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Neurotoxicity and neuroinflammatory effects of bisphenol A in male rats: the neuroprotective role of grape seed proanthocyanidins

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Abstract

Exposure to bisphenol A (BPA) contributes to neurological disorders, but the underlying mechanisms are still not completely understood. We studied the neurotoxic effect of BPA and how it promotes inflammation and alteration in the neurotransmission synthesis, release, and transmission. This study was also designed to investigate the neuroprotective effect of grape seed proanthocyanidins (GSPE) against BPA-induced neurotoxicity in rats. Rats were equally divided into 4 groups with 7 rats in each: control group, BPA group, GSPE + BPA group, and GSPE group. Rats were orally treated with their respective doses (50 mg BPA/kg BW and/or 200 mg GSPE/kg BW) daily for 70 days. BPA elicits significant elevation in malondialdehyde (MDA) and nitric oxide (NO) associated with a significant reduction in glutathione (GSH), total thiols, glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione-S-transferase (GST). BPA exposure results in increased dopamine and serotonin levels, elevation in acetylcholinesterase (AChE) activity, and reduction in Na/K-ATPase and total ATPase activities in the brain. Also, BPA induces upregulation in the gene expression of the inflammatory markers, tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2), and in the tumor suppressor and pro-oxidant p53 protein. The pretreatment with GSPE attenuates or ameliorate all the oxidative and neurotoxic parameters induced by BPA. Our results suggest that GSPE has a promising role in modulating BPA-induced neuroinflammation and neurotoxicity and its antioxidant and free radical scavenging activities may in part be responsible for such effects.

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References

  • Abd Elkader H-TAE, Abdou HM, Khamiss OA, Essawy AE (2021) Anti-anxiety and antidepressant-like effects of astragaloside IV and saponins extracted from Astragalus spinosus against the bisphenol A-induced motor and cognitive impairments in a postnatal rat model of schizophrenia. Environmental Science and Pollution Research, 1-17

  • Abdel-Daim MM, El-Ela FIA, Alshahrani FK, Bin-Jumah M, Al-Zharani M, Almutairi B, Alyousif MS, Bungau S, Aleya L, Alkahtani S (2020) Protective effects of thymoquinone against acrylamide-induced liver, kidney and brain oxidative damage in rats. Environmental Science and Pollution Research 27:37709–37717

    CAS  Google Scholar 

  • Adefeghaa S, Oboha G, Odubanjoa T, Ogunsuyia O (2015) A comparative study on the antioxidative activities, anticholinesterase properties and essential oil composition of clove (Syzygium aromaticum) bud and Ethiopian pepper (Xylopia aethiopica). Riv. Ital. Sost. Gr 92:257–268

    Google Scholar 

  • Agarwal S, Yadav A, Tiwari SK, Seth B, Chauhan LKS, Khare P, Ray RS, Chaturvedi RK (2016) Dynamin-related protein 1 inhibition mitigates bisphenol A-mediated alterations in mitochondrial dynamics and neural stem cell proliferation and differentiation. Journal of Biological Chemistry 291:15923–15939

    CAS  Google Scholar 

  • Almaliti J, Nada SE, Carter B, Shah ZA, Tillekeratne LV (2013) Natural products inspired synthesis of neuroprotective agents against H2O2-induced cell death. Bioorganic & Medicinal Chemistry Letters 23:1232–1237

  • Amjad S, Rahman MS, Pang M-G (2020): Role of Antioxidants in Alleviating Bisphenol A Toxicity. Biomolecules 10, 1105

  • Bagchi D, Bagchi M, Stohs SJ, Ray SD, Sen CK, Preuss HG (2002) Cellular protection with proanthocyanidins derived from grape seeds. Annals of the New York Academy of Sciences 957:260–270

    CAS  Google Scholar 

  • Balci A, Ozkemahli G, Erkekoglu P, Zeybek ND, Yersal N, Kocer-Gumusel B (2020) Histopathologic, apoptotic and autophagic, effects of prenatal bisphenol A and/or di (2-ethylhexyl) phthalate exposure on prepubertal rat testis. Environmental Science and Pollution Research 27:20104–20116

    CAS  Google Scholar 

  • Bilal M, Iqbal HM, Barceló D (2019) Mitigation of bisphenol A using an array of laccase-based robust bio-catalytic cues–a review. Science of the Total Environment 689:160–177

