27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer

Haonan Ruan; Jing Zhang; Yunyun Wang; Ying Huang; Jiashuo Wu; Chunjiao He; Tongwei Ke; Jiaoyang Luo; Meihua Yang

doi:10.1016/j.jpha.2023.08.002

Volume 14 Issue 3

Mar. 2024

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2024 > 14(3): 371-388

Haonan Ruan, Jing Zhang, Yunyun Wang, Ying Huang, Jiashuo Wu, Chunjiao He, Tongwei Ke, Jiaoyang Luo, Meihua Yang. 27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer[J]. Journal of Pharmaceutical Analysis, 2024, 14(3): 371-388. doi: 10.1016/j.jpha.2023.08.002

Citation:

Haonan Ruan, Jing Zhang, Yunyun Wang, Ying Huang, Jiashuo Wu, Chunjiao He, Tongwei Ke, Jiaoyang Luo, Meihua Yang. 27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer[J]. Journal of Pharmaceutical Analysis, 2024, 14(3): 371-388. doi: 10.1016/j.jpha.2023.08.002

Citation:

Haonan Ruan, Jing Zhang, Yunyun Wang, Ying Huang, Jiashuo Wu, Chunjiao He, Tongwei Ke, Jiaoyang Luo, Meihua Yang. 27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer[J]. Journal of Pharmaceutical Analysis, 2024, 14(3): 371-388. doi: 10.1016/j.jpha.2023.08.002

PDF( 8261 KB)

27-Hydroxycholesterol/liver X receptor/apolipoprotein E mediates zearalenone-induced intestinal immunosuppression: A key target potentially linking zearalenone and cancer

doi: 10.1016/j.jpha.2023.08.002

Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China

Funds:

This study was supported by the Fundamental Research Funds for the Central Universities, China (Grant No.: 3332022147), the CAMS Innovation Fund for Medical Sciences, China (Grant Nos.: 2021-I2M-1-071 and 2021-I2M-1-031), and the National Natural Science Foundation of China (Grant No.: 81872999).

Received Date: Mar. 10, 2023
Accepted Date: Aug. 07, 2023
Rev Recd Date: Jul. 07, 2023
Available Online: Apr. 02, 2024
Publish Date: Aug. 09, 2023

Abstract

Abstract

Zearalenone (ZEN) is a mycotoxin that extensively contaminates food and feed, posing a significant threat to public health. However, the mechanisms behind ZEN-induced intestinal immunotoxicity remain unclear. In this study, Sprague-Dawley (SD) rats were exposed to ZEN at a dosage of 5 mg/kg/day b.w. for a duration of 14 days. The results demonstrated that ZEN exposure led to notable pathological alterations and immunosuppression within the intestine. Furthermore, ZEN exposure caused a significant reduction in the levels of apolipoprotein E (ApoE) and liver X receptor (LXR) (P < 0.05). Conversely, it upregulated the levels of myeloid-derived suppressor cells (MDSCs) markers (P < 0.05) and decreased the presence of 27-hydroxycholesterol (27-HC) in the intestine (P < 0.05). It was observed that ApoE or LXR agonists were able to mitigate the immunosuppressive effects induced by ZEN. Additionally, a bioinformatics analysis highlighted that the downregulation of ApoE might elevate the susceptibility to colorectal, breast, and lung cancers. These findings underscore the crucial role of the 27-HC/LXR/ApoE axis disruption in ZEN-induced MDSCs proliferation and subsequent inhibition of T lymphocyte activation within the rat intestine. Notably, ApoE may emerge as a pivotal target linking ZEN exposure to cancer development.
- Zearalenone,
- Intestinal immunosuppression,
- Apolipoprotein E,
- Bioinformatics analysis,
- Cancer

FullText(HTML)

References(76)

