The Toxicity of Zearalenone: Comparison
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Zearalenone (ZEA) is one of the top five agriculturally important and of greatest concern mycotoxins. Its toxicity is mainly manifested in the following aspects: reproductive toxicity, hepatotoxicity, immunotoxicity, genotoxicity, and carcinogenicity. Several acute toxicity studies have given oral LD50s of ZEA, which are above 2000, 4000, and 5000 mg/kg bw in mice, rats, and Guinea pigs, respectively. The no-observed-effect level (NOEL) of ZEA in pigs and rats shown by 90-day sub-chronic oral toxicity studies were 40 and 100 μg/kg bw, respectively. Since ZEA has an estrogen-like structure, it binds to various estrogen receptors (ERs). Therefore, low-dose ZEA interferes with the physiological–metabolic response and affects the vital functions of the body. Reproductive toxicity is one of ZEA’s main toxic effects, which causes reproductive disorders in various animals. Besides, ZEA is a potential carcinogen. The International Agency for Research on Cancer (IARC) classifies ZEA as the first Class 3 carcinogen. Existing studies indicate that ZEA induces genotoxicity by DNA fragmentation, micronucleus formation, DNA adduct formation, chromosomal aberrations, and apoptosis. Additionally, ZEA induces liver lesions accompanied by cancer development. Moreover, ZEA is immunotoxic and nephrotoxic. It causes changes in immune parameters and chronic progressive nephropathy both in vivo and vitro.

  • mycotoxin
  • zearalenone
  • risk assessment
  • toxicity

1. Reproductive Toxicity

ZEA and its derivatives have estrogen-like effects in rats, mice, rabbits, and Guinea pigs. Toxicity to germ cell development and embryonic development in animals or humans is mainly attributed to the following four mechanisms: (1) binding to estrogen receptors as an estrogen compound, causing direct damage to germ cells and organs; (2) destroying the blood–testis barrier and damaging germ cells; (3) increasing oxidative stress and destroying the body’s antioxidant defense system; (4) and promoting cell apoptosis through DNA damage, causing inflammatory responses and leading to a hormone secretion disorder [1]. ZEA induces reproductive dysfunction (infertility or reduced fertility), ovarian and uterine dilation, vaginal prolapse, vulvar swelling, decreased sperm count, serum testosterone, and progesterone levels in rats, mice, pigs, and cattle. Additionally, ZEA may reduce fetal weight when exceeding its critical dose [2][3]. In addition, ZEA causes altered oocyte and follicle development, and preterm birth and miscarriage in mice [4]. Likewise, 42-day-old weaned piglets were treated by ZEA through daily diets to investigate its effects on growth performance, reproductive organs, and immune function. It was found that the piglets’ vulvae length, width, and area were significantly increased; their hypothalamic–pituitary–ovarian axis was disrupted; and the piglets’ estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone levels, and reproductive performance were significantly reduced [5].