    CAS  Google Scholar 

  • Braun JM, Muckle G, Arbuckle T, Bouchard MF, Fraser WD, Ouellet E, Séguin JR, Oulhote Y, Webster GM, Lanphear BP (2017) Associations of prenatal urinary bisphenol A concentrations with child behaviors and cognitive abilities. Environmental health perspectives 125:067008

    Google Scholar 

  • Chahine S, O'Donnell MJ (2011) Interactions between detoxification mechanisms and excretion in Malpighian tubules of Drosophila melanogaster. Journal of Experimental Biology 214:462–468

    CAS  Google Scholar 

  • Chomczynski P, Sacchi N (2006) The single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction: twenty-something years on. Nature protocols 1:581–585

    CAS  Google Scholar 

  • Chu H, Tang Q, Huang H, Hao W, Wei X (2016) Grape-seed proanthocyanidins inhibit the lipopolysaccharide-induced inflammatory mediator expression in RAW264. 7 macrophages by suppressing MAPK and NF-κb signal pathways. Environmental toxicology and pharmacology 41, 159-166

  • Chu KO, Chan S-O, Pang CP, Wang CC (2014) Pro-oxidative and antioxidative controls and signaling modification of polyphenolic phytochemicals: contribution to health promotion and disease prevention. Journal of agricultural and food chemistry 62:4026–4038

  • Cordani M, Butera G, Pacchiana R, Masetto F, Mullappilly N, Riganti C, Donadelli M (2020) Mutant p53-associated molecular mechanisms of ROS regulation in cancer cells. Biomolecules 10:361

    CAS  Google Scholar 

  • Davinelli S, Maes M, Corbi G, Zarrelli A, Willcox DC, Scapagnini G (2016) Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges. Immunity & Ageing 13:16

    Google Scholar 

  • Devi A, Jolitha AB, Ishii N (2006) Grape seed proanthocyanidin extract (GSPE) and antioxidant defense in the brain of adult rats. Medical Science Monitor 12:BR124–BR129

    CAS  Google Scholar 

  • Draper H, Hadley M (1990): [43] Malondialdehyde determination as index of lipid Peroxidation, Methods in enzymology. Elsevier, pp. 421-431

  • Elhelaly AE, AlBasher G, Alfarraj S, Almeer R, Bahbah EI, Fouda MM, Bungău SG, Aleya L, Abdel-Daim MM (2019) Protective effects of hesperidin and diosmin against acrylamide-induced liver, kidney, and brain oxidative damage in rats. Environmental Science and Pollution Research 26:35151–35162

    CAS  Google Scholar 

  • Ellman GL, Courtney KD, Andres V Jr, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology 7:88–95

    CAS  Google Scholar 

  • Eweda SM, Newairy ASA, Abdou HM, Gaber AS (2020) Bisphenol A-induced oxidative damage in the hepatic and cardiac tissues of rats: the modulatory role of sesame lignans. Experimental and Therapeutic Medicine 19:33–44

    CAS  Google Scholar 

  • Flohe L, Günzler WA (1984) [12] Assays of glutathione peroxidase. Methods in enzymology 105:114–120

    CAS  Google Scholar 

  • Griffith OW (1980) Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Analytical biochemistry 106:207–212

    CAS  Google Scholar 

  • Guevara I, Iwanejko J, Dembińska-Kieć A, Pankiewicz J, Wanat A, Anna P, Gołąbek I, Bartuś S, Malczewska-Malec M, Szczudlik A (1998) Determination of nitrite/nitrate in human biological material by the simple Griess reaction. Clinica Chimica Acta 274:177–188

    CAS  Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases the first enzymatic step in mercapturic acid formation. Journal of biological Chemistry 249:7130–7139

    CAS  Google Scholar 

  • Harbeoui H, Hichami A, Wannes WA, Lemput J, Tounsi MS, Khan N (2019) Anti-inflammatory effect of grape (Vitis vinifera L.) seed extract through the downregulation of NF-κB and MAPK pathways in LPS-induced RAW264. 7 macrophages. South African Journal of Botany 125:1–8

    CAS  Google Scholar 

  • Hassan HA, Al-Rawi MM (2013) Grape seeds proanthocyanidin extract as a hepatic-reno-protective agent against gibberellic acid induced oxidative stress and cellular alterations. Cytotechnology 65:567–576

