The Novel Neurotoxic and Neuroimmunotoxic Capabilities of Aflatoxin B1 on the Nervous System: A Review

Seidu A. Richard, Nana Y.B Manaphraim, Nii Korley Kortei

Abstract


Aflatoxins B1(AFB1) is an ancillary lethal metabolite archetypally spawned by Aspergillus flavus as well as A. parasiticus mostly found all over the world but more in tropic and humid regions. AFB1 has been isolated is almost all food products. The isolation of AFB1 in humans was demonstrated using human fluid like urine, serum as well as breast milk. Also, AFB1 was isolated in human placenta in pregnant women. ELISA is extremely sensitive in detecting AFB1. AFB1 was capable of compromising the activities of the blood-brain barrier (BBB). AFB1 was capable of triggering peripheral and central nervous degeneration. Acute central nervous system (CNS) symptoms like coma, cerebral edema as well as death has been observed in AFB1 exposure to the brain. Also, symptoms of brain destruction such as dullness, restlessness, muscle tremor, convulsions, loss of memory, epilepsy, idiocy, loss of muscle coordination, and abnormal sensations have been associated with deficiencies of these neurotransmitter during AFB1exposure. AFB1 was capable of influencing the end products of proteins as well as amino acid metabolism leading to hyper-ammonemia which easily cross the BBB to trigger the synthesis of glutamate neurotransmitters which are cytotoxic to the brain cells and causes encephalopathy. Glutathione (GHS) depletion resulted in destruction to critical cellular components such as DNA, lipids and proteins via the 8,9 epoxides of AFB1.This review therefore elucidates the novel neurotoxic and neuroimmunotoxic roles of AFB1 on the CNS.

Keywords


Aflatoxins B1, Glutathione, Neurotransmitter, Nervous system, Neurotoxin, Neuroimmunotoxic

Full Text:

PDF

References


Souza CF, Baldissera MD, Zeppenfeld CC, Descovi S, Stefani LM, Baldisserotto B, et al. Oxidative stress mediated the inhibition of cerebral creatine kinase activity in silver catfish fed with aflatoxin B 1-contaminated diet. Fish physiology and biochemistry. 2019;45:63-70.

Hussain D, Mateen A, Gatlin III DM. Alleviation of aflatoxin B1 (AFB1) toxicity by calcium bentonite clay: Effects on growth performance, condition indices and bioaccumulation of AFB1 residues in Nile tilapia (Oreochromis niloticus). Aquaculture. 2017;475:8-15.

Souto NS, Claudia Monteiro Braga A, Lutchemeyer de Freitas M, Rechia Fighera M, Royes LFF, Schneider Oliveira M, et al. Aflatoxin B1 reduces non-enzymatic antioxidant defenses and increases protein kinase C activation in the cerebral cortex of young rats. Nutritional neuroscience. 2018;21:268-75.

Benkerroum N. Chronic and Acute Toxicities of Aflatoxins: Mechanisms of Action. International journal of environmental research and public health. 2020;17:423.

Shyamal S, Latha P, Suja S, Shine V, Anuja G, Sini S, et al. Hepatoprotective effect of three herbal extracts on aflatoxin B1-intoxicated rat liver. Singapore medical journal. 2010;51:326.

Scafuri B, Varriale A, Facchiano A, D’Auria S, Raggi ME, Marabotti A. Binding of mycotoxins to proteins involved in neuronal plasticity: a combined in silico/wet investigation. Scientific reports. 2017;7:15156.

Ikegwuonu FI. The neurotoxicity of aflatoxin B1 in the rat. Toxicology. 1983;28:247-59.

Jayasekara S, Drown D, Coulombe R, Sharma R. Alteration of biogenic amines in mouse brain regions by alkylating agents. I. Effects of aflatoxin B 1 on brain monoamines concentrations and activities of metabolizing enzymes. Archives of environmental contamination and toxicology. 1989;18:396-403.

Ahmed K, Zieve L, Quarfoth G. Effects of methanethiol on erythrocyte membrane stabilization and on Na+, K+-adenosine triphosphatase: relevance to hepatic coma. Journal of Pharmacology and Experimental Therapeutics. 1984;228:103-8.