References

[1]	A. Rai, M. Das, A. Tripathi, Occurrence and toxicity of a fusarium mycotoxin, Zearalenone, Crit. Rev. Food Sci. Nutr. 60 (2020) 2710-2729.
[2]	J. Bai, Y. Zhou, X. Luo, et al., Roles of stress response-related signaling and its contribution to the toxicity of Zearalenone in mammals, Compr. Rev. Food Sci. Food Saf. 21 (2022) 3326-3345.
[3]	K. Ropejko, M. Twaruzek, Zearalenone and its metabolites-General overview, occurrence, and toxicity, Toxins 13 (2021), 35.
[4]	C. Arnold, Tracking Zearalenone:Placental transfer of a fungal toxin, Environ. Health Perspect. 128 (2020), 74001.
[5]	H. Ruan, Q. Lu, J. Wu, et al., Hepatotoxicity of food-borne mycotoxins:Molecular mechanism, anti-hepatotoxic medicines and target prediction, Crit. Rev. Food Sci. Nutr. 62 (2022) 2281-2308.
[6]	E. Commission, Presence of Deoxynivalenol, Zearalenone, Ochratoxin A, T-2 and HT-2 and Fumonisins in Products Intended for Animal Feeding, August 17, 2006, Brussels, Belgium, 2006.
[7]	S. Zhang, S. Zhou, Y.Y. Gong, et al., Human dietary and internal exposure to Zearalenone based on a 24-hour duplicate diet and following morning urine study, Environ. Int. 142 (2020), 105852.
[8]	K. De Ruyck, I. Huybrechts, S. Yang, et al., Mycotoxin exposure assessments in a multi-center European validation study by 24-hour dietary recall and biological fluid sampling, Environ. Int. 137 (2020), 105539.
[9]	S. Marin, A.J. Ramos, G. Cano-Sancho, et al., Mycotoxins:Occurrence, toxicology, and exposure assessment, Food Chem. Toxicol. 60 (2013) 218-237.
[10]	L. Toporova, P. Balaguer, Nuclear receptors are the major targets of endocrine disrupting chemicals, Mol. Cell. Endocrinol. 502 (2020), 110665.
[11]	F. Lai, X. Liu, N. Li, et al., Phosphatidylcholine could protect the defect of Zearalenone exposure on follicular development and oocyte maturation, Aging 10 (2018) 3486-3506.
[12]	T. Wang, Y. Ye, J. Ji, et al., Diet composition affects long-term Zearalenone exposure on the gut-blood-liver axis metabolic dysfunction in mice, Ecotoxicol. Environ. Saf. 236 (2022), 113466.
[13]	H. Wang, Y. Xiao, C. Xu, et al., Integrated metabolomics and transcriptomics analyses reveal metabolic mechanisms in porcine intestinal epithelial cells under Zearalenone stress, J. Agric. Food Chem. 70 (2022) 6561-6572.
[14]	Y. Sun, K. Huang, M. Long, et al., An update on immunotoxicity and mechanisms of action of six environmental mycotoxins, Food Chem. Toxicol. 163 (2022), 112895.
[15]	W. Fan, Y. Lv, S. Ren, et al., Zearalenone (ZEA)-induced intestinal inflammation is mediated by the NLRP3 inflammasome, Chemosphere 190 (2018) 272-279.
[16]	A.M. Mowat, W.W. Agace, Regional specialization within the intestinal immune system, Nat. Rev. Immunol. 14 (2014) 667-685.
[17]	G. Cai, S. Xia, F. Zhong, et al., Zearalenone and deoxynivalenol reduced Th1-mediated cellular immune response after Listeria monocytogenes infection by inhibiting CD4+ T cell activation and differentiation, Environ. Pollut. 284 (2021), 117514.
[18]	L. Soler, A. Stella, J. Seva, et al., Proteome changes induced by a short, non-cytotoxic exposure to the mycoestrogen Zearalenone in the pig intestine, J. Proteom. 224 (2020), 103842.