    CAS  Google Scholar 

  • Hassani FV, Mehri S, Abnous K, Birner-Gruenberger R, Hosseinzadeh H (2017) Protective effect of crocin on BPA-induced liver toxicity in rats through inhibition of oxidative stress and downregulation of MAPK and MAPKAP signaling pathway and miRNA-122 expression. Food and Chemical Toxicology 107:395–405

    Google Scholar 

  • Jembrek MJ, Slade N, Hof PR, Šimić G (2018) The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease. Progress in Neurobiology 168:104–127

    Google Scholar 

  • Jiao J, Wei Y, Chen J, Chen X, Zhang Y (2017) Anti-aging and redox state regulation effects of A-type proanthocyanidins-rich cranberry concentrate and its comparison with grape seed extract in mice. Journal of Functional Foods 30:63–73

    CAS  Google Scholar 

  • Kamran H, Raza I, Saleem Y, Aslam M (2020) Health perspectives of grape seed extract (GSE). Asian Journal of Allied Health Sciences (AJAHS) 5:88–98

    Google Scholar 

  • Khan S, Beigh S, Chaudhari BP, Sharma S, Aliul Hasan Abdi S, Ahmad S, Ahmad F, Parvez S, Raisuddin S (2016) Mitochondrial dysfunction induced by Bisphenol A is a factor of its hepatotoxicity in rats. Environmental toxicology 31:1922–1934

    CAS  Google Scholar 

  • Khan J, Salhotra S, Goswami P, Akhter J, Jahan S, Gupta S, Sharma S, Banerjee BD, Parvez S, Gupta S (2019) Bisphenol A triggers axonal injury and myelin degeneration with concomitant neurobehavioral toxicity in C57BL/6J male mice. Toxicology 428:152299

    CAS  Google Scholar 

  • Lacy SH, Woeller CF, Thatcher TH, Maddipati KR, Honn KV, Sime PJ, Phipps RP (2016) Human lung fibroblasts produce proresolving peroxisome proliferator-activated receptor-γ ligands in a cyclooxygenase-2-dependent manner. American Journal of Physiology-Lung Cellular and Molecular Physiology 311:L855–L867

    Google Scholar 

  • Liu D, Xu Y (2011) p53, oxidative stress, and aging. Antioxidants & redox signaling 15:1669–1678

    CAS  Google Scholar 

  • Liu J, Hu S, Zhu B, Shao S, Yuan L (2020) Grape seed procyanidin suppresses inflammation in cigarette smoke-exposed pulmonary arterial hypertension rats by the PPAR-γ/COX-2 pathway. Nutrition, Metabolism and Cardiovascular Diseases 30:347–354

    CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. Journal of biological chemistry 193:265–275

    CAS  Google Scholar 

  • Makkar R, Behl T, Bungau S, Zengin G, Mehta V, Kumar A, Uddin M, Ashraf GM, Abdel-Daim MM, Arora S (2020) Nutraceuticals in neurological disorders. International Journal of Molecular Sciences 21:4424

    CAS  Google Scholar 

  • Marklund S, Marklund G (1974) Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. European journal of biochemistry 47:469–474

    CAS  Google Scholar 

  • Martín-González MZ, Palacios-Jordan H, Mas-Capdevila A, Rodríguez MA, Bravo FI, Muguerza B, Aragonès G (2021) A multifunctional ingredient for the management of metabolic syndrome in cafeteria diet-fed rats. Food & Function 12:815–824

    Google Scholar 

  • Masato A, Plotegher N, Boassa D, Bubacco L (2019) Impaired dopamine metabolism in Parkinson’s disease pathogenesis. Molecular neurodegeneration 14, 1-21

  • Michałowicz J (2014) Bisphenol A–sources, toxicity and biotransformation. Environmental Toxicology and Pharmacology 37:738–758

    Google Scholar 

  • Mohammed ET, Hashem KS, Ahmed AE, Aly MT, Aleya L, Abdel-Daim MM (2020) Ginger extract ameliorates bisphenol A (BPA)-induced disruption in thyroid hormones synthesis and metabolism: involvement of Nrf-2/HO-1 pathway. Science of the Total Environment 703:134664