Gesing A, Karbownik‐Lewinska M. Protective effects of melatonin and N‐acetylserotonin on aflatoxin B1‐induced lipid peroxidation in rats. Cell Biochemistry and Function: Cellular biochemistry and its modulation by active agents or disease. 2008;26:314-9.

Mistry K, Krishna M, Bhattacharya R. Effect of aflatoxin B1 on phosphoinositide signal transduction pathway during regeneration of liver cells following partial hepatectomy. 2001.

Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature. 1984;308:693.

Zhu J-q, Zhang L-s, Hu X, Xiao Y, Chen J-s, Xu Y-c, et al. Correlation of dietary aflatoxin B1 levels with excretion of aflatoxin M1 in human urine. Cancer research. 1987;47:1848-52.

Jager AV, Ramalho FS, Zambelli LN, Oliveira CAF. Biomarkers of aflatoxin exposure and its relationship with the hepatocellular carcinoma. Aflatoxins-Biochemistry and Molecular Biology: IntechOpen; 2011.

Groopman JD, Jiaqi Z, Donahue PR, Pikul A, Lisheng Z, Jun-shi C, et al. Molecular dosimetry of urinary aflatoxin-DNA adducts in people living in Guangxi Autonomous Region, People's Republic of China. Cancer research. 1992;52:45-52.

Groopman JD, Hall AJ, Whittle H, Hudson GJ, Wogan GN, Montesano R, et al. Molecular dosimetry of aflatoxin-N7-guanine in human urine obtained in The Gambia, West Africa. Cancer Epidemiology and Prevention Biomarkers. 1992;1:221-7.

Wild C, Rasheed F, Jawla M, Hall A, Jansen L, Montesano R. In-utero exposure to aflatoxin in West Africa. Lancet. 1991;337:1602.

Wild CP, Jiang Y-Z, Sabbioni G, Chapot B, Montesano R. Evaluation of methods for quantitation of aflatoxin-albumin adducts and their application to human exposure assessment. Cancer Research. 1990;50:245-51.

Gan L-S, Skipper PL, Peng X, Groopman JD, Chen J-s, Wogan GN, et al. Serum albumin adducts in the molecular epidemiology of aflatoxin carcinogenesis: correlation with aflatoxin B 1 intake and urinary excretion of aflatoxin M 1. Carcinogenesis. 1988;9:1323-5.

Turner PC, Collinson AC, Cheung YB, Gong Y, Hall AJ, Prentice AM, et al. Aflatoxin exposure in utero causes growth faltering in Gambian infants. International journal of epidemiology. 2007;36:1119-25.

Wang LY, Hatch M, Chen CJ, Levin B, You SL, Lu SN, et al. Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan. International journal of cancer. 1996;67:620-5.

Qureshi H, Hamid SS, Ali SS, Anwar J, Siddiqui AA, Khan NA. Cytotoxic effects of aflatoxin B1 on human brain microvascular endothelial cells of the blood-brain barrier. Medical mycology. 2015;53:409-16.

Bbosa GS, Kitya D, Lubega A, Ogwal-Okeng J, Anokbonggo WW, Kyegombe DB. Review of the biological and health effects of aflatoxins on body organs and body systems. Aflatoxins-recent advances and future prospects. 2013;12:239-65.

Oyelami O, Maxwell S, Adelusola K, Aladekoma T, Oyelese A. Aflatoxins in the autopsy brain tissue of children in Nigeria. Mycopathologia. 1995;132:35-8.

Wang H, Dick R, Yin H, Licad-Coles E, Kroetz DL, Szklarz G, et al. Structure− function relationships of human liver cytochromes P450 3A: aflatoxin B1 metabolism as a probe. Biochemistry. 1998;37:12536-45.

Uetsuka K. Mechanisms of mycotoxin-induced neurotoxicity through oxidative stress-associated pathways. International journal of molecular sciences. 2011;12:5213-37.

Halliwell B. Oxidative stress and cancer: have we moved forward? Biochemical Journal. 2006;401:1-11.

Bonsi P, Augusti-Tocco G, Palmery M, Giorgi M. Aflatoxin B1 is an inhibitor of cyclic nucleotide. General Pharmacology: The Vascular System. 1999;32:615-9.

de Lores Arnaiz GR, Ordieres MGL. Brain Na+, K+-ATPase activity in aging and disease. International journal of biomedical science: IJBS. 2014;10:85.

