Abstract
The present study was aimed at evaluating the influence of the subchronic exposure of cadmium (Cd), copper (Cu), and nickel (Ni) mixtures on affective behaviors, memory impairment, and oxidative stress (OS) in the hippocampus. Thirty male Wistar rats were divided into 5 equal groups. Group 1 (control) received a saline solution (NaCl 0.9%). Groups 2, 3, and 4 received Cd (0.25 mg/kg), Cu (0.5 mg/kg), and Ni (0.25 mg/kg), respectively, while group 5 received a Cd, Cu, and Ni mixture through intraperitoneal injections for 2 months. After the exposure period, all rats were submitted to behavioral tests. Subsequently, OS markers and histological changes in the rats’ hippocampi were assessed. Results showed that a 2-month exposure to the mixtures of metals (MM) has led to higher anxiety-like and depression-like behaviors and cognitive deficits in rats when compared to the control group and the individual metals. Furthermore, the MM induced heightened OS, evidenced by the rise in lipid peroxidation and nitric oxide levels. These effects were accompanied by a decrease in superoxide dismutase and catalase activities in the hippocampus. The histopathological analysis also supported that MM caused a neuronal loss in the CA3 sub-region. Overall, this study underscores that subchronic exposure to the Cd, Cu, and Ni mixture induces an OS status and histological changes in the hippocampus, with important affective and cognitive behavior variations in rats.
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References
Barbosa F (2017) Toxicology of metals and metalloids: promising issues for future studies in environmental health and toxicology. J Toxicol Environ Health A 80:137–144. https://doi.org/10.1080/15287394.2016.1259475
Lamtai M, Azirar S, Zghari O et al (2021) Melatonin ameliorates cadmium-induced affective and cognitive impairments and hippocampal oxidative stress in rat. Biol Trace Elem Res 199:1445–1455. https://doi.org/10.1007/s12011-020-02247-z
El Brouzi MY, Lamtai M, Zghari O et al (2021) Intrahippocampal effects of nickel injection on the affective and cognitive response in Wistar rat: potential role of oxidative stress. Biol Trace Elem Res 199:3382–3392. https://doi.org/10.1007/s12011-020-02457-5
Zhou F, Yin G, Gao Y et al (2020) Insights into cognitive deficits caused by low-dose toxic heavy metal mixtures and their remediation through a postnatal enriched environment in rats. J Hazard Mater 388:122081. https://doi.org/10.1016/j.jhazmat.2020.122081
Costa M, Salnikow K, Sutherland JE et al (2002) The role of oxidative stress in nickel and chromate genotoxicity. Mol Cell Biochem 234–235:265–275. https://doi.org/10.1023/A:1015909127833
Das KK, Das SN, Dhundasi SA (2008) Nickel, its adverse health effects & oxidative stress. Indian J Med Res 128:412–425
Babić Leko M, Langer Horvat L, Španić Popovački E et al (2023) Metals in Alzheimer’s disease. Biomedicines 11:1161. https://doi.org/10.3390/biomedicines11041161
Scheiber IF, Mercer JFB, Dringen R (2014) Metabolism and functions of copper in brain. Prog Neurobiol 116:33–57. https://doi.org/10.1016/j.pneurobio.2014.01.002
Sunderman FW, Dingle B, Hopfer SM, Swift T (1988) Acute nickel toxicity in electroplating workers who accidently ingested a solution of nickel sulfate and nickel chloride. Am J Ind Med 14:257–266. https://doi.org/10.1002/ajim.4700140303
Piotrowska A, Siwek A, Wolak M et al (2013) Involvement of the monoaminergic system in the antidepressant-like. J Physiol Pharmacol 64:493–498