2. Hepatotoxicity

In addition to the reproductive organs, the liver is another target organ for ZEA toxicity. ZEA may change the activity of liver enzymes, the degree of lipid peroxidation, the content of liver protein, the antioxidant capacity, and the inflammatory response, which leads to hepatotoxicity. Additionally, ZEA may cause DNA damage to hepatocytes and severe damage to liver function. The liver damage extents can be assessed by testing specific liver enzymes. A quantity of 40 mg/kg bw ZEA intake increases serum ALP, AST, and ALT levels in mice [6]. After 7 and 14 days of exposure to 100 μg/kg bw ZEA, the serum ALT, ALP, AST, and γ-glutamyltransferase (GGT) activities increased in rabbits, indicating ZEA’s liver toxicity [7]. ZEA increased serum ALT, ALP, and AST activities in rats dose-dependently, and decreased the serum level of total protein and albumin levels [8]. ZEA exposure (40 mg/kg bw) significantly increased the BALB/c mice’s liver tissue malondialdehyde (MAD) levels, protein carbonyl generation, catalase, superoxide dismutase (SOD) activities, expression of the heat-shock protein (HSP 70), and caused oxidative stress in liver tissue [9].
The combination of ZEA and its reduced products (α-ZOL and β-ZOL) has synergistic toxic effects on HepG2 cells at high concentrations, which can significantly change the expression of inflammation-related genes IL-1β, TNF-α, and IL-8. Additionally, the toxin reduces cell viability and triggers inflammatory responses [10]. Besides, ZEA regulates cytochromes (HCYP) in the liver. Existing research treated three types of hepatocytes with ZEA in different concentrations to examine the gene expression of the cytochrome P450 family. The study found that ZEA activated the mRNA levels of human PXR, CAR, and AhR. At a concentration as low as 0.1 μM, the target genes involved in the metabolism of its phase-I reaction were mainly CYP3A4, CYP2B6, and CYP1A1. The transcriptional expression of CYP3A, CYP2B, and CYP1A were regulated by the nuclear receptor PXR and (or) the CAR pathway and AhR-mediated pathway, respectively [11]. Another study confirmed these findings and explored the effect of metabolism-related molecules in the liver phase-II reaction. The authors found that 20 μg/mL ZEA significantly activated Nrf 2 and increased the mRNA level of UGT1A. However, 40 μg/mL ZEA did not increase the mRNA levels of Nrf 2 and UGT1A. It suggested that ER stress caused by high ZEA concentrations may be one of the reasons for the decreased expression of phase-II reaction metabolism-related molecules (Nrf 2 and UGT1A), disrupting the normal hepatocyte detoxification process and reducing the expression of phase-I/II reaction enzymes [12].
Recent studies have explored ZEA’s effect on the overall methylation, histone modification, and transcriptional profiles of chromatin-modifying enzymes in HepG2 cells from the level of cellular epigenetics and gene expression. It was found that ZEA and α-ZOL at concentrations of 1, 10, and 50 μM significantly increased the overall methylation and histone modification levels (H3K27me3, H3K9me3, and H3K9ac) and changed the AhR, LXRα, PPARα, PPARγ, L-Fabp, LDLR, Glut 2, Akt 1, and HK2 gene expressions associated with nuclear receptors and metabolic pathways. PPARγ, which is related to lipid metabolism, was the critical regulator. Further research found that the gene’s promoter methylation of PPARγ reduced significantly, indicating that epigenetic modification may be one of the ways that ZEA impacts the metabolic pathways [13].

3. Immunotoxicity

ZEA impairs immune function, causes monocyte proliferation, induces immune organ damage, and modulates the levels of inflammatory factors and immunoglobulins. Leukocytes, NK cells, proinflammatory cytokines, immunoglobulins (IgG and IgM), some subtypes of B and T cell (CD3, CD4, and CD8) levels decreased in BALB/c mice treated with 40 mg/kg bw ZEA for two weeks [14]. Additionally, ZEA resulted in a decreasing expression of tumor necrosis factor-alpha (TNF-α) in mice and pigs. Treating ovariectomized rats with 3.0 mg/kg ZEA for 28 days damaged their lymphoid organs, modulated immune responses, caused thymus atrophy, and inhibited T cell-mediated immune responses [15]. In primary splenic T lymphocytes of mice activated with concanavalin, ZEA treatment inhibited T lymphocyte activity, caused intracellular and surface ultrastructural damage, and inhibited the expression of CD25 and CD278. Additionally, ZEA inhibited the synthesis of some effector molecules and over-activated the MAPK signaling pathway to promote the apoptosis of T lymphocytes and thus inhibited immune functions [16]. ZEA has a cytotoxic effect on human leukemic cell lines, HL60 (promyelocytic) and U937 (monocytic), and peripheral blood mononuclear cells (PBMCs). ZEA causes hypodiploid peaks and G1-phase arrest. Its mechanism of inducing apoptosis is to decline the mitochondrial membrane potential, activate caspase-3 and -8, generate reactive oxygen species, cause endoplasmic reticulum stress, and release cytochrome c from mitochondria into the cytoplasm [17]. Additionally, ZEA inhibits the chemotaxis of T cells by inhibiting the expression of cell adhesion and migration-related proteins. An existing study activated the spleen lymphoid T cells of BALB/c mice with concanavalin and administered the cell with ZEA (10, 20, and 40 μM). The results showed that ZEA treatment caused ultrastructural damage on the surface and interior of T cells, inhibited T cell chemotaxis mediated by CCL 19 or CCL 21, disrupted the balance of T cell subtypes, and inhibited T cell chemokines. The decreased expression of receptors inhibited the secretion of chemokines such as RANTES and MIP-1α from T cells, inhibited the migration of the cells, and limited their immune functions [18].