Zala D, Hinckelmann M-V, Yu H, Da Cunha MML, Liot G, Cordelières FP, et al. Vesicular glycolysis provides on-board energy for fast axonal transport. Cell. 2013;152:479-91.

Glaser V, Leipnitz G, Straliotto MR, Oliveira J, dos Santos VV, Wannmacher CMD, et al. Oxidative stress-mediated inhibition of brain creatine kinase activity by methylmercury. Neurotoxicology. 2010;31:454-60.

Schlattner U, Tokarska-Schlattner M, Wallimann T. Mitochondrial creatine kinase in human health and disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2006;1762:164-80.

Schlattner U, Klaus A, Rios SR, Guzun R, Kay L, Tokarska-Schlattner M. Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites. Amino Acids. 2016;48:1751-74.

Venkataraman P, Krishnamoorthy G, Selvakumar K, Arunakaran J. Oxidative stress alters creatine kinase system in serum and brain regions of polychlorinated biphenyl (Aroclor 1254)‐exposed rats: protective role of melatonin. Basic & clinical pharmacology & toxicology. 2009;105:92-7.

den Heever Van L, Dirr H. Effect of aflatoxin B1 on human platelet protein kinase C. The International journal of biochemistry. 1991;23:839-43.

Pedemonte CH, Pressley TA, Lokhandwala MF, Cinelli AR. Regulation of Na, K-ATPase transport activity by protein kinase C. The Journal of membrane biology. 1997;155:219-27.

Gopalakrishna R, Jaken S. Protein kinase C signaling and oxidative stress. Free Radical Biology and Medicine. 2000;28:1349-61.

Obis T, Hurtado E, Nadal L, Tomàs M, Priego M, Simon A, et al. The novel protein kinase C epsilon isoform modulates acetylcholine release in the rat neuromuscular junction. Molecular brain. 2015;8:80.

Towner RA, Qian SY, Kadiiska MB, Mason RP. In vivo identification of aflatoxin-induced free radicals in rat bile. Free Radical Biology and Medicine. 2003;35:1330-40.

Yener Z, Celik I, Ilhan F, Bal R. Effects of Urtica dioica L. seed on lipid peroxidation, antioxidants and liver pathology in aflatoxin-induced tissue injury in rats. Food and Chemical Toxicology. 2009;47:418-24.

Kanbur M, Eraslan G, Sarıca ZS, Aslan Ö. The effects of evening primrose oil on lipid peroxidation induced by subacute aflatoxin exposure in mice. Food and Chemical Toxicology. 2011;49:1960-4.

Olson LC, Bourgeois CH, Cotton RB, Harikul S, Grossman RA, Smith TJ. Encephalopathy and fatty degeneration of the viscera in northeastern Thailand. Clinical syndrome and epidemiology. Pediatrics. 1971;47:707-16.

Fung F, Clark RF. Health effects of mycotoxins: a toxicological overview. Journal of Toxicology: Clinical Toxicology. 2004;42:217-34.

Kimbrough T, Llewellyn G, Weekley L. The effect of Aflatoxin B 1 exposure on serotonin metabolism: Response to a tryptophan load. Metabolic brain disease. 1992;7:175-82.

Coulombe Jr RA, Sharma R. Clearance and excretion of intratracheally and orally administered aflatoxin B1 in the rat. Food and chemical toxicology. 1985;23:827-30.

Egbunike GN, Ikegwuonu FI. Effect of aflatoxicosis on acetylcholinesterase activity in the brain and adenohypophysis of the male rat. Neuroscience letters. 1984;52:171-4.

Coulombe Jr RA, Sharma RP. Effect of repeated dietary exposure of aflatoxin B1 on brain biogenic amines and metabolites in the rat. Toxicology and applied pharmacology. 1985;80:496-501.

Bahey NG, Elaziz HOA, Gadalla KKES. Toxic effect of aflatoxin B1 and the role of recovery on the rat cerebral cortex and hippocampus. Tissue and cell. 2015;47:559-66.

Tanaka T, Mizukami S, Hasegawa-Baba Y, Onda N, Sugita-Konishi Y, Yoshida T, et al. Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats. Toxicology. 2015;336:59-69.

da Silva AS, Santurio JM, Roza LF, Bottari NB, Galli GM, Morsch VM, et al. Aflatoxins produced by Aspergillus parasiticus present in the diet of quails increase the activities of cholinesterase and adenosine deaminase. Microbial pathogenesis. 2017;107:309-12.