Batool Z, Agha F, Tabassum S et al (2019) Prevention of cadmium-induced neurotoxicity in rats by essential nutrients present in nuts. Acta Neurobiol Exp (Warsz) 79:169–183. https://doi.org/10.21307/ane-2019-015
Neely CLC, Lippi SLP, Lanzirotti A, Flinn JM (2019) Localization of free and bound metal species through X-ray synchrotron fluorescence microscopy in the rodent brain and their relation to behavior. Brain Sci 9:74. https://doi.org/10.3390/brainsci9040074
Rezqaoui A, Ibouzine-dine L, Elhamzaoui A et al (2023) Potential role of oxidative stress in the effects of chronic administration of iron on affective and cognitive behavior on male Wistar rat. Biol Trace Elem Res 201:4812–4826. https://doi.org/10.1007/s12011-023-03560-z
Wu X, Cobbina SJ, Mao G et al (2016) A review of toxicity and mechanisms of individual and mixtures of heavy metals in the environment. Environ Sci Pollut Res 23:8244–8259. https://doi.org/10.1007/s11356-016-6333-x
Anyachor CP, Orish CN, Ezejiofor AN et al (2023) Nickel and aluminium mixture elicit memory impairment by activation of oxidative stress, COX-2, and diminution of AChE, BDNF and NGF levels in cerebral cortex and hippocampus of male albino rats. Curr Res Toxicol 5:100129. https://doi.org/10.1016/j.crtox.2023.100129
Karri V, Schuhmacher M, Kumar V (2016) Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: a general review of metal mixture mechanism in brain. Environ Toxicol Pharmacol 48:203–213. https://doi.org/10.1016/j.etap.2016.09.016
Lamtai M, Zghari O, Azirar S et al (2022) Melatonin modulates copper-induced anxiety-like, depression-like and memory impairments by acting on hippocampal oxidative stress in rat. Drug Chem Toxicol 45:1707–1715. https://doi.org/10.1080/01480545.2020.1858853
Wang H, Zhang L, Abel GM et al (2018) Cadmium exposure impairs cognition and olfactory memory in male C57BL/6 mice. Toxicol Sci 161:87–102. https://doi.org/10.1093/toxsci/kfx202
Kumar J, Sathua KB, Flora SJS (2019) Chronic copper exposure elicit neurotoxic responses in rat brain: assessment of 8-hydroxy-2-deoxyguanosine activity, oxidative stress and neurobehavioral parameters. Cell Mol Biol 65:27–35. https://doi.org/10.14715/cmb/2019.65.1.5
Smith MK, George EL, Stober JA et al (1993) Perinatal toxicity associated with nickel chloride exposure. Environ Res 61:200–211. https://doi.org/10.1006/enrs.1993.1064
Zamani beidokhti M, Mehrabadi S (2022) Effects of chronic administration of nickel on memory function, hippocampal neuronal morphology and oxidative stress factors in male adult rats. Arch Adv Biosci 13:1–5. https://doi.org/10.22037/aab.v13i2.35890
Janković S, Stošić M, Miljaković EA et al (2023) Cadmium dietary exposure assessment in the adult population and pre-school children in the Republic of Serbia. Food Addit Contam Part A 40:67–80. https://doi.org/10.1080/19440049.2022.2141467
Scientific Committee EFSA, More SJ, Bampidis V et al (2023) Re-evaluation of the existing health-based guidance values for copper and exposure assessment from all sources. EFSA J 21. https://doi.org/10.2903/j.efsa.2023.7728
EFSA Panel on Contaminants in the Food Chain (CONTAM), Schrenk D, Bignami M et al (2020) Update of the risk assessment of nickel in food and drinking water. EFSA J 18. https://doi.org/10.2903/j.efsa.2020.6268
Naranjo-Rodriguez EB, Osornio AO, Hernandez-Avitia E et al (2000) Anxiolytic-like actions of melatonin, 5-metoxytryptophol, 5-hydroxytryptophol and benzodiazepines on a conflict procedure. Prog Neuropsychopharmacol Biol Psychiatry 24:117–129. https://doi.org/10.1016/S0278-5846(99)00075-5
Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391. https://doi.org/10.1016/0014-2999(78)90118-8