[19]	H. Zhang, Y. Wang, X. Zhou, et al., Zearalenone induces immuno-compromised status via TOR/NF/κB pathway and aggravates the spread of Aeromonas hydrophila to grass carp gut (Ctenopharyngodon idella), Ecotoxicol. Environ. Saf. 225 (2021), 112786.
[20]	F. Wu, J.D. Groopman, J.J. Pestka, Public health impacts of foodborne mycotoxins, Annu. Rev. Food Sci. Technol. 5 (2014) 351-372.
[21]	J.M. Llovet, J. Zucman-Rossi, E. Pikarsky, et al., Hepatocellular carcinoma, Nat. Rev. Dis. Primers 2 (2016), 16018.
[22]	V. Ostry, F. Malir, J. Toman, et al., Mycotoxins as human carcinogens-the IARC Monographs classification, Mycotoxin Res. 33 (2017) 65-73.
[23]	D.E. Bredesen, Inhalational Alzheimer's disease:An unrecognized-and treatable-epidemic, Aging 8 (2016) 304-313.
[24]	D. Payros, S. Menard, J. Laffitte, et al., The food contaminant, deoxynivalenol, modulates the Thelper/Treg balance and increases inflammatory bowel diseases, Arch. Toxicol. 94 (2020) 3173-3184.
[25]	J.X. Hu, C.E. Thomas, S. Brunak, Network biology concepts in complex disease comorbidities, Nat. Rev. Genet. 17 (2016) 615-629.
[26]	G. Miao, D. Zhuo, X. Han, et al., From degenerative disease to malignant tumors:Insight to the function of ApoE, Biomed. Pharmacother. 158 (2023), 114127.
[27]	B. Hui, C. Lu, H. Li, et al., Inhibition of APOE potentiates immune checkpoint therapy for cancer, Int. J. Biol. Sci. 18 (2022) 5230-5240.
[28]	A. Serrano-Pozo, S. Das, B.T. Hyman, APOE and Alzheimer's disease:Advances in genetics, pathophysiology, and therapeutic approaches, Lancet Neurol. 20 (2021) 68-80.
[29]	C. Liu, Z. Li, Z. Song, et al., Choline and butyrate beneficially modulate the gut microbiome without affecting atherosclerosis in APOE∗3-Leiden.CETP mice, Atherosclerosis 362 (2022) 47-55.
[30]	A.M. Bea, F. Civeira, V. Marco-Benedi, et al., Contribution of APOE genetic variants to dyslipidemia, Atherosclerosis 355 (2022), 175.
[31]	K. Mao, A.P. Baptista, S. Tamoutounour, et al., Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism, Nature 554 (2018) 255-259.
[32]	W. Zhang, S. Zhang, J. Wang, et al., Changes in intestinal barrier functions and gut microbiota in rats exposed to Zearalenone, Ecotoxicol. Environ. Saf. 204 (2020), 111072.
[33]	Y. Li, Q. Kong, J. Yue, et al., Genome-edited skin epidermal stem cells protect mice from cocaine-seeking behaviour and cocaine overdose, Nat. Biomed. Eng. 3 (2019) 105-113.
[34]	W. Zhou, C. Chen, Y. Shi, et al., Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy, Cell Stem Cell 21 (2017) 591-603.e4.
[35]	O. Maller, A.P. Drain, A.S. Barrett, et al., Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression, Nat. Mater. 20 (2021) 548-559.
[36]	S.C. Baksh, P.K. Todorova, S. Gur-Cohen, et al., Extracellular serine controls epidermal stem cell fate and tumour initiation, Nat. Cell Biol. 22 (2020) 779-790.
[37]	Y. Jing, L. Luo, Y. Chen, et al., SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, Signal Transduct. Target. Ther. 6 (2021), 345.
[38]	M. Wang, Z. Zhang, J. Liu, et al., Gefitinib and fostamatinib target EGFR and SYK to attenuate silicosis:A multi-omics study with drug exploration, Signal Transduct. Target. Ther. 7 (2022), 157.
