Zearalenone Regulates Key Factors of the Kelch-like Erythroid Cell-derived Protein with CNC Homology-associated Protein 1-nuclear Factor Erythroid 2-related Factor 2 Signaling Pathway in Duodenum of Post-weaning Gilts

Overview

Journal Anim Biosci

Specialty Veterinary Medicine

Date 2020 Nov 5

PMID 33152220

Citations 4

Authors

Qun Cheng

Shu Zhen Jiang

Li Bo Huang

Wei Ren Yang

Zai Bin Yang

Affiliations

Soon will be listed here.

Abstract

Objective: This study explored the mechanism of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway under conditions of zearalenone (ZEA)-induced oxidative stress in the duodenum of post-weaning gilts.

Methods: Forty post-weaning gilts were randomly allocated to four groups and fed diets supplemented with 0, 0.5, 1.0, or 1.5 mg/kg ZEA.

Results: The results showed significant reductions in the activity of the antioxidant enzymes total superoxide dismutase and glutathione peroxidase and increases the malondialdehyde content with increasing concentrations of dietary ZEA. Immunohistochemical analysis supported these findings by showing a significantly increased expression of Nrf2 and glutathione peroxidase 1 (GPX1) with increasing concentrations of ZEA. The relative mRNA and protein expression of Nrf2, GPX1 increased linearly (p<0.05) and quadratically (p<0.05), which was consistent with the immunohistochemical results. The relative mRNA expression of Keap1 decreased linearly (p<0.05) and quadratically (p<0.05) in the duodenum as the ZEA concentration increased in the diet. The relative mRNA expression of modifier subunit of glutamate-cysteine ligase (GCLM) increased quadratically (p<0.05) in all ZEA treatment groups and the relative mRNA expression of quinone oxidoreductase 1 (NQO1) catalytic subunit of glutamate-cysteine ligase decreased linearly (p<0.05) and quadratically (p<0.05) in the ZEA1.0 group and ZEA1.5 group. The relative protein expression of Keap1 and GCLM decreased quadratically (p<0.05) in the duodenum as the ZEA concentration increased in the diet, respectively. The relative protein expression of NQO1 increased linearly (p<0.05) and quadratically (p<0.05) in all ZEA treatment groups in the duodenum.

Conclusion: These findings suggest that ZEA regulates the expression of key factors of the Keap1-Nrf2 signaling pathway in the duodenum, which enables resistance to ZEA-induced oxidative stress. Further studies are needed to examine the effects of ZEA induced oxidative stress on other tissues and organs in post-weaning gilts.

Citing Articles

Reproductive Toxicity of Zearalenone and Its Molecular Mechanisms: A Review.

Lv Q, Xu W, Yang F, Wei W, Chen X, Zhang Z Molecules. 2025; 30(3).

PMID: 39942610 PMC: 11821083. DOI: 10.3390/molecules30030505.

Quercetin Attenuates the Combined Effects of Zearalenone and Lipopolysaccharide on IPEC-J2 Cell Injury through Activating the Nrf2 Signaling Pathway.

Wang C, Fu Y, Wang R, Wang Q, Yu H, Zhang J Toxins (Basel). 2023; 15(12).

PMID: 38133183 PMC: 10748267. DOI: 10.3390/toxins15120679.

Zearalenone Exposure Affects the Keap1-Nrf2 Signaling Pathway and Glucose Nutrient Absorption Related Genes of Porcine Jejunal Epithelial Cells.

Cheng Q, Jiang S, Huang L, Wang Y, Yang W Toxins (Basel). 2022; 14(11).

PMID: 36422967 PMC: 9696209. DOI: 10.3390/toxins14110793.

Quantitative Proteomic Analysis of Zearalenone-Induced Intestinal Damage in Weaned Piglets.

Ma L, Jiang Y, Lu F, Wang S, Liu M, Liu F Toxins (Basel). 2022; 14(10).

PMID: 36287972 PMC: 9609629. DOI: 10.3390/toxins14100702.

The impact of Zearalenone on heat-stressed skeletal muscle in pigs.

Rudolph T, Roach C, Baumgard L, Ross J, Keating A, Selsby J J Anim Sci. 2022; 100(8).

PMID: 35908787 PMC: 9339304. DOI: 10.1093/jas/skac215.

References

Ye Y, Li J, Yuan Z . Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta-analysis of randomized controlled trials. PLoS One. 2013; 8(2):e56803. PMC: 3577664. DOI: 10.1371/journal.pone.0056803. View

Chen X, Yang C, Huang L, Niu Q, Jiang S, Chi F . Zearalenone Altered the Serum Hormones, Morphologic and Apoptotic Measurements of Genital Organs in Post-weaning Gilts. Asian-Australas J Anim Sci. 2015; 28(2):171-9. PMC: 4283161. DOI: 10.5713/ajas.14.0329. View

Kubo E, Chhunchha B, Singh P, Sasaki H, Singh D . Sulforaphane reactivates cellular antioxidant defense by inducing Nrf2/ARE/Prdx6 activity during aging and oxidative stress. Sci Rep. 2017; 7(1):14130. PMC: 5658327. DOI: 10.1038/s41598-017-14520-8. View

