Environmental Science and Pollution Research

, Volume 26, Issue 10, pp 9632–9639 | Cite as

Cadmium level in brain correlates with memory impairment in F1 and F2 generation mice: improvement with quercetin

  • Sumita HalderEmail author
  • Rajarshi Kar
  • Sucharita Chakraborty
  • Swapan K. Bhattacharya
  • Pramod K. Mediratta
  • Basu D. Banerjee
Research Article


The increased exposure to cadmium (Cd) through environmental pollutants, food and cigarette smoke is a concern worldwide. The association of Cd with impaired learning disabilities led us to hypothesise that cadmium levels in brain tissue could be dose-dependently related to the extent of memory impairment and oxidative stress. In this study, we proposed to study whether cadmium exposure to dams could alter the brain Cd levels, memory parameters, antioxidant enzymes in brain and their gene expression in the F1-F2 generation mice and whether quercetin could modulate this effect. Animals were administered Cd alone and in combination with quercetin for 7 days during their gestation period. Their newborn pups (F1 and F2 mice) were reared until adulthood and were tested for memory using Morris water maze and step-down latency test. The brain tissue of F1 mice was collected. Cd levels were estimated using the atomic absorption spectrophotometer. G-S-transferase (GST) and catalase (CAT) activity were measured and fold increase in their respective gene expression was observed using the RT-PCR method. Cd levels were significantly increased in the brain tissue of animals exposed to Cd but cotreatment with quercetin showed decreased levels in both generations. Memory impairment was observed in animals of F1 generation exposed to Cd and cotreatment with quercetin (100 mg/kg) reversed this effect. Cd exposure significantly enhanced both activity and expression of GST and CAT in the brain tissue of F1 generation mice and quercetin attenuated this effect. In F2 generation, results were variable. GST activity and expression increased with Cd and decreased with quercetin cotreatment. However, CAT activity showed no significant change despite a decrease in gene expression. Quercetin cotreatment enhanced activity as well gene expression in F2 generation. Our study insinuates that Cd levels could act as a predictor of memory impairment and altered enzyme activity and gene expression in brain tissue. Quercetin helped to reduce Cd levels in brain tissue of F1 and F2 generation and modulated the antioxidant system of the cell by affecting expression of antioxidant enzymes at the transcription level.


Cadmium Atomic absorption spectrophotometer  Morris water maze Step-down latency 



The authors are grateful to the Metal Speciation Lab at CSIR, National Institute of Oceanography, Dona Paula, Goa, India for the estimation of metals in the samples.