4. Genotoxicity

ZEA has been reported to be genotoxic. It may lead to an increased production of reactive oxygen species, chromosome aberration, lipid peroxidation, DNA adduct and breakage, SOS repair, cell apoptosis, and so on. ZEA treatment in cultured bovine lymphocytes resulted in chromosomal aberrations (CAs) and sister chromatid exchanges (SCE), as well as the reduced mitotic index (MI) and cell viability, mediating programmed cell death [19]. Another study in BALB/c mice with a single injection of ZEA at a dose of 2 mg/kg bw detected multiple DNA adducts in the mouse kidneys [20]. ZEA binds to 17-β-estradiol receptors, induces lipid peroxidation in cells, causes cell death, and inhibits protein and DNA synthesis. ZEA treatment was found to significantly reduce CaCo-2 cells’ viability, inhibit protein and DNA synthesis, and cause a significant increase in the lipid Peroxidation MDA [21]. A quantity of 40 μM ZEA was found to inhibit the proliferation of porcine intestinal epithelial cells IPEC-J2, arrest the cell cycle at the G2/M phase, and affect the cellular transcriptional profile. A total of 783 differentially expressed genes (DEGs) were identified. The KEGG pathway analysis revealed that PERK regulates gene expression. Toll-like receptors stimulate signaling pathway, mitosis, metaphase and anaphase, DNA replication, and the G2/M checkpoint were involved in cell cycle pathways. Eleven critical genes related to the G2/M checkpoint were verified by the qPCR method, indicating that the G2/M checkpoint is the most important signaling pathway affecting the cell cycle [22]. Additionally, ZEA at this concentration (40 μM) was reported to induce apoptosis in the kidney cells that originated from male Swiss mice. The mRNA expression and protein levels of Bax, caspase-12, caspase-3, Bip (possible targets), CHOP, and JNK increased, while the mRNA expression and protein levels of Bcl-2 decreased [23]. Likewise, ZEA treatment to BALB/c mice increased their renal cell caspase-3 activity and relevant mRNA levels (MDA, IL-10, IL-6, TNF-α, and Bax). Additionally, ZEA treatment decreased the mice’s total antioxidant activity (TAC) and relevant mRNA expressions (GSH-Px, CAT, and Bcl-2) indicating that ZEA induced oxidative stress in renal cells and caused genotoxic effects [24]. Besides, ZEA was found to induce ROS-mediated cell cycle arrest and apoptosis in mouse Sertoli cells via endoplasmic reticulum (ER) stress and the ATP/AMPK pathway. Treating TM4 cells with 0–30 μM ZEA led to ROS accumulation, which induced ER stress, inhibited cell proliferation through the ATP/AMPK pathway, affected cell cycle distribution, and induced apoptosis [25]. Additionally, ZEA caused autophagy, apoptosis, and destruction of the cytoskeleton structure in mouse TM4 cells, through oxidative stress, ER stress, PI3K-AKT-mTOR, and MAPK signaling pathways [26]. In rat insulinoma INS-1 cells, 50, 100, and 500 μM ZEA were found to induce NF-κB p65 activation, which promotes the activation of NLRP 3 inflammatory bodies in INS-1 cells, formats inflammatory response and phagocytosis, and induces NLRP 3-dependent inflammatory cell death [12].

