Abstract
Benzo[a]pyrene (BaP) is an environmental contaminant produced during incomplete combustion of organic material that is well known as a mutagenic and carcinogenic toxin. There are few studies addressing the molecular and cellular basis of behavioural alterations related to BaP exposure. The aim of this study was to evaluate the effect of subchronic oral administration of BaP on behavioral and neurochemical parameters. Wistar male rats received BaP (2 mg/kg) or corn oil (control), once a day for 28 days (n = 12/group). Spontaneous locomotor activity and short- and long-term memories were evaluated. Glial fibrillary acid protein and S100B content in the hippocampus, serum and CSF were measured using ELISA and total and phosphorylated forms of mitogen activated protein kinases (MAPKs) named extracellular signal-regulated kinases 1 and 2, p38MAPK and c-Jun amino-terminal kinases 1 and 2, in the hippocampus, were evaluated by western blotting. BaP induced a significant increase on locomotor activity and a decrease in short-term memory. S100B content was increased significantly in cerebrospinal fluid. BaP induced a decrease on ERK2 phosphorylation in the hippocampus. Thus, BaP subchronic treatment induces an astroglial response and impairs both motor and cognitive behavior, with parallel inhibition of ERK2, a signaling enzyme involved in the hippocampal neuroplasticity. All these effects suggest that BaP neurotoxicity is a concern for environmental pollution.
Similar content being viewed by others
References
ATSDR (1995) Toxicological profile for polycyclic aromatic hydrocarbons (PAHs). In: Agency for Toxic Substances and Disease Registry, Atlanta, GA
Liu SH, Wang JH, Chuu JJ, Lin-Shiau SY (2002) Alterations of motor nerve functions in animals exposed to motorcycle exhaust. J Toxicol Environ Health A 65:803–812
IARC (2012) Benzo[a]pyrene. NB: overall evaluation upgraded to Group 1 based on mechanistic and other relevant data. IARC Monogr Eval Carcinog Risk Chem Man 92:111–144
Enomoto M, Tierney WJ, Nozaki K (2008) Risk of human health by particulate matter as a source of air pollution—comparison with tobacco smoking. J Toxicol Sci 33:251–267
IARC (1973) Certain polycyclic aromatic hydrocarbons and heterocyclic compounds. IARC Monogr Eval Carcinog Risk Chem Man 3:1–271
Das M, Mukhtar H, Seth P (1985) Distribution of benzo(a)pyrene in discrete regions of rat brain. Bull Environ Contam Toxicol 35:500–504
Yan T, Chengzhi C, Haiyan Y, Baijie T (2010) Distribution of benzo[a]pyrene in discrete regions of rat brain tissue using light microscopic autoradiography and gamma counting. Toxicol Environ Chem 92:1309–1317
Zola-Morgan SM, Squire LR (1990) The primate hippocampal formation: evidence for a time-limited role in memory storage. Science 250:288–290
Lubenov EV, Siapas AG (2009) Hippocampal theta oscillations are travelling waves. Nature 459:534–539
Tang Q, Xia YY, Cheng SQ, Tu BJ (2011) Modulation of behavior and glutamate receptor mRNA expression in rats after sub-chronic administration of benzo(a)pyrene. Biomed Environ Sci 24:408–414
Xia Y, Cheng S, He J, Liu X, Tang Y, Yuan H, He L, Lu T, Tu B, Wang Y (2011) Effects of subchronic exposure to benzo[a]pyrene (B[a]P) on learning and memory, and neurotransmitters in male Sprague–Dawley rat. Neurotoxicology 32:188–198
Nie J, Duan L, Yan Z, Niu Q (2013) Tau hyperphosphorylation is associated with spatial learning and memory after exposure to benzo[a]pyrene in SD rats. Neurotox Res 24:461–471
Patri M, Singh A, Mallick BN (2013) Protective role of noradrenaline in benzo[a]pyrene-induced learning impairment in developing rat. J Neurosci Res 91:1450–1462
Chengzi C, Yan T, Shuqun C, Xuejun J, Youbin Q, Yinyin X, Quian T, Baijie T (2011) New candidate proteins for benzo(a)pyrene-induced spatial learning and memory deficits. J Toxicol Sci 36:163–171
Chongying Q, Bin P, Shuqun C, Yinyian X, Baijie T (2013) The effect of occupational exposure to benzo[a]pyrene on neurobehavioral function in coke oven workers. Am J Ind Med 56:347–355
Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25:1439–1451
Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, Tubaro C, Giambanco I (2009) S100B’s double life: intracellular regulator and extracellular signal. Biochim Biophys Acta 1793:1008–1022
Van Eldik LJ, Wainwright MS (2003) The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 21:97–108
Andreazza AC, Cassini C, Rosa AR, Leite MC, de Almeida LM, Nardin P, Cunha AB, Cereser KM, Santin A, Gottfried C, Salvador M, Kapczinski F, Gonçalves CA (2007) Serum S100B and antioxidant enzymes in bipolar patients. J Psychiatr Res 41:523–529