    CAS  Google Scholar 

  • Mohammed ET, Safwat GM (2020) Grape Seed Proanthocyanidin Extract Mitigates Titanium Dioxide Nanoparticle (TiO 2-NPs)–Induced Hepatotoxicity Through TLR-4/NF-κB Signaling Pathway. Biological trace element research 196, 579-589

  • Montgomery SL, Bowers WJ (2012) Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. Journal of neuroimmune pharmacology 7:42–59

    Google Scholar 

  • Monzani E, Nicolis S, DellʼAcqua S, Capucciati A, Bacchella C, Zucca FA, Mosharov EV, Sulzer D, Zecca L, Casella L (2019) Dopamine, oxidative stress and protein–quinone modifications in Parkinsonʼs and other neurodegenerative diseases. Angewandte Chemie International Edition 58:6512–6527

    CAS  Google Scholar 

  • Mucci F, Marazziti D, Della Vecchia A, Baroni S, Morana P, Carpita B, Mangiapane P, Morana F, Morana B, Dell’Osso L (2020) State-of-the-art: inflammatory and metabolic markers in mood disorders. Life 10:82

    CAS  Google Scholar 

  • Musachio EAS, Araujo SM, Bortolotto VC, de Freitas CS, Dahleh MMM, Poetini MR, Jardim EF, Meichtry LB, Ramborger BP, Roehrs R (2020) Bisphenol A exposure is involved in the development of Parkinson like disease in Drosophila melanogaster. Food and Chemical Toxicology 137:111128

    CAS  Google Scholar 

  • Niranjan R (2018) Recent advances in the mechanisms of neuroinflammation and their roles in neurodegeneration. Neurochemistry international 120:13–20

    CAS  Google Scholar 

  • Oprea OB, Apostol L, Bungau S, Cioca G, Samuel AD, Badea M, Gaceu L (2018) Researches on the chemical composition and the rheological properties of wheat and grape epicarp flour mixes. Rev. Chim 69:70–75

    CAS  Google Scholar 

  • Paul R, Phukan BC, Thenmozhi AJ, Manivasagam T, Bhattacharya P, Borah A (2018) Melatonin protects against behavioral deficits, dopamine loss and oxidative stress in homocysteine model of Parkinsonʼs disease. Life sciences 192:238–245

    CAS  Google Scholar 

  • Raisuddin S, Sharma S (2017) Endocrine-disrupting chemicals in food and their toxicological implications, Food Toxicology. Apple Academic Press, pp.:199–250

  • Razavi BM, Hosseinzadeh H (2020): Antioxidant effects of Curcuma longa and its active constituent, curcumin, for the therapy of neurological disorders, oxidative stress and dietary antioxidants in neurological diseases. Elsevier, pp. 249-269

  • Resnik DB, Elliott KC (2015) Bisphenol A and risk management ethics. Bioethics 29:182–189

    Google Scholar 

  • Salvadó MJ, Casanova E, Fernández-Iglesias A, Arola L, Bladé C (2015) Roles of proanthocyanidin rich extracts in obesity. Food & function 6:1053–1071

    Google Scholar 

  • Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellmanʼs reagent. Analytical biochemistry 25:192–205

    CAS  Google Scholar 

  • Shrivastava AN, Triller A, Melki R (2020) Cell biology and dynamics of Neuronal Na+/K+-ATPase in health and diseases. Neuropharmacology 169:107461

  • Singh A, Kukreti R, Saso L, Kukreti S (2019) Oxidative stress: a key modulator in neurodegenerative diseases. Molecules 24:1583

    CAS  Google Scholar 

  • Solleiro-Villavicencio H, Rivas-Arancibia S (2018) Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4+ T cells in neurodegenerative diseases. Frontiers in Cellular Neuroscience 12:114

  • Song H, Park J, Bui PT, Choi K, Gye MC, Hong Y-C, Kim JH, Lee YJ (2017) Bisphenol A induces COX-2 through the mitogen-activated protein kinase pathway and is associated with levels of inflammation-related markers in elderly populations. Environmental Research 158:490–498

    CAS  Google Scholar 

  • Stoker C, Andreoli MF, Kass L, Bosquiazzo VL, Rossetti MF, Canesini G, Luque EH, Ramos JG (2020) Perinatal exposure to bisphenol A (BPA) impairs neuroendocrine mechanisms regulating food intake and kisspetin system in adult male rats. Evidences of metabolic disruptor hypothesis. Molecular and cellular endocrinology 499:110614

