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Zinc inhibits the reproductive toxicity of Zearalenone in immortalized murine ovarian granular KK-1 cells.

ABSTRACT: Zearalenone (ZEA) mainly injures the reproductive system of mammals. In the present study, we aimed to explore the mechanism by which zinc inhibits ZEA-induced reproductive damage in KK-1 cells for the first time. The results shown that both zinc sulfate and zinc gluconate addition increased the intracellular zinc concentration and influenced the expression of zinc transporters (Slc30a1 and Slc39a1) in a time-dependent manner. Co-incubation of zinc with ZEA significantly reduced the ZEA-induced reactive oxygen species and malondialdehyde elevation by promoting the transcription of Mtf1 and Mt2. Meanwhile, two different zincs inhibited the ZEA-induced loss of mitochondrial membrane potential and elevation of late-stage apoptosis via activating the mitochondrial apoptotic pathway by recovering the mRNA and protein expression of pro-apoptotic genes (Bax, Casp3, Casp9). Zinc also recovered cells from S-phase cell cycle arrest. In addition, both of them promoted the ZEA-induced estrogen production but regulated the expression of steroidogenic enzymes (Star, Cyp11a1, Hsd3b1, Cyp17a1) in different way. All these results indicated that zinc could inhibit the reproductive toxicity of ZEA.

SUBMITTER: Li Y

PROVIDER: S-EPMC4585791 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Zinc inhibits the reproductive toxicity of Zearalenone in immortalized murine ovarian granular KK-1 cells.

Li Yijia Y He Xiaoyun X Yang Xuan X Huang Kunlun K Luo Yunbo Y Zhu Liye L Li Yuzhe Y Xu Wentao W

Scientific reports 20150923

Zearalenone (ZEA) mainly injures the reproductive system of mammals. In the present study, we aimed to explore the mechanism by which zinc inhibits ZEA-induced reproductive damage in KK-1 cells for the first time. The results shown that both zinc sulfate and zinc gluconate addition increased the intracellular zinc concentration and influenced the expression of zinc transporters (Slc30a1 and Slc39a1) in a time-dependent manner. Co-incubation of zinc with ZEA significantly reduced the ZEA-induced ...[more]

PMID: 26395757

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Project description:Zearalenone (ZEA), α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) (ZEA's metabolites) are co/present in cereals, fruits or their products. All three with other compounds, constitute a cocktail-mixture that consumers (and also animals) are exposed and never entirely evaluated, nor in vitro nor in vivo. Effect of ZEA has been correlated to endocrine disruptor alterations as well as its metabolites (α-ZEL and β-ZEL); however, toxic effects associated to metabolites generated once ingested are unknown and difficult to study. The present study defines the metabolomics profile of all three mycotoxins (ZEA, α-ZEL and β-ZEL) and explores the prediction of their toxic effects proposing an in silico workflow by using three programs of predictions: MetaTox, SwissADME and PASS online. Metabolomic profile was also defined and toxic effect evaluated for all metabolite products from Phase I and II reaction (a total of 15 compounds). Results revealed that products describing metabolomics profile were: from O-glucuronidation (1z and 2z for ZEA and 1 ab, 2 ab and 3 ab for ZEA's metabolites), S-sulfation (3z and 4z for ZEA and 4 ab, 5 ab and 6 ab for ZEA's metabolites) and hydrolysis (5z and 7 ab for ZEA's metabolites, respectively). Lipinsky's rule-of-five was followed by all compounds except those coming from O-glucuronidation (HBA>10). Metabolite products had better properties to reach blood brain barrier than initial mycotoxins. According to Pa values (probability of activation) order of toxic effects studied was carcinogenicity > nephrotoxic > hepatotoxic > endocrine disruptor > mutagenic (AMES TEST) > genotoxic. Prediction of inhibition, induction and substrate function on different isoforms of Cytochrome P450 (CYP1A1, CYP1A2, CYP2C9 and CYP3A4) varied for each compounds analyzed; similarly, for activation of caspases 3 and 8. Relying to our findings, the metabolomics profile of ZEA, α-ZEL and β-ZEL analyzed by in silico programs predicts alteration of systems/pathways/mechanisms that ends up causing several toxic effects, giving an excellent sight and direct studies before starting in vitro or in vivo assays contributing to 3Rs principle; however, confirmation can be only demonstrated by performing those assays.