Kouadio J, Dano S, Moukha S, Mobio T, Creppy E . Effects of combinations of Fusarium mycotoxins on the inhibition of macromolecular synthesis, malondialdehyde levels, DNA methylation and fragmentation, and viability in Caco-2 cells. Toxicon. 2006; 49(3):306-17. DOI: 10.1016/j.toxicon.2006.09.029. View

Yang L, Zhou M, Huang L, Yang W, Yang Z, Jiang S . Zearalenone-Promoted Follicle Growth through Modulation of Wnt-1/β-Catenin Signaling Pathway and Expression of Estrogen Receptor Genes in Ovaries of Postweaning Piglets. J Agric Food Chem. 2018; 66(30):7899-7906. DOI: 10.1021/acs.jafc.8b02101. View

Price W, Lovell R, McChesney D . Naturally occurring toxins in feedstuffs: Center for Veterinary Medicine Perspective. J Anim Sci. 1993; 71(9):2556-62. DOI: 10.2527/1993.7192556x. View

Wielogorska E, Elliott C, Danaher M, Connolly L . Validation and application of a reporter gene assay for the determination of estrogenic endocrine disruptor activity in milk. Food Chem Toxicol. 2014; 69:260-6. DOI: 10.1016/j.fct.2014.04.028. View

Jiang S, Yang Z, Yang W, Wang S, Wang Y, Broomhead J . Effect on hepatonephric organs, serum metabolites and oxidative stress in post-weaning piglets fed purified zearalenone-contaminated diets with or without Calibrin-Z. J Anim Physiol Anim Nutr (Berl). 2011; 96(6):1147-56. DOI: 10.1111/j.1439-0396.2011.01233.x. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

10.

Cheng Q, Jiang S, Huang L, Ge J, Wang Y, Yang W . Zearalenone induced oxidative stress in the jejunum in postweaning gilts through modulation of the Keap1-Nrf2 signaling pathway and relevant genes1. J Anim Sci. 2019; 97(4):1722-1733. PMC: 6447257. DOI: 10.1093/jas/skz051. View

11.

Gajecka M, Rybarczyk L, Jakimiuk E, Zielonka L, Obremski K, Zwierzchowski W . The effect of experimental long-term exposure to low-dose zearalenone on uterine histology in sexually immature gilts. Exp Toxicol Pathol. 2011; 64(6):537-42. DOI: 10.1016/j.etp.2010.11.009. View

12.

Xiao D, Yuan D, Tan B, Wang J, Liu Y, Tan B . The Role of Nrf2 Signaling Pathway in Flavones Regulating Oxidative Stress in the Intestine of Piglets. Oxid Med Cell Longev. 2019; 2019:9719618. PMC: 6745127. DOI: 10.1155/2019/9719618. View

13.

Mine Y, Young D, Yang C . Antioxidative stress effect of phosphoserine dimers is mediated via activation of the Nrf2 signaling pathway. Mol Nutr Food Res. 2014; 59(2):303-14. DOI: 10.1002/mnfr.201400381. View

14.

Chang H, Kim W, Park J, Kim D, Kim C, Chung S . The Occurrence of Zearalenone in South Korean Feedstuffs between 2009 and 2016. Toxins (Basel). 2017; 9(7). PMC: 5535170. DOI: 10.3390/toxins9070223. View

15.

Palliyaguru D, Chartoumpekis D, Wakabayashi N, Skoko J, Yagishita Y, Singh S . Withaferin A induces Nrf2-dependent protection against liver injury: Role of Keap1-independent mechanisms. Free Radic Biol Med. 2016; 101:116-128. PMC: 5154810. DOI: 10.1016/j.freeradbiomed.2016.10.003. View

16.

Shanmugam G, Challa A, Litovsky S, Devarajan A, Wang D, Jones D . Enhanced Keap1-Nrf2 signaling protects the myocardium from isoproterenol-induced pathological remodeling in mice. Redox Biol. 2019; 27:101212. PMC: 6859568. DOI: 10.1016/j.redox.2019.101212. View

17.

Ren Z, Wang Y, Deng H, Deng Y, Deng J, Zuo Z . Deoxynivalenol induces apoptosis in chicken splenic lymphocytes via the reactive oxygen species-mediated mitochondrial pathway. Environ Toxicol Pharmacol. 2015; 39(1):339-46. DOI: 10.1016/j.etap.2014.11.028. View

18.

Ren Z, Deng H, Wang Y, Deng J, Zuo Z, Wang Y . The Fusarium toxin zearalenone and deoxynivalenol affect murine splenic antioxidant functions, interferon levels, and T-cell subsets. Environ Toxicol Pharmacol. 2016; 41:195-200. DOI: 10.1016/j.etap.2015.12.007. View

19.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

20.

Przybylska-Gornowicz B, Tarasiuk M, Lewczuk B, Prusik M, Ziolkowska N, Zielonka L . The effects of low doses of two Fusarium toxins, zearalenone and deoxynivalenol, on the pig jejunum. A light and electron microscopic study. Toxins (Basel). 2015; 7(11):4684-705. PMC: 4663528. DOI: 10.3390/toxins7114684. View