[39]	A. Florido, E.R. Velasco, C.M. Soto-Faguas, et al., Sex differences in fear memory consolidation via Tac2 signaling in mice, Nat. Commun. 12 (2021), 2496.
[40]	Y. Liu, X. Liang, W. Dong, et al., Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation, Cancer Cell 33 (2018) 480-494.e7.
[41]	C. Sun, P. Shou, H. Du, et al., THEMIS-SHP1 recruitment by 4-1BB tunes LCK-mediated priming of chimeric antigen receptor-redirected T cells, Cancer Cell 37 (2020) 216-225.e6.
[42]	T. Li, J. Fu, Z. Zeng, et al., TIMER2.0 for analysis of tumor-infiltrating immune cells, Nucleic Acids Res. 48 (2020) W509-W514.
[43]	D.S. Chandrashekar, B. Bashel, S.A.H. Balasubramanya, et al., UALCAN:A portal for facilitating tumor subgroup gene expression and survival analyses, Neoplasia 19 (2017) 649-658.
[44]	M. Ju, J. Bi, Q. Wei, et al., Pan-cancer analysis of NLRP3 inflammasome with potential implications in prognosis and immunotherapy in human cancer, Brief. Bioinform. 22 (2021), bbaa345.
[45]	E. Cerami, J. Gao, U. Dogrusoz, et al., The cBio cancer genomics portal:An open platform for exploring multidimensional cancer genomics data, Cancer Discov. 2 (2012) 401-404.
[46]	W.M. Song, P. Agrawal, R. Von Itter, et al., Network models of primary melanoma microenvironments identify key melanoma regulators underlying prognosis, Nat. Commun. 12 (2021), 1214.
[47]	D. Biswas, N.J. Birkbak, R. Rosenthal, et al., A clonal expression biomarker associates with lung cancer mortality, Nat. Med. 25 (2019) 1540-1548.
[48]	J.R. Evans, S.G. Zhao, S.L. Chang, et al., Patient-level DNA damage and repair pathway profiles and prognosis after prostatectomy for high-risk prostate cancer, JAMA Oncol. 2 (2016) 471-480.
[49]	J. Hu, Z. Chen, L. Bao, et al., Single-cell transcriptome analysis reveals intratumoral heterogeneity in ccRCC, which results in different clinical outcomes, Mol. Ther. 28 (2020) 1658-1672.
[50]	X. Liu, S. Jin, S. Hu, et al., Single-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma, Nat. Commun. 13 (2022), 1158.
[51]	X. Zhang, Y. Lan, J. Xu, et al., CellMarker:A manually curated resource of cell markers in human and mouse, Nucleic Acids Res. 47 (2019) D721-D728.
[52]	G. Cai, K. Sun, T. Wang, et al., Mechanism and effects of Zearalenone on mouse T lymphocytes activation in vitro, Ecotoxicol. Environ. Saf. 162 (2018) 208-217.
[53]	M.N. Bradley, C. Hong, M. Chen, et al., Ligand activation of LXRβ reverses atherosclerosis and cellular cholesterol overload in mice lacking LXRα and apoE, J. Clin. Invest. 117 (2007) 2337-2346.
[54]	M.F. Tavazoie, I. Pollack, R. Tanqueco, et al., LXR/ApoE activation restricts innate immune suppression in cancer, Cell 172 (2018) 825-840.e18.
[55]	H. Wu, Y. Zhen, Z. Ma, et al., Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus, Sci. Transl. Med. 8 (2016), 331ra40.
[56]	E.R. Nelson, S.E. Wardell, J.S. Jasper, et al., 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology, Science 342 (2013) 1094-1098.
[57]	D. Killock, Immunotherapy:Targeting MDSCs with LXR agonists, Nat. Rev. Clin. Oncol. 15 (2018) 200-201.
[58]	V. Kumar, Q. Wang, B. Sethi, et al., Polymeric nanomedicine for overcoming resistance mechanisms in hedgehog and Myc-amplified medulloblastoma, Biomaterials 278 (2021), 121138.