    CAS  Google Scholar 

  • Sutcliffe TC, Winter AN, Punessen NC, Linseman DA (2017) Procyanidin B2 protects neurons from oxidative, nitrosative, and excitotoxic stress. Antioxidants 6:77

    Google Scholar 

  • Tyl R, Myers C, Marr M, Thomas B, Keimowitz A, Brine D, Veselica M, Fail P, Chang T, Seely J (2002) Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats. Toxicological Sciences 68:121–146

    CAS  Google Scholar 

  • Ullah A, Munir S, Badshah SL, Khan N, Ghani L, Poulson BG, Emwas A-H, Jaremko M (2020) Important flavonoids and their role as a therapeutic agent. Molecules 25:5243

    CAS  Google Scholar 

  • Unusan N (2020) Proanthocyanidins in grape seeds: an updated review of their health benefits and potential uses in the food industry. Journal of Functional Foods 67:103861

    CAS  Google Scholar 

  • Wu J-P, Li M-H (2015) Inhibitory effects of pain relief drugs on neurological enzymes: implications on their potential neurotoxicity to aquatic animals. Environmental toxicology and pharmacology 39:898–905

    CAS  Google Scholar 

  • Yousef M, Saad A, El-Shennawy L (2009) Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. Food and Chemical Toxicology 47:1176–1183

    CAS  Google Scholar 

  • Yun S, Chu D, He X, Zhang W, Feng C (2020) Protective effects of grape seed proanthocyanidins against iron overload-induced renal oxidative damage in rats. Journal of Trace Elements in Medicine and Biology 57:126407

    CAS  Google Scholar 

  • Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Lu D, Wei W, Wang Y, Li H (2019) Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Scientific reports 9:1–12

    Google Scholar 

  • Zhou D-Y, Du Q, Li R-R, Huang M, Zhang Q, Wei G-Z (2011) Grape seed proanthocyanidin extract attenuates airway inflammation and hyperresponsiveness in a murine model of asthma by downregulating inducible nitric oxide synthase. Planta medica 77:1575–1581

    CAS  Google Scholar 

  • Zhou F, Yin M, Liu Y, Han X, Guo J, Ren C, Wang W, Huang W, Zhan J, You Y (2019) Grape seed flour intake decreases adiposity gain in high-fat-diet induced obese mice by activating thermogenesis. Journal of Functional Foods 62:103509

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Zoology, Faculty of Science, Alexandria University, Alexandria, 21561, Egypt

    Heba M. Abdou & Amel H. El-Gendy

  2. Zoology, Biological and Geological Sciences Department, Faculty of Education, Alexandria University, Alexandria, Egypt

    Heba-Tallah Abd Elrahim Abd Elkader

  3. Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, 21561, Egypt

    Saber Mohamed Eweda

  4. Medical Laboratories Technology Department, College of Applied Medical Sciences, Taibah University, Madinah, Kingdom of Saudi Arabia

    Saber Mohamed Eweda

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  1. Heba M. Abdou
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  2. Heba-Tallah Abd Elrahim Abd Elkader
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  4. Saber Mohamed Eweda
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Contributions

Heba Mohamed Abdou and Heba-Tallah Abd Elkader conceived and designed the study and collected the data. Heba Mohamed Abdou, Heba-Tallah Abd Elkader, Saber M. Eweda, and Amel H. El-Gendy performed the experiments, analyzed the data, and prepared the figures and/or tables. Saber M. Eweda wrote the manuscript. All authors read, authored, and approved the final manuscript submitted for publication.

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All the experimental and animal handling procedures were performed according to the guidelines approved by Alexandria University Institutional Animal Care and Use Committee (ALEXU-IACUC), a member of the International Council for Laboratory Animal Science (ICLAS) (Approval number: AU04200125201).

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Abdou, .M., Abd Elkader, HT.A.E., El-Gendy, A.H. et al. Neurotoxicity and neuroinflammatory effects of bisphenol A in male rats: the neuroprotective role of grape seed proanthocyanidins. Environ Sci Pollut Res 29, 9257–9268 (2022). https://doi.org/10.1007/s11356-021-16311-1

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