5. Carcinogenicity

In addition to the above toxicity studies, ZEA may induce liver cancer, breast cysts, chronic progressive nephropathy, retinopathy, and cataracts, as it promotes cell proliferation. ZEA may induce liver cancer from liver injuries in mice, which was first reported in 1982. Additionally, it was found that ZEA treatment causes prostate inflammation, mammary cysts, and hepatocyte vacuoles in rats [18]. ZEA resulted in a higher incidence of increased trabecular formation in the femoral bone marrow of Wistar rats at 3 mg/kg bw [27]. Additionally, ZEA was found to stimulate the growth of human breast cancer cells, as the cells have estrogen receptors, which leads to an increased incidence of breast cancer [28]. In 2018, a study examined the effect of 10 and 30 μM ZEA on tumorigenic gene expressions on ovarian granulosa cells obtained from CD1 mice. The results showed that 30 μM ZEA exploration increased the expression of multiple cancer-associated genes, such as the Hippo signaling pathway and related genes (CCND 1, SMAD 3, Tead3, YAP 1, and WWTR1). Furthermore, immunohistochemistry explored that 30 μM ZEA treatment increased the protein levels of YAP 1, WWTR1, and CCND 1, resulting in abnormal cell morphology and an increased tumorigenic risk [29].

6. Gastrointestinal Health

In addition to basic toxicological research, mycotoxins and gut health have received increasing attention in recent years. When humans and animals ingest mycotoxins, the gut is the first to be affected. Mainly, the toxin may affect gut histomorphology and gut microbes. The intestinal barrier refers to the physical, chemical, biological, and immune barriers. ZEA may destroy these barriers, thus resulting in decreased intestinal resistance to toxins and affecting the immune function. ZEA’s effect on intestinal morphology and histopathology has been accessed in 21-day-old SD rats. After a 4-week treatment with ZEA at different concentrations (0.2, 1.0, and 5.0 mg/kg bw), significant intestinal villi and glands damages, and mucosal epithelium and lamina propria separations were observed. The microvilli coefficient and length/recess depth of jejunal villus decreased, and the intestinal permeability increased significantly. The remarkable expression increases of IL-1β, IL-6, TNF-α, IFN-γ, and CCL 20 cytokines, and the decrease of IL-10, indicated that ZEA caused intestinal inflammation and reduced the expression of tight junction-associated proteins. Although ZEA treatment slightly increased the α-diversity of gut microbes in terms of cecal microflora diversity composition, it significantly decreased the β-diversity, indicating that the integrity of the intestinal barrier and the balance of intestinal flora was disrupted [30]. It was found that the oral admission of 4.5 mg/kg bw ZEA for a week increased the mRNA expression of inflammasome NLRP 3, pro-interleukin-1β (pro-IL-1β), and pre-IL-18 (pro-IL-18) from 0.5-fold to 1-fold in BALB/c mice. Additionally, their IL-1β and IL-18 release increased by one-fold. Loose stools were observed clinically. Besides, the histology showed marked inflammatory cell infiltration and colon tissue damage. Additionally, this study summarized the potential mechanism of intestinal inflammation caused by ZEA: (1) ZEA initially had a direct toxic effect on the epithelial barrier, enhancing the accumulation of ROS, and then, macrophages were activated by ROS, thereby enhancing the transcription of pro-IL-1β and pro-IL-18; (2) the induction of caspase-1 activation by the NLRP 3 inflammasome cleaves pro-IL-1β and pro-IL-18 into biologically active forms that initiate the intestinal inflammatory cascade [31]. In IPEC-J2 cells, ZEA increased lactate dehydrogenase (LDH) activity, cell permeability, and reactive oxygen species levels. It reduced the expression of intestinal immune barrier-associated immunoglobulin (IG A\G\M) and intestinal physical barrier-related genes (PBD-1, PBD-2, MUC-2, ZO-1, occludin, and claudin-3). Thus, ZEA induced oxidative stress and intestinal epithelial barrier damage in IPEC-J2 cells [32].

