Metabolomic Analysis Reveals the Mechanisms of Hepatotoxicity Induced by Aflatoxin M1 and Ochratoxin A

Overview

Journal Toxins (Basel)

Publisher MDPI

Specialty Toxicology

Date 2022 Feb 24

PMID 35202168

Authors

Ya-Nan Gao

Chen-Qing Wu

Jia-Qi Wang

Nan Zheng

Affiliations

Soon will be listed here.

Abstract

Aflatoxin M1 (AFM1) is the only toxin with the maximum residue limit in milk, and ochratoxin A (OTA) represents a common toxin in cereals foods. It is common to find the co-occurrence of these two toxins in the environment. However, the interactive effect of these toxins on hepatoxicity and underlying mechanisms is still unclear. The liver and serum metabolomics in mice exposed to individual AFM1 at 3.5 mg/kg b.w., OTA at 3.5 mg/kg b.w., and their combination for 35 days were conducted based on the UPLC-MS method in the present study. Subsequent metabolome on human hepatocellular liver carcinoma (Hep G2) cells was conducted to narrow down the key metabolites. The phenotypic results on liver weight and serum indicators, such as total bilirubin and glutamyltransferase, showed that the combined toxins had more serious adverse effects than an individual one, indicating that the combined AFM1 and OTA displayed synergistic effects on liver damage. Through the metabolic analysis in liver and serum, we found that (i) a synergistic effect was exerted in the combined toxins, because the number of differentially expressed metabolites on combination treatment was higher than the individual toxins, (ii) OTA played a dominant role in the hepatoxicity induced by the combination of AFM1, and OTA and (iii) lysophosphatidylcholines (LysoPCs), more especially, LysoPC (16:1), were identified as the metabolites most affected by AFM1 and OTA. These findings provided a new insight for identifying the potential biomarkers for the hepatoxicity of AFM1 and OTA.

Citing Articles

Proteomic Analysis of the Murine Liver Response to Oral Exposure to Aflatoxin B1 and Ochratoxin A: The Protective Role to Bioactive Compounds.

Trombetti S, Cimbalo A, Grosso M, Vila-Donat P, Manes J, Manyes L Toxins (Basel). 2025; 17(1).

PMID: 39852982 PMC: 11768807. DOI: 10.3390/toxins17010029.

Enzymatic Oxidation of Aflatoxin M in Milk Using CotA Laccase.

Guo Y, Lv H, Rao Z, Wang Z, Zhang W, Tang Y Foods. 2024; 13(22).

PMID: 39594116 PMC: 11593616. DOI: 10.3390/foods13223702.

Determination of aflatoxin M and ochratoxin A in breast milk in rural centers of Yazd, Iran: Exposure assessment and risk characterization.

Rezaei Z, Hamzeh Pour S, Ezati P, Akrami-Mohajeri F Mycotoxin Res. 2024; 40(2):211-221.

PMID: 38285127 DOI: 10.1007/s12550-024-00519-4.

Chitosan nanoparticle encapsulation increased the prophylactic efficacy of Lactobacillus plantarum RM1 against AFM-induced hepatorenal toxicity in rats.

Hassanen E, Ahmed L, Fahim K, Shehata M, Badr A Environ Sci Pollut Res Int. 2023; 30(59):123925-123938.

PMID: 37995030 PMC: 10746602. DOI: 10.1007/s11356-023-31016-3.

May phytophenolics alleviate aflatoxins-induced health challenges? A holistic insight on current landscape and future prospects.

Rasouli H, Nayeri F, Khodarahmi R Front Nutr. 2022; 9:981984.

PMID: 36386916 PMC: 9649842. DOI: 10.3389/fnut.2022.981984.

References

Oh H, Lee H, Park S, Lim Y, Kwon O, Kim J . Analysis of plasma metabolic profiling and evaluation of the effect of the intake of Angelica keiskei using metabolomics and lipidomics. J Ethnopharmacol. 2019; 243:112058. DOI: 10.1016/j.jep.2019.112058. View

Johnson C, Ivanisevic J, Siuzdak G . Metabolomics: beyond biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. 2016; 17(7):451-9. PMC: 5729912. DOI: 10.1038/nrm.2016.25. View

Ji J, Zhu P, Blazenovic I, Cui F, Gholami M, Sun J . Explaining combinatorial effects of mycotoxins Deoxynivalenol and Zearalenone in mice with urinary metabolomic profiling. Sci Rep. 2018; 8(1):3762. PMC: 5830882. DOI: 10.1038/s41598-018-21555-y. View

. Some traditional herbal medicines, some mycotoxins, naphthalene and styrene. IARC Monogr Eval Carcinog Risks Hum. 2003; 82:1-556. PMC: 4781602. View

Xu L, Tang X, Hao F, Gao Y . Hepatotoxicity and nephrotoxicity assessment on ethanol extract of Fructus Psoraleae in Sprague Dawley rats using a UPLC-Q-TOF-MS analysis of serum metabolomics. Biomed Chromatogr. 2021; 35(6):e5064. DOI: 10.1002/bmc.5064. View