Sierksma ASR, Van Den Hove DLA, Pfau F et al (2014) Improvement of spatial memory function in APPswe/PS1dE9 mice after chronic inhibition of phosphodiesterase type 4D. Neuropharmacology 77:120–130. https://doi.org/10.1016/j.neuropharm.2013.09.015
Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Method 11:47–60
Draper HH, Hadley M (1990) Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 186:421–431. https://doi.org/10.1016/0076-6879(90)86135-I
Chao CC, Hu S, Molitor TW et al (1992) Injury via a nitric oxide mechanism. Activated microglia mediate oxide neuronal cell injury via a nitric mechanism’. J Immunol 149:2736–2741
Beauchamp C, Fridovich I (1971) Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44:276–287. https://doi.org/10.1016/0003-2697(71)90370-8
Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126. https://doi.org/10.1016/S0076-6879(84)05016-3
Jalili C, Salahshoor MR, Pourmotabbed A et al (2014) The effects of aqueous extract of Boswellia Serrata on hippocampal region CA1 and learning deficit in kindled rats. Res Pharm Sci 9:351–358
Geronimo ACR, Melo ESP, Silva KRN et al (2021) Human health risk assessment of heavy metals and metalloids in herbal medicines used to treat anxiety: monitoring of safety. Front Pharmacol 12:772928. https://doi.org/10.3389/fphar.2021.772928
Bogdanova OV, Kanekar S, D’Anci KE, Renshaw PF (2013) Factors influencing behavior in the forced swim test. Physiol Behav 118:227–239. https://doi.org/10.1016/j.physbeh.2013.05.012
Adebiyi O, Adigun K, David-Odewumi P et al (2022) Gallic and ascorbic acids supplementation alleviate cognitive deficits and neuropathological damage exerted by cadmium chloride in Wistar rats. Sci Rep 12:14426. https://doi.org/10.1038/s41598-022-18432-0
Lamtai M, Chaibat J, Ouakki S et al (2018) Effect of chronic administration of cadmium on anxiety-like, depression-like and memory deficits in male and female rats: possible involvement of oxidative stress mechanism. J Behav Brain Sci 08:240–268. https://doi.org/10.4236/jbbs.2018.85016
Lamtai M, Chaibat J, Ouakki S et al (2018) Effect of chronic administration of nickel on affective and cognitive behavior in male and female rats: possible implication of oxidative stress pathway. Brain Sci 8:141. https://doi.org/10.3390/brainsci8080141
Lamtai M, Zghari O, Ouakki S et al (2020) Chronic copper exposure leads to hippocampus oxidative stress and impaired learning and memory in male and female rats. Toxicol Res 36:359–366. https://doi.org/10.1007/s43188-020-00043-4
Arruebarrena MA, Hawe CT, Lee YM, Branco RC (2023) Mechanisms of cadmium neurotoxicity. Int J Mol Sci 24:16558. https://doi.org/10.3390/ijms242316558
Song X, Fiati Kenston SS, Kong L, Zhao J (2017) Molecular mechanisms of nickel induced neurotoxicity and chemoprevention. Toxicology 392:47–54. https://doi.org/10.1016/j.tox.2017.10.006
Bulcke F, Dringen R, Scheiber IF (2017) Neurotoxicity of copper. In: Aschner M, Costa LG (eds) Neurotoxicity of metals. Springer International Publishing, Cham, pp 313–343
Maes M, Galecki P, Chang YS, Berk M (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 35:676–692. https://doi.org/10.1016/j.pnpbp.2010.05.004
Taniguti EH, Ferreira YS, Stupp IJV et al (2018) Neuroprotective effect of melatonin against lipopolysaccharide-induced depressive-like behavior in mice. Physiol Behav 188:270–275. https://doi.org/10.1016/j.physbeh.2018.02.034
Kalita J, Kumar V, Misra UK, Bora HK (2017) Memory and learning dysfunction following copper toxicity: biochemical and immunohistochemical basis. Mol Neurobiol 55:3800–3811. https://doi.org/10.1007/s12035-017-0619-y