7. Endocrine-Disrupting Effects

The estrogenic effects of ZEA have been extensively demonstrated in many species. ZEA binds to estrogen receptors (ER-alpha and ER-beta) with a high affinity to ER-alpha and activates the transcription of estrogen-responsive genes. Therefore, it acts as an endocrine disruptor through ERs in vivo. The endocrine disturbance caused by ZEA is closely related to the release of pituitary hormones. Zearalenone and its metabolites have been reported to regulate luteinizing hormone (LH) production by modulating the estradiol receptor GPR 30, and dietary exposure to prepubertal rats decreased the premature activation of Kisspeptin–Gpr54–GnRH hypothalamic signaling [33]. Oral administration of 20 mg/kg bw ZEA to male 10-week-old rats for five consecutive weeks resulted in a significant increase in serum prolactin concentration, whereas their serum luteinizing hormone, follicle-stimulating hormone levels, and germ cell numbers remained unchanged [34]. ZEA was found to promote follicle growth through an ERs/GSK-dependent Wnt-1/β-catenin pathway in pigs [35]. Additionally, ZEA was found to inhibit the testosterone synthesis in mouse Leydig cells by inhibiting the orphan nuclear receptor Nur 77 [36]. Besides, ZEA induces precocious puberty in female rats through early stimulation of the hypothalamic KiSS1/GPR54 pathway [37]. In addition to the toxin’s estrogen-like structure-leaded chronic toxicity and sub-chronic toxicity on the endocrine disorder, which causes reproductive disorders, the mentioned studies explored the effect of ZEA on body metabolism from the perspective of endocrine disruption. However, the intuitive ability of endocrine disruption on obesity, abnormal blood lipids, blood sugar, and blood pressure remains unknown. Few studies have been performed to verify the relationship between metabolic disease and ZEA toxicity in terms of metabolism interference. Some researchers found that obesity increased the ovarian responses to ZEA (40 μg/kg bw) among seven-week-old female wild-type nonagouti KK.Cg-a/a mice (lean) and agouti lethal yellow KK.Cg-Ay/J mice (obese) [38][39].
The molecular mechanisms and related pathways involved in these studies may be the key factors to the association of zearalenone with metabolic diseases. However, few studies have proved their relationships directly, and it is difficult to carry out epidemiological investigations and cohort studies when studying their correlations with metabolic diseases. Therefore, at present, those studies strongly rely on animal experiments. Table 1 summarizes some pathways involved in different types of toxicity of Zea.
Table 1. Summary of ZEA-induced toxicity.
Toxic Type Animal/Cell Model Dose Exposure Time Phenotypic Modulation Pathway Reference
Reproductive toxicity Postweaning piglets 3 mg/kg bw 28 d Vulvar malformation, decreased immune response, and disorder of the level of serum hormones. Hypothalamic–pituitary–ovarian axis pathway. [5]
TM4 cells 0~30 μM 24 h TM4 cell autophagy, oxidative stress, and cytoskeletal structure destruction. PI3K/Akt/mTOR and MAPK signaling pathway. [26]
TM3 cells 50 μM 24 h Decreased cell viability and testosterone concentration, increased LDH, and cell apoptosis. PI3K/Akt, PTEN/Nrf 2/Bip, and ER-stress signaling pathway. [40]
Sertoli cells (SCs) 0~80 μM 24 h Cell cycle arrest, inhibited SCs proliferation, and cell morphological autophagy. PI3K/Akt/mTOR signaling pathway. [41]