[59]	G.R. Villa, J.J. Hulce, C. Zanca, et al., An LXR-cholesterol axis creates a metabolic co-dependency for brain cancers, Cancer Cell 30 (2016) 683-693.
[60]	L. Claeys, C. Romano, K. De Ruyck, et al., Mycotoxin exposure and human cancer risk:A systematic review of epidemiological studies, Compr. Rev. Food Sci. Food Saf. 19 (2020) 1449-1464.
[61]	E.K.K. Lo, X. Wang, P.K. Lee, et al., Mechanistic insights into Zearalenone-accelerated colorectal cancer in mice using integrative multi-omics approaches, Comput. Struct. Biotechnol. J. 21 (2023) 1785-1796.
[62]	T.Y. Hou, D.N. McMurray, R.S. Chapkin, Omega-3 fatty acids, lipid rafts, and T cell signaling, Eur. J. Pharmacol. 785 (2016) 2-9.
[63]	M. Pajewska, M. Lojko, K. Cendrowski, et al., The determination of Zearalenone and its major metabolites in endometrial cancer tissues, Anal. Bioanal. Chem. 410 (2018) 1571-1582.
[64]	K.E. Przybylowicz, T. Arlukowicz, A. Danielewicz, et al., Association between mycotoxin exposure and dietary habits in colorectal cancer development among a Polish population:A study protocol, Int. J. Environ. Res. Public Health 17 (2020), 698.
[65]	E.K.K. Lo, J.C.Y. Lee, P.C. Turner, et al., Low dose of Zearalenone elevated colon cancer cell growth through G protein-coupled estrogenic receptor, Sci. Rep. 11 (2021), 7403.
[66]	F. Veglia, M. Perego, D. Gabrilovich, Myeloid-derived suppressor cells coming of age, Nat. Immunol. 19 (2018) 108-119.
[67]	C. Wang, R. Najm, Q. Xu, et al., Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector, Nat. Med. 24 (2018) 647-657.
[68]	D.R. Gustafson, K. Backman, N. Scarmeas, et al., Dietary fatty acids and risk of Alzheimer's disease and related dementias:Observations from the Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP), Alzheimers. Dement. 16 (2020) 1638-1649.
[69]	J. Delrieu, P. Payoux, I. Carrie, et al., Multidomain intervention and/or omega-3 in nondemented elderly subjects according to amyloid status, Alzheimers Dement. 15 (2019) 1392-1401.
[70]	H.N. Yassine, M.N. Braskie, W.J. Mack, et al., Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers:A Review. JAMA Neurol. 74 (2017) 339-347.
[71]	X. Pei, W. Zhang, H. Jiang, et al., Food-origin mycotoxin-induced neurotoxicity:Intend to break the rules of neuroglia cells, Oxid. Med. Cell. Longev. 2021 (2021), 9967334.
[72]	C.C. Wei, N.C. Yang, C. Huang, Zearalenone induces dopaminergic neurodegeneration via DRP-1-involved mitochondrial fragmentation and apoptosis in a Caenorhabditis elegans Parkinson's disease model, J. Agric. Food Chem. 69 (2021) 12030-12038.
[73]	F. Ruan, J.G. Chen, L. Chen, et al., Food poisoning caused by deoxynivalenol at a school in Zhuhai, Guangdong, China, in 2019, Foodborne Pathog. Dis. 17 (2020) 429-433.
[74]	C. Yang, G. Song, W. Lim, Effects of mycotoxin-contaminated feed on farm animals, J. Hazard. Mater. 389 (2020), 122087.
[75]	L. Zhao, L. Zhang, Z. Xu, et al., Occurrence of aflatoxin B1, deoxynivalenol and Zearalenone in feeds in China during 2018-2020, J. Anim. Sci. Biotechnol. 12 (2021), 74.
[76]	E.D. Pack, S. Weiland, R. Musser, et al., Survey of Zearalenone and type-B trichothecene mycotoxins in swine feed in the USA, Mycotoxin Res. 37 (2021) 297-313.