Project description:Zearalenone (ZEA) contamination is a very serious problem around the world as it can induce reproductive disorders in animals and affect the health of humans. Therefore, reducing the damage it causes to humans and animals is a current focus of research. In this study, we assess the removing capacity of Pediococcus pentosaceus xy46 towards ZEA and investigate the mechanism responsible for its action, thus confirming if it can alleviate ZEA toxicity to the reproductive systems of male mice. Our results show that the rate at which the strain removes ZEA is as high as 89.2% in 48 h when the concentration of ZEA is 4 ?g/mL in the liquid medium. Heat and acid treatment significantly enhanced the ability of the bacteria to remove ZEA. The animal experiments results show that the oral administration of xy46 to mice (0.2 mL daily at a concentration of 109 CFU/mL for 28 days) significantly reduces the degree of testicular pathomorphological changes and apoptosis induced by ZEA when the mice are intragastric administration with 40 mg/kg ZEA daily for 28 days. Moreover, oral administration of xy46 enhances the decrease in the testosterone level and improves the oxidative stress injury induced by ZEA. Furthermore, oral administration of xy46 reverts the expression of these genes and proteins in the testicular tissues of the mice involved in the blood-testis barrier and apoptosis (e.g., Vim, caspase 12, Cldn11, N-cad, Bax, and Bcl-2). However, xy46 cannot significantly revert in some of these evaluated parameters, especially in sperm quantity and quality when the mice were given 70 mg/kg ZEA daily for 28 days. In conclusion, our results suggest that the strain Pediococcus pentosaceus xy46 can efficiently remove ZEA from the liquid medium, the mechanism responsible for its action is absorption, and it can alleviate the toxicity of ZEA to the reproductive systems of male mice when the mice are given 40 mg/kg ZEA daily, However, it cannot completely alleviate the reproductive toxicity of higher dosage of zearalenone through its ability to adsorb ZEA.

Project description:It is known that zearalenone (ZON) interacts directly with estrogen receptors, and its in vivo effects on reproduction have been well-documented in several species. In contrast, reports of ZON's impact on horse reproduction are conflicting and inconclusive, some studies confounded by the presence of mycotoxins such as deoxynivalenol in the feed. This study assesses the effect of chronic consumption of zearalenone on reproduction in cycling mares fed >95% pure ZON (0, 2, or 8 mg/da; n = 7 mares/treatment) for three estrous cycles, followed by artificial insemination, through 16 days of pregnancy. Animals were on ZON treatment for between 70 and 121 days (average 84) depending on individual cycle patterns. ZON-induced changes in serum concentration of estradiol (E2) and progesterone (P4), and total estrogenicity were measured using RIAs and the E-screen assay, respectively. Effects on reproductive physiology and pregnancy were monitored by ultrasound and clinical parameters. No significant changes were found in reproductive hormone levels of E2, or P4 for mares on ZON treatments compared to controls, although there was a significant (P < 0.01) increase in P4 levels across Cycle number in High ZON (8 mg/da) treated mares. There was also an increasing trend in the interovulatory interval in the High ZON treatment group. The overall estrogenicity was similar across treatments and over time, not differing from controls or between ZON treatment groups. Adverse uterine and ovarian effects were also not observed, but pregnancy rates were mixed with only 4 of 7 mares on Low ZON becoming pregnant, and only 3 maintaining pregnancy and fetal heartbeat by Day 30, compared to 5 of 6 control mares and all 7 mares on High ZON. Because reproductive efficiency and hormone concentrations are highly variable across individuals, this study did not demonstrate that ZON at 2 or 8 mg/da was detrimental to mares' reproduction. Yet, inferring that ZON treatments were completely without effect is also not appropriate, as the absence of measurable significant differences could be attributed to the limited sample size. Most importantly, there were no extreme signs of toxicology, in contrast to previous reports when ZON was fed at these "doses."

Project description:Background Cancer/testis antigens (CTAs) participate in the regulation of malignant biological behaviors in breast cancer. However, the function and mechanism of KK-LC-1, a member of the CTA family, in breast cancer are still unclear. Methods Bioinformatic tools, immunohistochemistry, and western blotting were utilized to detect the expression of KK-LC-1 in breast cancer and to explore the prognostic effect of KK-LC-1 expression in breast cancer patients. Cell function assays, animal assays, and next-generation sequencing were utilized to explore the function and mechanism of KK-LC-1 in the malignant biological behaviors of triple-negative breast cancer. Small molecular compounds targeting KK-LC-1 were also screened and drug susceptibility testing was performed. Results KK-LC-1 was significantly highly expressed in triple-negative breast cancer tissues than in normal breast tissues. KK-LC-1 high expression was related to poor survival outcomes in patients with breast cancer. In vitro studies suggested that KK-LC-1 silencing can inhibit triple-negative breast cancer cell proliferation, invasion, migration, and scratch healing ability, increase cell apoptosis ratio, and arrest the cell cycle in the G0–G1 phase. In vivo studies have suggested that KK-LC-1 silencing decreases tumor weight and volume in nude mice. Results showed that KK-CL-1 can regulate the malignant biological behaviors of triple-negative breast cancer via the MAL2/MUC1-C/PI3K/AKT/mTOR pathway. The small-molecule compound Z839878730 had excellent KK-LC-1 targeting ability and cancer cell killing ability. The EC50 value was 9.7 μM for MDA-MB-231 cells and 13.67 µM for MDA-MB-468 cells. Besides, Z839878730 has little tumor-killing effect on human normal mammary epithelial cells MCF10A and can inhibit the malignant biological behaviors of triple-negative breast cancer cells by MAL2/MUC1-C/PI3K/AKT/mTOR pathway. Conclusions Our findings suggest that KK-LC-1 may serve as a novel therapeutic target for triple-negative breast cancer. Z839878730, which targets KK-LC-1, presents a new path for breast cancer clinical treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-023-04030-9.

Dataset Information

Zinc inhibits the reproductive toxicity of Zearalenone in immortalized murine ovarian granular KK-1 cells.

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Zinc inhibits the reproductive toxicity of Zearalenone in immortalized murine ovarian granular KK-1 cells.

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