Behzadfar L, Abdollahi M, Sabzevari O et al (2017) Potentiating role of copper on spatial memory deficit induced by beta amyloid and evaluation of mitochondrial function markers in the hippocampus of rats. Metallomics 9:969–980. https://doi.org/10.1039/c7mt00075h
Braun JM, Gennings C, Hauser R, Webster TF (2016) What can epidemiological studies tell us about the impact of chemical mixtures on human health? Environ Health Perspect 124. https://doi.org/10.1289/ehp.1510569
Ogunrinola OO, Wusu DA, Fajana OO et al (2016) Effect of low level cadmium exposure on superoxide dismutase activity in rat. Trop J Pharm Res 15:115. https://doi.org/10.4314/tjpr.v15i1.16
Das P, Samantaray S, Rout GR (1997) Studies on cadmium toxicity in plants: a review. Environ. Pollut. 98:29–36
Yu H, Jiang X, Lin X et al (2018) Hippocampal subcellular organelle proteomic alteration of copper-treated mice. Toxicol Sci 164:250–263. https://doi.org/10.1093/toxsci/kfy082
Misra M, Rodriguez RE, Kasprzak KS (1990) Nickel induced lipid peroxidation in the rat: correlation with nickel effect on antioxidant defense systems. Toxicology 64:1–17. https://doi.org/10.1016/0300-483X(90)90095-X
Poliandri AHB, Esquifino AI, Cano P et al (2006) In vivo protective effect of melatonin on cadmium-induced changes in redox balance and gene expression in rat hypothalamus and anterior pituitary. J Pineal Res 41:238–246. https://doi.org/10.1111/j.1600-079X.2006.00360.x
Manto M (2014) Abnormal copper homeostasis: mechanisms and roles in neurodegeneration. Toxics 2:327–345. https://doi.org/10.3390/toxics2020327
Garry PS, Ezra M, Rowland MJ et al (2015) The role of the nitric oxide pathway in brain injury and its treatment - from bench to bedside. Exp Neurol 263:235–243. https://doi.org/10.1016/j.expneurol.2014.10.017
Moncada S, Bolaños JP (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97:1676–1689. https://doi.org/10.1111/j.1471-4159.2006.03988.x
Albendea CD, Gómez-Trullén EM, Fuentes-Broto L et al (2007) Melatonin reduces lipid and protein oxidative damage in synaptosomes due to aluminium. J Trace Elem Med Biol 21:261–268. https://doi.org/10.1016/j.jtemb.2007.04.002
Acknowledgements
We are appreciative to the Biology Department staff at Ibn Tofail University’s Faculty of Science for their technical support. In addition, the authors would like to express their heartfelt and deepest condolences to the family and friends of Prof. Ali Ouichou, for his loss. The neuroscience family in Morocco will miss one of its significant members, and the University Ibn Tofail has lost a great academic professor, who has contributed to the growth of the neuroscience community in Morocco.
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Mouloud Lamtai, Hajar Benmhammed, and Sofia Azirar performed the experiments, analyzed the data, and wrote the paper. Ayoub Rezqaoui, Oussama Zghari, and Yassine Chahirou participated in behavioral analysis and statistical significance. Abdelghafour El Hamzaoui, Mohamed Yassine El Brouzi, Samir Bikri, and Abdelhalem Mesfioui reviewed and provided comments on the content and interpretation of the manuscript. Aboubaker El Hessni supervised the work and revised and approved the manuscript.
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Lamtai, M., Benmhammed, H., Azirar, S. et al. Subchronic Exposure to Mixture of Cadmium, Copper, and Nickel Induces Neurobehavioral Deficits and Hippocampal Oxidative Stress of Wistar Rats. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-024-04166-9
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DOI: https://doi.org/10.1007/s12011-024-04166-9