Compliance with ethical standards

The study was duly approved by the Institutional Animal Ethics Committee, University College of Medical Sciences, Delhi.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Acharya U, Mishra M, Patro J, Panda M (2008) Effect of vitamins C and E on spermatogenesis in mice exposed to cadmium. Reprod Toxicol 25:84–88CrossRefGoogle Scholar
  2. Alvarez AI, Real R, Pérez M, Mendoza G, Prieto JG, Merino G (2010) Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response. J Pharm Sci 99:598–617CrossRefGoogle Scholar
  3. Brand W, Schutte ME, Williamson G, van Zanden JJ, Cnubben NH, Groten JP, van Bladeren PJ, Rietjens IM (2006) Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed Pharmacother 60:508–519CrossRefGoogle Scholar
  4. Brandeis R, Brandys Y, Yehuda S (1989) The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48:29–69CrossRefGoogle Scholar
  5. Fongsupa S, Soodvilai S, Muanprasat C, Chatsudthipong V, Soodvilai S (2015) Activation of liver X receptors inhibits cadmium-induced apoptosis of human renal proximal tubular cells. Toxicol Lett 236:145–153CrossRefGoogle Scholar
  6. Chakraborty P, Ramteke D, Chakraborty S, Chennuri K, Bardhan P (2015) Relationship between the lability of sediment-bound Cd and its bioaccumulation in edible oyster. Mar Pollut Bull 100:344–351Google Scholar
  7. Goering P, Waalkes M, Klaasen C (1994) Toxicology of cadmium. In: Goyer R, Cherian M (eds) Handbook of experimental pharmacology: toxicology of metals, biochemical effects, vol 115. Springer-Verlag, New York, pp 189–214Google Scholar
  8. Gupta S, Garg GR, Bharal N, Mediratta PK, Banerjee BD, Sharma KK (2009) Reversal of propoxur-induced impairment of step-down passive avoidance, transfer latency and oxidative stress by piracetam and ascorbic acid in rats. Environ Toxicol Pharmacol 28:403–408CrossRefGoogle Scholar
  9. Halder S, Kar R, Chandra N, Nimesh A, Mehta AK, Bhattacharya SK, Mediratta PK, Banerjee BD (2018) Alteration in cognitive behaviour, brain antioxidant enzyme activity their gene expression in F1 generation mice, following Cd exposure during the late gestation period: modulation by quercetin. Metab Brain Dis 33:1935–1943CrossRefGoogle Scholar
  10. Halder S, Kar R, Galav V, Mehta AK, Bhattacharya SK, Mediratta PK, Banerjee BD (2016a) Cadmium exposure during lactation causes learning and memory-impairment in F1 generation mice: amelioration by quercetin. Drug Chem Toxicol 39:272–278CrossRefGoogle Scholar
  11. Halder S, Kar R, Mehta AK, Bhattacharya SK, Mediratta PK, Banerjee BD (2016b) Quercetin modulates the effects of chromium exposure on learning, memory and antioxidant enzyme activity in F1 generation mice. Biol Trace Elem Res 171:391–398CrossRefGoogle Scholar
  12. Hasanuzzaman M, Nahar K, Anee TI, Fujita M (2017) Exogenous silicon attenuates cadmium-induced oxidative stress in Brassica napus L. by modulating AsA-GSH pathway and glyoxalase system. Front Plant Sci 8:1061CrossRefGoogle Scholar
  13. Ivanina AV, Sokolova IM (2008) Effects of cadmium exposure on expression and activity of P-glycoprotein in eastern oysters, Crassostrea virginica Gmelin. Aquat Toxicol 88:19–28CrossRefGoogle Scholar
  14. Jacobo-Estrada T, Santoyo-Sánchez M, Thévenod F, Barbier O (2017) Cadmium handling, toxicity and molecular targets involved during pregnancy: lessons from experimental models. Int J Mol Sci 18:7CrossRefGoogle Scholar
  15. Jiang HM, Han GA, He ZL (1990) Clinical significance of hair cadmium content in the diagnosis of mental retardation of children. Chin Med J 103:331–334Google Scholar
  16. Jiang W, Hu M (2012) Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways. RSC Adv 2:7948–7963CrossRefGoogle Scholar
  17. Jin YH, Clark AB, Slebos RJ, Al-Refai H, Taylor JA, Kunkel TA, Resnick MA, Gordenin DA (2003) Cadmium is a mutagen that acts by inhibiting mismatch repair. Nat Genet 34:326–329CrossRefGoogle Scholar
  18. Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220CrossRefGoogle Scholar
  19. Kumar A, Sehgal N, Kumar P, Padi SS, Naidu PS (2008) Protective effect of quercetin against ICV colchicine-induced cognitive dysfunctions and oxidative damage in rats. Phytother Res 22:1563–1569CrossRefGoogle Scholar
  20. Li R, Luo X, Zhu Y, Zhao L, Li L, Peng Q, Ma M, Gao Y (2017) ATM signals to AMPK to promote autophagy and positively regulate DNA damage in response to cadmium-induced ROS in mouse spermatocytes. Environ Pollut 231:1560–1568CrossRefGoogle Scholar
  21. Lin Y, Miao LH, Pan WJ, Huang X, Dengu JM, Zhang WX, Ge XP, Liu B, Ren MC, Zhou QL, Xie J, Pan LK, Xi BW (2018) Effect of nitrite exposure on the antioxidant enzymes and glutathione system in the liver of bighead carp, Aristichthys nobilis. Fish Shellfish Immunol 76:126–132CrossRefGoogle Scholar
  22. Liu Y, Luo X, Yang C, Yang T, Zhou J, Shi S (2016) Impact of quercetin-induced changes in drug-metabolizing enzyme and transporter expression on the pharmacokinetics of cyclosporine in rats. Mol Med Rep 14:3073–3085CrossRefGoogle Scholar
  23. Luck H (1974) Estimation of catalase activity. In: Bergmeyer U (ed) Methods of enzymology. Academic Press, New York, p 885Google Scholar
  24. Mannervik B, Danielson UH (1988) Glutathione transferases structure and catalytic activity. CRC Crit Rev Biochem 23:283–337CrossRefGoogle Scholar