Hepatotoxicity Balb/c mice 40 mg/kg bw 24 h Increased MDA level, protein carbonylation, SOD activity, CAT activity, and the expression level of HSP70. Oxidative stress pathway. [9]
HepG2 cells 0~100 μM 72 h Decreased cell viability and the expression of liver inflammation-related factors. Inhibit inflammatory response and liver immunity. [10]
HepG2 cells 0~40 μM 24 h Decreased cell viability, increased production of ROS, and regulated phase-I/II metabolism, resulting in autophagy and apoptosis. Oxidative stress, ER-stress, and PERK/eIF2α pathway. [12]
Immunotoxicity T lymphocytes 0~40 μM 24 h Decreased cell viability, damaged cell surface and intracellular ultrastructure of T lymphocytes, and decreased secretion of cytokines, resulting in cell apoptosis. MAPK signaling pathway, TNF-α-independent JNK signaling pathway. [16]
HL-60, U937, PBMCs 0~50 μM 24 h Decreased cell viability, increased production of ROS, and cell apoptosis. The death receptor pathway with direct involvement of caspase-8, the mitochondrial pathway, and ER-stress pathway. [17]
T lymphocytes 0~40 μM 48 h Surface and intracellular ultrastructural damage of T lymphocytes. Chemokines MIP-1α and RANTES secreted by T lymphocytes and chemokine receptor CCR2 and CCR7. [18]
T lymphocytes 0~40 μM 24 h Decreased cell viability and the expression of different activation signals in T cells inhibited the secretion of cytokines. Co-stimulatory signal and PI3K/Akt/mTOR signaling pathway. [42][43]
Genotoxicity Kunming mice 40 mg/kg bw 28 d Damaged kidney resulting in oxidative stress and renal cell apoptosis. Bip, CHOP, caspase-12, and JNK signaling pathway [23]
TM4 cells 0~100 μM 24 h Inhibited cell proliferation, cell cycle arrest, and cell apoptosis. ROS and ER stress, ATP/AMPK pathway. [25]
Carcinogenicity INS-1 cells 0~800 μM 24 h NLRP3 inflammasome activation, decreased cell viability, cell autophagy, and pyroptosis. NF-κB p65 activation and nuclear translocation. [44]
Mouse granulosa cells 10&30 μM 72 h Changed cell morphology, cell cycle arrest, and increased expression of genes related to tumorigenesis. Hippo signaling pathway. [29]
TM3 cells 0~90 μM 24 h Decreased cell viability. Ras, Rap1, PI3K/AKT, Foxo, and AMPK signaling pathway. [45]
Gastrointestinal health IPEC-J2 cells 0~80 μM 24 h Decreased the cell viability and increased LDH activity, and inhibited cell proliferation, resulting in cell cycle arrest. Pathways involved in the cell cycle G2 phase. [22]
SD mice 0~5.0 mg/kg bw 28 d Impaired intestinal barrier, increased permeability and imbalance of intestinal microbiota, and increased systematic intestinal inflammation. RhoA/ROCK signal pathway. [30]
Balb/c mice 4.5 mg/kg bw 7 d NLRP3 inflammasome activation and intestine inflammatory. NLRP3 signaling pathway. [31]
Endocrine-disrupting effects Postweaning piglets 0~3.2 mg/kg bw 18 d Inhibited LH secretion. Kisspeptin–Gpr54–GnRH Pathway. [33]
Postweaning piglets 0~1.5 mg/kg bw 35 d Inhibited follicles maturation and ovarian development. ERs/GSK-3β-dependent Wnt-1/β-catenin signaling pathway. [35]
SD mice 0~5 mg/kg bw 5 d Released gonadotropin early—resulted from the advancement of vaginal opening and enlargement of the uterus at the periphery. Hypothalamic kisspeptin–GPR54 signaling pathway. [46]

 

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