Journal of Molecular Neuroscience

, Volume 49, Issue 1, pp 140–149 | Cite as

Formaldehyde Impairs Learning and Memory Involving the Disturbance of Hydrogen Sulfide Generation in the Hippocampus of Rats

  • Xiao-Qing TangEmail author
  • Yuan-Yuan Zhuang
  • Ping ZhangEmail author
  • Heng-Rong Fang
  • Cheng-Fang Zhou
  • Hong-Feng Gu
  • Hui Zhang
  • Chun-Yan Wang


Formaldehyde (FA), a well-known indoor and outdoor pollutant, has been implicated as the responsible agent in the development of neurocognitive disorders. Hydrogen sulfide (H2S), the third gasotransimitter, is an endogenous neuromodulator, which facilitates the induction of hippocampal long-term potentiation, involving the functions of learning and memory. In the present study, we analyzed the effects of intracerebroventricular injection of FA on the formation of learning and memory and the generation of endogenous H2S in the hippocampus of rats. We found that the intracerebroventricular injection of FA in rats impairs the function of learning and memory in the Morris water maze and novel object recognition test and increases the formation of apoptosis and lipid peroxidation in the hippocampus. We also showed that FA exposure inhibits the expression of cystathionine β-synthase, the major enzyme responsible for endogenous H2S generation in hippocampus and decreases the production of endogenous H2S in hippocampus in rats. These results suggested that FA-disturbed generation of endogenous H2S in hippocampus leads to the oxidative stress-mediated neuron damage, ultimately impairing the function of learning and memory. Our findings imply that the disturbance of endogenous H2S generation in hippocampus is a potential contributing mechanism underling FA-caused learning and memory impairment.


Formaldehyde Hydrogen sulfide Learning and memory Morris water maze Novel object recognition test 



This study was supported by Natural Science Foundation of China (81071005 and 81200985) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry ([2010]508).


