-1, microsomal prostaglandin E synthase-1; AP-1, activator protein 1; C/EBP, CAAT (Controlled Amino Acid Therapy)/enhancer binding protein; CREB, cAMP response element-binding protein; PKR, protein kinase R; ZON, zearalenone.