  25. Mehta KD, Garg GR, Mehta AK, Arora T, Sharma AK, Khanna N, Tripathi AK, Sharma KK (2010) Reversal of propoxur-induced impairment of memory and oxidative stress by 4'-chlorodiazepam in rats. Naunyn Schmiedebergs Arch Pharmacol 381:1–10Google Scholar
  26. Morales AI, Vicente-Sánchez C, Sandoval JM, Egido J, Mayoral P, Arévalo MA, Fernández-Tagarro M, López-Novoa JM, Pérez-Barriocanal F (2006) Protective effect of quercetin on experimental chronic cadmium nephrotoxicity in rats is based on its antioxidant properties. Food Chem Toxicol 44:2092–2100CrossRefGoogle Scholar
  27. Morris RGM, Garrud P, Rawlins JN, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683CrossRefGoogle Scholar
  28. Niu Y, Cao W, Zhao Y, Zhai H, Zhao Y, Tang X, Chen Q (2018) The levels of oxidative stress and antioxidant capacity in hibernating Nanorana parkeri. Comp Biochem Physiol A Mol Integr Physiol 219-220:19–27CrossRefGoogle Scholar
  29. Nones J, Spohr TC, Gomes FC (2012) Effects of the flavonoid hesperidin in cerebral cortical progenitors in vitro: indirect action through astrocytes. Int J Dev Neurosci 30:303–313CrossRefGoogle Scholar
  30. Ognjanovic B, Markovic S, Dordevic N et al (2010) Cadmium-induced lipid peroxidation and changes in antioxidant defense system in the rat testes: protective role of coenzyme Q10 and vitamin E. Reprod Toxicol 29:191–197CrossRefGoogle Scholar
  31. Rehman S, Adnan M, Khalid N, Shaheen L (2011) Calcium supplements: an additional source of lead contamination. Biol Trace Elem Res 143:178–187CrossRefGoogle Scholar
  32. Santos FW, Oro T, Zeni G, Rocha JB, do Nascimento PC, Nogueira CW (2004) Cadmium induced testicular damage and its response to administration of succimer and diphenyl diselenide in mice. Toxicol Lett 152:255–263CrossRefGoogle Scholar
  33. Sbartai H, Djebar MR, Sbartai I, Berrabbah H (2012) Bioaccumulation of cadmium and zinc in tomato (Lycopersicon esculentum L.). C R Biol 335:585–593CrossRefGoogle Scholar
  34. Singh P, Prasad SM (2018) Antioxidant enzyme responses to the oxidative stress due to chlorpyrifos, dimethoate and dieldrin stress in palak (Spinacia oleracea L.) and their toxicity alleviation by soil amendments in tropical croplands. Sci Total Environ 630:839–848CrossRefGoogle Scholar
  35. Skipper A, Sims JN, Yedjou CG, Tchounwou PB (2016) Cadmium chloride induces DNA damage and apoptosis of human liver carcinoma cells via oxidative stress. Int J Environ Res Public Health 13:88CrossRefGoogle Scholar
  36. Spiazzi CC, Manfredini V, Barcellos da Silva FE, Flores EM, Izaguirry AP, Vargas LM, Soares MB, Santos FW (2013) γ-Oryzanol protects against acute cadmium-induced oxidative damage in mice testes. Food Chem Toxicol 55:526–532CrossRefGoogle Scholar
  37. Tanu T, Anjum A, Jahan M, Nikkon F, Hoque M, Roy AK, Haque A, Himeno S, Hossain K, Saud ZA (2018) Antimony-induced neurobehavioral and biochemical perturbations in mice. Biol Trace Elem Res 186:199–207CrossRefGoogle Scholar
  38. Tota S, Awasthi H, Kamat PK, Nath C, Hanif K (2010) Protective effect of quercetin against intracerebral streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav Brain Res 209:73–79CrossRefGoogle Scholar
  39. Ukai M, Miura M, Kameyama T (1995) Effects of galanin on passive avoidance response, elevated plus-maze learning, and spontaneous alternation performance in mice. Peptides 16:1283–1286CrossRefGoogle Scholar
  40. van Zanden JJ, Wortelboer HM, Bijlsma S, Punt A, Usta M, Bladeren PJ, Rietjens IM, Cnubben NH (2005) Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem Pharmacol 69:699–708CrossRefGoogle Scholar
  41. Vicente-Sanchez C, Egido J, Sanchez-Gonzalez PD et al (2008) Effect of the flavonoid quercetin on cadmium-induced hepatotoxicity. Food Chem Toxicol 46:2279–2287CrossRefGoogle Scholar
  42. Waalkes MP (2003) Cadmium carcinogenesis. Mutat Res 533:107–120CrossRefGoogle Scholar
  43. Wajdzik M, Halecki W, Kalarus K, Gąsiorek M, Pająk M (2017) Relationship between heavy metal accumulation and morphometric parameters in European hare (Lepus europaeus) inhabiting various types of landscapes in southern Poland. Ecotoxicol Environ Saf 145:16–23CrossRefGoogle Scholar
  44. Yu Y, Ma R, Yu L, Cai Z, Li H, Zuo Y, Wang Z, Li H (2018) Combined effects of cadmium and tetrabromobisphenol a (TBBPA) on development, antioxidant enzymes activity and thyroid hormones in female rats. Chem Biol Interact 289:23–31CrossRefGoogle Scholar
  45. Zhang R, Zhang N, Zhang H, Liu C, Dong X, Wang X, Zhu Y, Xu C, Liu L, Yang S, Huang S, Chen L (2017a) Celastrol prevents cadmium-induced neuronal cell death by blocking reactive oxygen species-mediated mammalian target of rapamycin pathway. Br J Pharmacol 174:82–100CrossRefGoogle Scholar
  46. Zhang W, Wu T, Zhang C, Luo L, Xie M, Huang H (2017b) Cadmium exposure in newborn rats ovary induces developmental disorders of primordial follicles and the differential expression of SCF/c-kit gene. Toxicol Lett 280:20–28CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity College of Medical Sciences and G. T. B. HospitalNew DelhiIndia
  2. 2.Department of BiochemistryUniversity College of Medical Sciences and G. T. B. HospitalNew DelhiIndia
  3. 3.National Institute of OceanologyDona PaulaIndia
  4. 4.Department of PharmacologyNorth Delhi Municipal Corporation Medical College and Hindu Rao HospitalNew DelhiIndia
  5. 5.Department of Pharmacology, School of Medical Sciences and ResearchSharda UniversityGreater NoidaIndia

Personalised recommendations