  1. Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071PubMedGoogle Scholar
  2. Ahmed S, Tsukahara S, Tin Tin Win S, Yamamoto S, Kunugita N, Arashidani K, Fujimaki H (2007) Effects of low-level formaldehyde exposure on synaptic plasticity-related gene expression in the hippocampus of immunized mice. J Neuroimmunol 186:104–111PubMedCrossRefGoogle Scholar
  3. An L, Li Z, Yang Z, Zhang T (2012) Melamine induced cognitive impairment associated with oxidative damage in rat's hippocampus. Pharmacol Biochem Behav 102:196–202PubMedCrossRefGoogle Scholar
  4. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nature medicine 10 Suppl:S18–S25Google Scholar
  5. Andersen ME, Clewell HJ 3rd, Bermudez E, Dodd DE, Willson GA, Campbell JL, Thomas RS (2010) Formaldehyde: integrating dosimetry, cytotoxicity, and genomics to understand dose-dependent transitions for an endogenous compound. Toxicol Sci 118:716–731PubMedCrossRefGoogle Scholar
  6. Bell IR, Miller CS, Schwartz GE (1992) An olfactory-limbic model of multiple chemical sensitivity syndrome: possible relationships to kindling and affective spectrum disorders. Biol Psychiat 32:218–242Google Scholar
  7. Binetti R, Costamagna FM, Marcello I (2006) Development of carcinogenicity classifications and evaluations: the case of formaldehyde. Ann Ist Super Sanita 42:132–143PubMedGoogle Scholar
  8. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedCrossRefGoogle Scholar
  9. Caceres LG, Aon Bertolino L, Saraceno GE, Zorrilla Zubilete MA, Uran SL, Capani F, Guelman LR (2010) Hippocampal-related memory deficits and histological damage induced by neonatal ionizing radiation exposure. Role of oxidative status. Brain Res 1312:67–78PubMedCrossRefGoogle Scholar
  10. Cohen BI, Pagnillo MK, Musikant BL, Deutsch AS (1998) Formaldehyde evaluation from endodontic materials. Oral health 88:37–39PubMedGoogle Scholar
  11. Cooke SF, Bliss TV (2006) Plasticity in the human central nervous system. Brain 129:1659–1673PubMedCrossRefGoogle Scholar
  12. D'Hooge R, De Deyn PP (2001) Applications of the Morris water maze in the study of learning and memory. Brain Res Brain Res Rev 36:60–90PubMedCrossRefGoogle Scholar
  13. Eichenbaum H (1999) The hippocampus and mechanisms of declarative memory. Behav Brain Res 103:123–133PubMedCrossRefGoogle Scholar
  14. Eichenbaum H (2000) A cortical-hippocampal system for declarative memory. Nat Rev Neurosci 1:41–50PubMedCrossRefGoogle Scholar
  15. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res 31:47–59PubMedCrossRefGoogle Scholar
  16. Eto K, Kimura H (2002) The production of hydrogen sulfide is regulated by testosterone and S-adenosyl-l-methionine in mouse brain. J Neurochem 83:80–86PubMedCrossRefGoogle Scholar
  17. Eto K, Ogasawara M, Umemura K, Nagai Y, Kimura H (2002) Hydrogen sulfide is produced in response to neuronal excitation. J Neurosci 22:3386–3391PubMedGoogle Scholar
  18. Fukui K, Onodera K, Shinkai T, Suzuki S, Urano S (2001) Impairment of learning and memory in rats caused by oxidative stress and aging, and changes in antioxidative defense systems. Ann N Y Acad Sci 928:168–175PubMedCrossRefGoogle Scholar
  19. Gurel A, Coskun O, Armutcu F, Kanter M, Ozen OA (2005) Vitamin E against oxidative damage caused by formaldehyde in frontal cortex and hippocampus: biochemical and histological studies. J Chem Neuroanat 29:173–178PubMedCrossRefGoogle Scholar
  20. Henninger N, Feldmann RE Jr, Futterer CD, Schrempp C, Maurer MH, Waschke KF, Kuschinsky W, Schwab S (2007) Spatial learning induces predominant downregulation of cytosolic proteins in the rat hippocampus. Genes Brain Behav 6:128–140PubMedCrossRefGoogle Scholar
  21. Hu LF, Lu M, Tiong CX, Dawe GS, Hu G, Bian JS (2010) Neuroprotective effects of hydrogen sulfide on Parkinson's disease rat models. Aging Cell 9:135–146PubMedCrossRefGoogle Scholar
  22. Kamoun P, Belardinelli MC, Chabli A, Lallouchi K, Chadefaux-Vekemans B (2003) Endogenous hydrogen sulfide overproduction in Down syndrome. Am J Med Genet A 116A:310–311PubMedCrossRefGoogle Scholar
