Table 2.
Main data characteristic of reviewed studies which deal with non-estrogen-dependent effects.
| First Author | Reference Number | Species | In Vitro/In Vivo | Method (Oral, ip, etc.) | Dose | Exposure Period | Results |
|---|---|---|---|---|---|---|---|
| Benzoni | [34] | Swine sperm | In vitro | Single exposure | 10−8–20 μM ZEA, α-zearalenol and β-zearalenol | 24 h and 48 h | Reduced cell viability and motility, increased rate of apoptosis and DNA fragmentation. |
| Bielas | [35] | Wild boars | In vivo | (i) Orally once a day for 7 days in every 2 months, (ii) orally once a day | (i) 150 μg/kg bw and (ii) 50 μg/kg bw ZEA | 1 y | Reduced sperm movement parameters. |
| Chao | [36] | Sertoli cells | In vitro | Single exposure | 0–50 μM ZEA | 24 h and 48 h | Reduced cell viability, increased rate of apoptosis and ROS production, increased expression of γH2AX and RAD51 DNA repairing enzymes, decrement in the expression of occludin and connexin 43, proteins that are present in the testis–blood barrier and gap junctions of Sertoli cells, respectively. |
| Chen | [37] | Mouse Leydig (TM3) cells | In vitro | Single exposure | 50 μM/L ZEA | 24 h | Increased rate of apoptosis via PTEN, inhibition of PI3K/AKT signal pathway. |
| Filannino | [38] | Stallion sperm | In vitro | Single exposure | 1 pM–0.1 mM ZEA, α-zearalenol and β-zearalenol | 2 h | Hyperactivated motility of equine sperm cells, premature completion of the acrosome reaction and diminished sperm physiology. The α form of zearalenol still possessed the estrogenic ability to induce hyperactivated motility, whereas its β stereo-isomere had lost this property. |
| Krejcárková | [40] | Pig sperm | In vitro | Single exposure | 0–20 μM ZEA and α-zearalenol | 2 h and 4 h | Inhibitory effects of ZEA concentrations above 5 μM on sperm motility. |
| Savard | [45] | Immature Sertoli TM4 cell line | In vitro | Single exposure | 0–100 μM ZEA | 24 h | Activation of MAPK signaling pathway, increased ROS formation, ZEA could be detrimental to the early steps of Sertoli cell differentiation. |
| Tassis | [47] | Boar semen | In vitro | Single exposure | 62.8 μM ZEA | 4 h | Reduced cell viability and increased rate of cellular abnormalities. |
| Wang | [48] | Rat Leydig cells | In vitro | Single exposure | 0–20 μg/mL ZEA | 12 h | Inhibition of cell proliferation and increased rate of apoptosis, increased Bax expression and cytochrome c release, activation of Caspase-3 and Caspase-9, cleavage of PARP, upregulation of LC3-II and Beclin-1. |
| Tsakmakidis | [89] | Pietrain boar semen | In vitro | Single exposure | 0–250 μm ZEA | 4 h | Decreased sperm motility and viability, disrupted acrosome reaction. |
| Zheng | [92] | Rat Leydig cells | In vitro | Single exposure | 0–20 μg/mL ZEA | 24 h | Disruption of α-tubulin filaments and F-actin bundles, and damage to the nucleus of Sertoli cells. Decrease in the levels of inhibin-β and transferrin in the cultural supernatants. |
| Xu | [93] | Sprague Dawley rats Sertoli cells | In vitro | Single exposure | 0–100 μM ZEA | 24 h | Increased ratio of Bax/Bcl-2and expressions of FasL, caspases-3, 28, and 29. Reduced proliferation of Sertoli cells, induction of apoptosis and necrosis in cells via extrinsic and intrinsic apoptotic pathways. |
| Abid-Essefi | [109] | Vero and Caco-2 cells | In vitro | Single exposure | 0–40 μM ZEA | 24 h | Reduces cell viability correlated to cell cycle perturbation, inhibited protein and DNA syntheses and increased MDA formation. |
| Gazzah | [110] | HepG2 cells | In vitro | Single exposure | 0–100 µM ZEA | 60 h | Induction of Hsp70 protein, increased ROS formation, DNA fragmentation and cell-cycle arrest. Increased Bax expression, decreased Bcl-2 expression and mitochondrial membrane potential, increase cytochrome c release, activation of caspase-3 and caspase-9. |
| Kouadio | [112] | Caco-2 cells | In vitro | Single exposure | 0–150 μM ZEA, deoxynivalenol and fumonisin B1 | 72 h | The three mycotoxins inducing lipid peroxidation (MDA production) in potency order fumonisin B1 > deoxynivalenol > ZEA. This effect seems to be related to their common target that is the mitochondria. Deoxynivalenol and ZEA also adversely affect lysosomes in contrast to fumonisin B1. The three mycotoxins inhibit protein synthesis. DNA synthesis seems to be restored for fumonisin B1 and deoxynivalenol suggesting a promoter activity. |
| Ouanes | [114] | Vero cells and Balb/c male mice | In vitro and in vivo | Single exposure | 0–20 μM and 0–40 mg 6 kg bw ZEA | 24 h and 48 h | ZEA induce micronuclei in cultured Vero cells as well as in mouse bone marrow cells. Vitamin E was found to prevent these toxic effects, most likely acting either as a structural analogue of ZEA or as an antioxidant. |