Vicente E, Boer M, Leite M, Silva M, Tramontina F, Porciuncula L, Dalmaz C, Gonçalves CA (2004) Cerebrospinal fluid S100B increases reversibly in neonates of methyl mercury-intoxicated pregnant rats. Neurotoxicology 25:771–777
Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:1–7
Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183
Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83
Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH (2001) MAP kinases. Chem Rev 101:2449–2476
Jerusalinsky D, Ferreira MB, Walz R, Da Silva RC, Bianchin M, Ruschel AC, Zanatta MS, Medina JH, Izquierdo I (1992) Amnesia by post-training infusion of glutamate receptor antagonists into the amygdala, hippocampus, and entorhinal cortex. Behav Neural Biol 58:76–80
Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76:1–10
Runchel C, Matsuzawa A, Ichijo H (2011) Mitogen-activated protein kinases in mammalian oxidative stress responses. Antioxid Redox Signal 15:205–218
Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405
Sanderson JL, Dell’Acqua ML (2011) AKAP signaling complexes in regulation of excitatory synaptic plasticity. Neuroscientist 17:321–336
Olfert ED, Cross BM, McWilliam A (1998) Manual sobre el cuidado y uso de los animales de experimentación. Canadian Council on Animal Care, Ontario
OECD (1995) Organisation for Economic Co-operation and Development. Guideline 407: repeated Dose 28-day Oral Toxicity Study in Rodent. Head of Publications Service, Paris
Creese I, Burt DR, Snyder SH (1976) Dopamine-receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483
Schröder N, O’Dell SJ, Marshall JF (2003) Neurotoxic methamphetamine regimen severely impairs recognition memory in rats. Synapse 49:89–96
de Lima MNM, Laranja DC, Caldana F, Bromberg E, Roesler R, Schröder N (2005) Reversal of age-related deficits in object recognition memory in rats with l-deprenyl. Exp Gerontol 40:506–511
de Lima MNM, Polydoro M, Laranja DC, Bonatto F, Bromberg E, Moreira JC, Dal-Pizzol F, Schröder N (2005) Recognition memory impairment and brain oxidative stress induced by postnatal iron administration. Eur J Neurosci 2:2521–2528
Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1. Behavioral data. Behav Brain Res 31:47–59
Soellner DE, Grandys T, Nuñez JL (2009) Chronic prenatal caffeine exposure impairs novel object recognition and radial arm maze behaviors in adult rats. Behav Brain Res 205:191–199
Moojen VKM, Damiani-Neves M, Bavaresco BV, Pescador BB, Comim CM, Quevedo J, Boeck CR (2012) NMDA preconditioning prevents object recognition memory impairment and increases brain viability in mice exposed to traumatic brain injury. Brain Res 23:82–90
Netto CB, Conte S, Leite MC, Pires C, Martins TL, Vidal P, Benfato MS, Giugliani R, Gonçalves CA (2006) Serum S100B protein is increased in fasting rats. Arch Med Res 37:683–686
Lopes MW, Soares FM, de Mello N, Nunes JC, Caiado AG, de Brito D, de Cordova FM, da Cunha RM, Walz R, Leal RB (2013) Time-dependent modulation of AMPA receptor phosphorylation and mRNA expression of NMDA receptors and glial glutamate transporters in the rat hippocampus and cerebral cortex in a pilocarpine model of apilepsy. Exp Brain Res 226:153–163
Leite MC, Galland F, Brolese G, Guerra MC, Bortolotto JW, Freitas R, Almeida LM, Gottfried C, Gonçalves CA (2008) A simple, sensitive and widely applicable ELISA for S100B: methodological features of the measurement of this glial protein. J Neurosci Methods 169:93–99
Tramontina F, Leite MC, Cereser K, de Souza DF, Tramontina AC, Nardin P, Andreazza AC, Gottfried C, Kapczinski F, Gonçalves CA (2007) Immunoassay for glial fibrillary acidic protein: antigen recognition is affected by its phosphorylation state. J Neurosci Methods 162:282–286
Oliveira CS, Rigon AP, Leal RB, Rossi FM (2008) The activation of ERK1/2 and p38 mitogen-activated protein kinases is dynamically regulated in the developing rat visual system. Int J Dev Neurosci 26:355–362
Peterson GLA et al (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83:346–356
Leal RB, Cordova FM, Herd L, Bobrovskaya L, Dunkley PR (2002) Lead-stimulated p38 MAPK-dependent Hsp27 phosphorylation. Toxicol Appl Pharmacol 178:44–51
Cordova FM, Rodrigues AL, Giacomelli MB, Oliveira CS, Posser T, Dunkley PR, Leal RB (2004) Lead stimulates ERK1/2 and p38 MAPK phosphorylation in the hippocampus of immature rats. Brain Res 998:65–72