  23. Kilburn KH (1994) Neurobehavioral impairment and seizures from formaldehyde. Arch Environ Health 49:37–44PubMedCrossRefGoogle Scholar
  24. Kilburn KH, Warshaw R, Thornton JC (1987) Formaldehyde impairs memory, equilibrium, and dexterity in histology technicians: effects which persist for days after exposure. Arch Environ Health 42:117–120PubMedCrossRefGoogle Scholar
  25. Kimura H (2002) Hydrogen sulfide as a neuromodulator. Mol Neurobiol 26:13–19PubMedCrossRefGoogle Scholar
  26. Li WZ, Li WP, Huang DK, Kan HW, Wang X, Wu WY, Yin YY, Yao YY (2012) Dexamethasone and Abeta(2)(5)-(3)(5) accelerate learning and memory impairments due to elevate amyloid precursor protein expression and neuronal apoptosis in 12-month male rats. Behav Brain Res 227:142–149PubMedCrossRefGoogle Scholar
  27. Liu Y, Ye Z, Yang H, Zhou L, Fan D, He S, Chui D (2010) Disturbances of soluble N-ethylmaleimide-sensitive factor attachment proteins in hippocampal synaptosomes contribute to cognitive impairment after repetitive formaldehyde inhalation in male rats. Neuroscience 169:1248–1254PubMedCrossRefGoogle Scholar
  28. Lu Z, Li CM, Qiao Y, Yan Y, Yang X (2008) Effect of inhaled formaldehyde on learning and memory of mice. Indoor Air 18:77–83PubMedCrossRefGoogle Scholar
  29. Main DM, Hogan TJ (1983) Health effects of low-level exposure to formaldehyde. J Occup Med 25:896–900PubMedCrossRefGoogle Scholar
  30. Malek FA, Moritz KU, Fanghanel J (2003) A study on the effect of inhalative formaldehyde exposure on water labyrinth test performance in rats. Ann Anat 185:277–285PubMedCrossRefGoogle Scholar
  31. Meng JL, Mei WY, Dong YF, Wang JH, Zhao CM, Lan AP, Yang CT, Chen PX, Feng JQ, Hu CH (2011) Heat shock protein 90 mediates cytoprotection by HS against chemical hypoxia-induced injury in PC12 cells. Clin Exp Pharmacol Physiol 38:42–49PubMedCrossRefGoogle Scholar
  32. Milton VJ, Sweeney ST (2012) Oxidative stress in synapse development and function. Dev Neurobiol 72:100–110PubMedCrossRefGoogle Scholar
  33. Morris RG, Garrud P, Rawlins JN, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683Google Scholar
  34. Moore PK, Bhatia M, Moochhala S (2003) Hydrogen sulfide: from the smell of the past to the mediator of the future? Trends Pharmacol Sci 24:609–611PubMedCrossRefGoogle Scholar
  35. Nakao A, Sugimoto R, Billiar TR, McCurry KR (2009) Therapeutic antioxidant medical gas. J Clin Biochem Nutr 44:1–13PubMedCrossRefGoogle Scholar
  36. Nilsson JA, Zheng X, Sundqvist K, Liu Y, Atzori L, Elfwing A, Arvidson K, Grafstrom RC (1998) Toxicity of formaldehyde to human oral fibroblasts and epithelial cells: influences of culture conditions and role of thiol status. J Dent Res 77:1896–1903PubMedCrossRefGoogle Scholar
  37. Pitten FA, Kramer A, Herrmann K, Bremer J, Koch S (2000) Formaldehyde neurotoxicity in animal experiments. Pathol Res Pract 196:193–198PubMedCrossRefGoogle Scholar
  38. Qu K, Chen CP, Halliwell B, Moore PK, Wong PT (2006) Hydrogen sulfide is a mediator of cerebral ischemic damage. Stroke 37:889–893PubMedCrossRefGoogle Scholar
  39. Sarnak MJ, Long J, King AJ (1999) Intravesicular formaldehyde instillation and renal complications. Clin Nephrol 51:122–125PubMedGoogle Scholar
  40. Songur A, Ozen OA, Sarsilmaz M (2010) The toxic effects of formaldehyde on the nervous system. Rev Environ Contam Toxicol 203:105–118PubMedCrossRefGoogle Scholar
  41. Sorg BA, Willis JR, Nowatka TC, Ulibarri C, See RE, Westberg HH (1996) Proposed animal neurosensitization model for multiple chemical sensitivity in studies with formalin. Toxicology 111:135–145PubMedCrossRefGoogle Scholar
  42. Sorg BA, Willis JR, See RE, Hopkins B, Westberg HH (1998) Repeated low-level formaldehyde exposure produces cross-sensitization to cocaine: possible relevance to chemical sensitivity in humans. Neuropsychopharmacol 18:385–394CrossRefGoogle Scholar
  43. Sorg BA, Tschirgi ML, Swindell S, Chen L, Fang J (2001) Repeated formaldehyde effects in an animal model for multiple chemical sensitivity. Ann N Y Acad Sci 933:57–67PubMedCrossRefGoogle Scholar