| Bouaziz | [116] | HepG2 cells | In vitro | Single exposure | 0–120 µM ZEA, 0–60 nM T-2 toxin, 0–100 µM ochratoxin |
0–48 h | The three mycotoxins-induced a caspase-dependent mitochondrial apoptotic pathway. The mitochondrial alterations include: bax relocalisation into the mitochondrial outer membrane, loss of the mitochondrial transmembrane potential, PTPC opening, and cytochrome c release. In the presence of ZEA and T-2 toxin, ROS level was highly increased at an early stage even before mitochondrial alterations were observed. |
| Ayed-Boussema | [117] | HepG2 cells | In vitro | Single exposure | 0–220 μM ZEA | 24 h | Reduces cell proliferation, induced an upregulation of ATM and p53 genes family accompanied by an upregulation of GADD45 to arrest the cell cycle and to allow the repair mechanisms to take place. Increased the ratio of pro-apoptotic factors/anti-apoptotic factors which led to the loss of mitochondrial potential, Bax translocation and cytochrome c release. |
| Lee | [118] | GC-1 spermatogonia cells | In vitro | Single exposure | 0–100 μM ZEA | 24 h | The cleaved caspase-3 and -8, Bad, Bax, and phosphorylation of p53 and ERK1/2, were increased. Expression levels of the autophagy-related genes Atg5, Atg3, Beclin 1, LC3, Ulk1, Bnip 3, and p62 were higher. The protein levels of both LC3A/B and Atg12 were remarkably increased. ZEA has toxic effects on tGC-1 spermatogonia cells and induces both apoptosis and autophagy. |
| Hassen | [120] | HepG2 cells | In vitro | Single exposure | 0–350 μM ZEA | 3 h and 24 h | Reduced cell viability, increased rate of DNA breaks, elevated Hsp70 and 90, reduced total GSH in cells. |
| Abid-Essefi | [121] | Caco-2 cells | In vitro | Single exposure | 0–100 μM ZEA, α-zearalenol and β-zearalenol | 48 h | Reduced cell viability, increased MDA level, increased DNA fragmentation, increased Caspase-3 activity and decreased Bcl-2 level. |
| Abid-Essefi | [122] | Vero cells | In vitro | Single exposure | 0–120 μM ZEA | 24 h | Reduced cell viability, increased ROS production, increased CAT activity and DNA damage. Reduced negative effects after co-treatment of an antioxidant. |
| Bennour | [123] | HepG2 and Vero cells | In vitro | Single exposure | 0–120 μM ZEA | 0–40 h | Inhibited cell proliferation, induction of Hsp70 and 27, increased ROS production, antioxidants protect against ZEA. |
| Stadnik | [124] | Liver cells of male Wistar rats | In vivo | Orally once a day | 50–500 μg/kg bw ZEA | 10 d | Reduced activities of SOD and GPx. |
| Othmen | [125] | Vero cells | In vitro | Single exposure | 0–180 μM α-zearalenol and β-zearalenol | 24 h | Increased MDA level, inhibited protein and DNA synthesis, elevated Hsp27 and 70. |
| Mike | [127] | Schizosaccharomyces pombe | In vitro | Single exposure | 0–500 μM ZEA | 1 h | Decreased activities of GSH, GPx and G6PD, increased activities of SOD, CAT, GR and GST, increased ROS production, DNA fragmentation and cell cycle arrest. |
| Fan | [128] | IPEC-J2 | In vitro | Single exposure | 0–8 μg/mL ZEA | 2 h and 48 h | Increased MDA level and ROS production, decreased GSH, CAT and SOD activities, decreased mitochondrial membrane potential. |
| Liu | [129] | Jejunal tissue of pregnant Sprague-Dawley rats | In vivo | Orally once a day | 0–146 mg/kg bw ZEA | Gestation day 1 to 7 | Increased MDA and GPx levels, decreased SOD and CAT activities. |
| Salah-Abbés | [130] | Balb/c mice | In vivo | Orally once a day | 40 mg/kg bw ZEA | 28 d | Increased MDA level, decreased GPx, CAT and SOD activities, reduced testis, seminal vesicle and prostate weights, diminished sperm count and motility. |
| Boeira | [131] | Liver, kidney and testis of Swiss albino mice | In vivo | Single exposure, orally | 40 mg/kg bw ZEA | 48 h | Increased CAT and SOD activities, reduced GST activity. |
| Fu | [132] | Bovine mammary epithelial cell line MAC-T | In vitro | Single exposure | 0–100 μM ZEA | 24 h and 48 h | Reduced cell viability, increased ROS production, reduced mitochondrial membrane potential, altered expression of endoplasmic reticulum stress-related genes (Grp78, Hsp70, Eif2a, Atf6, Ask1 and Chop). |
| Kim | [133] | Male Sprague-Dawley rats | In vivo | Single exposure, i.p. | 5 mg/kg bw ZEA | 0–48 h | Germ cell degeneration and apoptosis. |
| Elweza | [134] | Bovine endometrial epithelial cells | In vitro | Single exposure | 0–1000 ng/mL ZEA | 24 h | Increased expression of inflammatory cytokines TNFA, IL1B and chemokine IL8, altered sperm-uterine crosstalk, reduced sperm motility. |
| Cai | [136] | Sertoli cells | In vitro | Single exposure | 0–20 μM/L | 24 h | Increased rate of apoptotic cells, decreased expression of Bcl-2, increased expression of Bax, tBID, Fas, FasL, FADD, Caspase-8 and Caspase-9, increased release of cytochrome c. |
bw: body weight; s.c.: subcutaneous injection; i.p.: intraperitoneal injection.