Bjerrum OJH, Heegaard NHH (1988) CRC handbook of immunoblotting of proteins, vol I. CRC Press, London
Posser T, de Aguiar CB, Garcez RC, Rossi FM, Oliveira CS, Trentin AG, Neto VM, Leal RB (2007) Exposure of C6 glioma cells to Pb(II) increases the phosphorylation of p38(MAPK) and JNK1/2 but not of ERK1/2. Arch Toxicol 81:407–414
Saunders CR, Ramesh A, Shockley DC (2002) Modulation of neurotoxic behavior in F-344 rats by temporal disposition of benzo(a)pyrene. Toxicol Lett 129:33–45
Saunders CR, Das SK, Ramesh A, Shockley DC, Mukherjee S (2006) Benzo(a)pyrene-induced acute neurotoxicity in the F-344 rat: role of oxidative stress. J Appl Toxicol 26:427–438
Sik A, van Nieuwehuyzen P, Prickaerts J, Blokland A (2003) Performance of different mouse strains in an object recognition task. Behav Brain Res 147:49–54
Farina M, Cereser V, Portela LV, Mendez A, Porciúncula LO, Fornaguera J, Gonçalves CA, Wofchuk ST, Rocha JB, Souza DO (2005) Methylmercury increases S100B content in rat cerebrospinal fluid. Environ Toxicol Pharmacol 19:249–253
Gonçalves CA, Leite MC, Nardin P (2008) Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem 41:755–763
Michetti F, Corvino V, Geloso MC, Lattanzi W, Bernardini C, Serpero L, Gazzolo D (2012) The S100B protein in biological fluids: more than a lifelong biomarker ofbrain distress. J Neurochem 120:644–659
Alvarez JI, Katayama T, Prat A (2013) Glial influence on the blood brain barrier. Glia 61:1939–1958
Gu J, Chan LS, Wong CK, Wong NS, Wong CK, Leung KN, Mak NK (2011) Effect of benzo[a]pyrene on the production of vascular endothelial growth factor by human eosinophilic leukemia EoL-1 cells. J Environ Pathol Toxicol Oncol 30:241–249
Gonçalves CA, Leite MC, Guerra MC (2010) Adipocytes as an important source of serum S100B and possible roles of this protein in adipose tissue. Cardiovasc Psychiatry Neurol 2010:790431
Chaves ML, Camozzato AL, Ferreira ED, Piazenski I, Kochhann R, Dall’Igna O, Mazzini GS, Souza DO, Portela LV (2010) Serum levels of S100B and NSE proteins in Alzheimer’s disease patients. J Neuroinflamm 7:6
Guerra MC, Tortorelli LS, Galland F, Da Ré C, Negri E, Engelke DS, Rodrigues L, Leite MC, Gonçalves CA (2011) Lipopolysaccharide modulates astrocytic S100B secretion: a study in cerebrospinal fluid and astrocyte cultures from rats. J Neuroinflamm 8:128
Lin T, Mak NK, Yang MS (2008) MAPK regulate p53 dependent cell death induced by benzo[a]pyrene: involvement of p53 phosphorylation and acetylation. Toxicology 247:145–153
Song MK, Kim YJ, Song M, Choi HS, Park YK, Ryu JC (2011) Polycyclic aromatic hydrocarbons induce migration in human hepatocellular carcinoma cells (HepG2) through reactive oxygen species-mediated p38 MAPK signal transduction. Cancer Sci 102:1636–1644
Torii S, Nakayama K, Yamamoto T, Nishida E (2004) Regulatory mechanisms and function of ERK MAP kinases. J Biochem 136:557–561
Iryo Y, Matsuoka M, Wispriyono B, Sugiura T, Igisu H (2000) Involvement of the extracellular signal regulated protein kinase (ERK) pathway in the induction of apoptosis by cadmium chloride in CCRFCEM cells. Biochem Pharmacol 60:1875–1882
Igaz LM, Winograd M, Cammarota M, Izquierdo LA, Alonso M, Izquierdo I, Medina JH (2006) Early activation of extracellular signal-regulated kinase signaling pathway in the hippocampus is required for short-term memory formation of a fear-motivated learning. Cell Mol Neurobiol 26:989–1002
Weng MW, Hsiao YM, Chen CJ, Wang JP, Chen WC, Ko JL (2004) Benzo[a]pyrene diol epoxide up-regulates COX-2 expression through NF-kappaB in rat astrocytes. Toxicol Lett 151:345–355
Bae MK, Kim SR, Lee HJ, Wee HJ, Yoo MA, Ock OS, Baek SY, Kim BS, Kim JB, Sik-Yoon, Bae SK (2006) Aspirin-induced blockade of NF-kappaB activity restrains up-regulation of glial fibrillary acidic protein in human astroglial cells. Biochim Biophys Acta 1763:282–289
Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW (2004) Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 89:1092–1100
Acknowledgments
The study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Instituto Nacional de Ciência e Tecnologia para (INCT) a Análise Integrada do Risco Ambiental.
Conflict of interest
The authors declared that there are no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Maciel, É.S., Biasibetti, R., Costa, A.P. et al. Subchronic Oral Administration of Benzo[a]pyrene Impairs Motor and Cognitive Behavior and Modulates S100B Levels and MAPKs in Rats. Neurochem Res 39, 731–740 (2014). https://doi.org/10.1007/s11064-014-1261-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-014-1261-y