Coulombe Jr RA. Nonhepatic disposition and effects of aflatoxin B1. The Toxicology of Aflatoxins: Elsevier; 1994. p. 89-101.

Lopez C, Ramos L, Bulacio L, Ramadan S, Rodriguez F. Aflatoxin B1 content in patients with hepatic diseases. MEDICINA-BUENOS AIRES-. 2002;62:313-6.

Bémeur C, Desjardins P, Butterworth RF. Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure. Journal of nutrition and metabolism. 2010;2010.

Butterworth RF. Complications of cirrhosis III. Hepatic encephalopathy. Journal of hepatology. 2000;32:171-80.

Lye MS, Ghazali AA, Mohan J, Alwin N, Nair RC. An outbreak of acute hepatic encephalopathy due to severe aflatoxicosis in Malaysia. The American journal of tropical medicine and hygiene. 1995;53:68-72.

Dvorackova I, Kusak V, Veselý D, Vesela J, Nesnidal P. Aflatoxin and encephalopathy with fatty degeneration of viscera (Reye). Annales de la nutrition et de l'alimentation1977. p. 977-89.

Ryan NJ, Hogan GR, Hayes AW, Unger PD, Siraj MV. Aflatoxin B1: its role in the etiology of Reye's syndrome. Pediatrics. 1979;64:71-5.

Cauli O. Brain Aquaporin 4 in Hyperammonemia. Medicina universitaria. 2010;12:47-53.

Wild CP, Montesano R. A model of interaction: aflatoxins and hepatitis viruses in liver cancer aetiology and prevention. Cancer letters. 2009;286:22-8.

Wu F, Khlangwiset P. Health economic impacts and cost-effectiveness of aflatoxin-reduction strategies in Africa: case studies in biocontrol and post-harvest interventions. Food Additives and Contaminants. 2010;27:496-509.

Strange RC, Spiteri MA, Ramachandran S, Fryer AA. Glutathione-S-transferase family of enzymes. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 2001;482:21-6.

Johnson WW, Ueng Y-F, Widersten M, Mannervik B, Hayes JD, Sherratt PJ, et al. Conjugation of highly reactive aflatoxin B1 exo-8, 9-epoxide catalyzed by rat and human glutathione transferases: estimation of kinetic parameters. Biochemistry. 1997;36:3056-60.

Stewart RK, Serabjit-Singh CJ, Massey TE. GlutathioneS-Transferase-Catalyzed Conjugation of Bioactivated Aflatoxin B1in Rabbit Lung and Liver. Toxicology and applied pharmacology. 1996;140:499-507.

Mehrzad J, Hosseinkhani S, Malvandi AM. Human Microglial Cells Undergo Proapoptotic Induction and Inflammatory Activation upon in vitro Exposure to a Naturally Occurring Level of Aflatoxin B1. Neuroimmunomodulation. 2018;25:176-83.

Mehrzad J, Malvandi AM, Alipour M, Hosseinkhani S. Environmentally relevant level of aflatoxin B1 elicits toxic pro-inflammatory response in murine CNS-derived cells. Toxicology letters. 2017;279:96-106.

Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends in neurosciences. 1996;19:312-8.

Parajuli B, Sonobe Y, Kawanokuchi J, Doi Y, Noda M, Takeuchi H, et al. GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. Journal of neuroinflammation. 2012;9:268.

Vogel DY, Kooij G, Heijnen PD, Breur M, Peferoen LA, van der Valk P, et al. GM‐CSF promotes migration of human monocytes across the blood brain barrier. European journal of immunology. 2015;45:1808-19.

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481.

Park S, Lee J-Y, You S, Song G, Lim W. Neurotoxic effects of aflatoxin B1 on human astrocytes in vitro and on glial cell development in zebrafish in vivo. Journal of hazardous materials. 2020;386:121639.




DOI: http://dx.doi.org/10.7575/aiac.abcmed.v.8n.3p.1

Refbacks

  • There are currently no refbacks.




Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

2013-2020 (CC-BY) Australian International Academic Centre PTY.LTD.

Advances in Bioscience and Clinical Medicine