  44. Sorg BA, Swindell S, Tschirgi ML (2004) Repeated low level formaldehyde exposure produces enhanced fear conditioning to odor in male, but not female, rats. Brain Res 1008:11–19PubMedCrossRefGoogle Scholar
  45. Tang XQ, Yang CT, Chen J, Yin WL, Tian SW, Hu B, Feng JQ, Li YJ (2008) Effect of hydrogen sulphide on beta-amyloid-induced damage in PC12 cells. Clin Exp Pharmacol Physiol 35:180–186PubMedGoogle Scholar
  46. Tang XQ, Shen XT, Huang YE, Ren YK, Chen RQ, Hu B, He JQ, Yin WL, Xu JH, Jiang ZS (2010) Hydrogen sulfide antagonizes homocysteine-induced neurotoxicity in PC12 cells. Neurosci Res 68:241–249PubMedCrossRefGoogle Scholar
  47. Tang XQ, Fan LL, Li YJ, Shen XT, Zhuan YY, He JQ, Xu JH, Hu B (2011a) Inhibition of hydrogen sulfide generation contributes to 1-methy-4-phenylpyridinium ion-induced neurotoxicity. Neurotox Res 19:403–411PubMedCrossRefGoogle Scholar
  48. Tang XQ, Shen XT, Huang YE, Chen RQ, Ren YK, Fang HR, Zhuang YY, Wang CY (2011b) Inhibition of endogenous hydrogen sulfide generation is associated with homocysteine-induced neurotoxicity: role of ERK1/2 activation. J Mol Neurosci 45:60–67PubMedCrossRefGoogle Scholar
  49. Thrasher JD, Kilburn KH (2001) Embryo toxicity and teratogenicity of formaldehyde. Arch Environ Health 56:300–311PubMedCrossRefGoogle Scholar
  50. Tong Z, Han C, Luo W, Wang X, Li H, Luo H, Zhou J, Qi J, He R (2012) Accumulated hippocampal formaldehyde induces age-dependent memory decline. Age (Dordr). doi: 10.1007/s11357-012-9388-8
  51. Triebig G, Zober MA (1984) Indoor air pollution by smoke constituents—a survey. Prev Med 13:570–581PubMedCrossRefGoogle Scholar
  52. Wang R (2002) Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16:1792–1798PubMedCrossRefGoogle Scholar
  53. Wang R (2010) Hydrogen sulfide: the third gasotransmitter in biology and medicine. Antioxid Redox Signal 12:1061–1064PubMedCrossRefGoogle Scholar
  54. Wang Y, Han TZ (2009) Prenatal exposure to heroin in mice elicits memory deficits that can be attributed to neuronal apoptosis. Neuroscience 160:330–338PubMedCrossRefGoogle Scholar
  55. Yin WL, He JQ, Hu B, Jiang ZS, Tang XQ (2009) Hydrogen sulfide inhibits MPP(+)-induced apoptosis in PC12 cells. Life Sci 85:269–275PubMedCrossRefGoogle Scholar
  56. Zararsiz I, Kus I, Akpolat N, Songur A, Ogeturk M, Sarsilmaz M (2006) Protective effects of omega-3 essential fatty acids against formaldehyde-induced neuronal damage in prefrontal cortex of rats. Cell Biochem Funct 24:237–244PubMedCrossRefGoogle Scholar
  57. Zararsiz I, Kus I, Ogeturk M, Akpolat N, Kose E, Meydan S, Sarsilmaz M (2007) Melatonin prevents formaldehyde-induced neurotoxicity in prefrontal cortex of rats: an immunohistochemical and biochemical study. Cell Biochem Funct 25:413–418PubMedCrossRefGoogle Scholar
  58. Zhao CH, Liu HQ, Cao R, Ji AL, Zhang L, Wang F, Yang RH (2012) Effects of dietary fish oil on learning function and apoptosis of hippocampal pyramidal neurons in streptozotocin-diabetic rats. Brain Res 1457:33–43PubMedCrossRefGoogle Scholar
  59. Zhou DX, Qiu SD, Zhang J, Tian H, Wang HX (2006) The protective effect of vitamin E against oxidative damage caused by formaldehyde in the testes of adult rats. Asian J Androl 8:584–588PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Xiao-Qing Tang
    • 1
    • 2
    Email author
  • Yuan-Yuan Zhuang
    • 2
    • 3
  • Ping Zhang
    • 4
    Email author
  • Heng-Rong Fang
    • 1
    • 2
  • Cheng-Fang Zhou
    • 1
    • 2
  • Hong-Feng Gu
    • 1
    • 2
  • Hui Zhang
    • 5
  • Chun-Yan Wang
    • 2
  1. 1.Department of Physiology, Medical CollegeUniversity of South ChinaHengyangPeople’s Republic of China
  2. 2.Institute of Cognition and Nervous Systems Disease, Medical CollegeUniversity of South ChinaHengyangPeople’s Republic of China
  3. 3.Division of Science and Technology ResearchKingmed Diagnostics CenterGuangzhouPeople’s Republic of China
  4. 4.Department of Neurology, Nanhua Affiliated HospitalUniversity of South ChinaHengyangPeople’s Republic of China
  5. 5.Hospital of OrthopedicsGeneral Hospital of Guangzhou Military Command of PLAGuangzhouPeople’s Republic of China

Personalised recommendations