Eskola M, Kos G, Elliott C, Hajslova J, Mayar S, Krska R . Worldwide contamination of food-crops with mycotoxins: Validity of the widely cited 'FAO estimate' of 25. Crit Rev Food Sci Nutr. 2019; 60(16):2773-2789. DOI: 10.1080/10408398.2019.1658570. View

Zhao Y, Lei P, Chen D, Feng Y, Bai X . Renal metabolic profiling of early renal injury and renoprotective effects of Poria cocos epidermis using UPLC Q-TOF/HSMS/MSE. J Pharm Biomed Anal. 2013; 81-82:202-9. DOI: 10.1016/j.jpba.2013.03.028. View

Ji J, Zhu P, Cui F, Pi F, Zhang Y, Li Y . The Antagonistic Effect of Mycotoxins Deoxynivalenol and Zearalenone on Metabolic Profiling in Serum and Liver of Mice. Toxins (Basel). 2017; 9(1). PMC: 5308260. DOI: 10.3390/toxins9010028. View

Fromme H, Gareis M, Volkel W, Gottschalk C . Overall internal exposure to mycotoxins and their occurrence in occupational and residential settings--An overview. Int J Hyg Environ Health. 2016; 219(2):143-65. DOI: 10.1016/j.ijheh.2015.11.004. View

10.

Sun M, Zhang J, Liang S, Du Z, Liu J, Sun Z . Metabolomic characteristics of hepatotoxicity in rats induced by silica nanoparticles. Ecotoxicol Environ Saf. 2020; 208:111496. DOI: 10.1016/j.ecoenv.2020.111496. View

11.

Liu Y, Wang R, Zheng K, Xin Y, Jia S, Zhao X . Metabonomics analysis of liver in rats administered with chronic low-dose acrylamide. Xenobiotica. 2020; 50(8):894-905. DOI: 10.1080/00498254.2020.1714791. View

12.

Xie G, Sun J, Zhong G, Shi L, Zhang D . Biodistribution and toxicity of intravenously administered silica nanoparticles in mice. Arch Toxicol. 2009; 84(3):183-90. DOI: 10.1007/s00204-009-0488-x. View

13.

Zhai S, Ruan D, Zhu Y, Li M, Ye H, Wang W . Protective effect of curcumin on ochratoxin A-induced liver oxidative injury in duck is mediated by modulating lipid metabolism and the intestinal microbiota. Poult Sci. 2020; 99(2):1124-1134. PMC: 7587726. DOI: 10.1016/j.psj.2019.10.041. View

14.

Cui J, Yin S, Zhao C, Fan L, Hu H . Combining Patulin with Cadmium Induces Enhanced Hepatotoxicity and Nephrotoxicity In Vitro and In Vivo. Toxins (Basel). 2021; 13(3). PMC: 8003173. DOI: 10.3390/toxins13030221. View

15.

Khaneghah A, Fakhri Y, Raeisi S, Armoon B, SantAna A . Prevalence and concentration of ochratoxin A, zearalenone, deoxynivalenol and total aflatoxin in cereal-based products: A systematic review and meta-analysis. Food Chem Toxicol. 2018; 118:830-848. DOI: 10.1016/j.fct.2018.06.037. View

16.

Sun L, Lei M, Zhang N, Zhao L, Krumm C, Qi D . Hepatotoxic effects of mycotoxin combinations in mice. Food Chem Toxicol. 2014; 74:289-93. DOI: 10.1016/j.fct.2014.10.020. View

17.

Huang X, Gao Y, Li S, Wu C, Wang J, Zheng N . Modulation of Mucin ( and ) mRNA Expression and Protein Production and Secretion in Caco-2/HT29-MTX Co-Cultures Following Exposure to Individual and Combined Aflatoxin M1 and Ochratoxin A. Toxins (Basel). 2019; 11(2). PMC: 6409803. DOI: 10.3390/toxins11020132. View

18.

Zhang H, Yan A, Liu X, Ma Y, Zhao F, Wang M . Melatonin ameliorates ochratoxin A induced liver inflammation, oxidative stress and mitophagy in mice involving in intestinal microbiota and restoring the intestinal barrier function. J Hazard Mater. 2020; 407:124489. DOI: 10.1016/j.jhazmat.2020.124489. View

19.

Yu J, Zhang H, Li Y, Sun S, Gao J, Zhong Y . Metabolomics revealed the toxicity of cationic liposomes in HepG2 cells using UHPLC-Q-TOF/MS and multivariate data analysis. Biomed Chromatogr. 2017; 31(12). DOI: 10.1002/bmc.4036. View

20.

Gao Y, Li S, Wang J, Luo C, Zhao S, Zheng N . Modulation of Intestinal Epithelial Permeability in Differentiated Caco-2 Cells Exposed to Aflatoxin M1 and Ochratoxin A Individually or Collectively. Toxins (Basel). 2017; 10(1). PMC: 5793100. DOI: 10.3390/toxins10010013. View