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Forced swimming stress increases natatory activity of lead-exposed mice

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Abstract

Recent evidence points to the relationship between lead toxicity and the function of the hypothalamic-pituitary-adrenal axis, which suggests that lead exposure could influence how an individual cope with stress. Here we test this hypothesis by investigating the behavioral effects of lead exposure in mice during the forced swimming test (FST), a parading in which animals are exposed to a stressful situation and environment. Swiss mice received either 180 ppm or 540 ppm of lead acetate (Pb) in their ad-lib water supply for 60–90 days, starting at postnatal day 30. Control (Ctrl) mice drank tap water. At the end of the exposure period, mice were submitted to a 5-min session of FST or to an open-field session of the same duration. Data from naïve animals showed that corticosterone levels were higher for animals tested in the FST compared to animals tested in the open-field. Blood-lead levels (BLL) in Pb-exposed mice ranged from 14.3 to 106.9 µg/dL. No differences were observed in spontaneous locomotion between Ctrl and Pb-exposed groups in the open-field. However, in the FST, Pb-treated mice displayed higher swimming activity than Ctrl ones and this effect was observed even for animals with BLL higher than 20 µg/dL. Furthermore, significant differences in brain glutathione levels, used as an indicator of led toxicity, were only observed for BLL higher than 40 µg/dL. Overall, these findings suggest that swimming activity in the FST is a good indicator of lead toxicity and confirm our prediction that lead toxicity influences behavioral responses associated to stress.

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References

  1. Benson SM, Talbott EO, Brink LAL et al (2017) Environmental lead and childhood blood lead levels in US children: NHANES, 1999–2006. Arch Environ Occup Heal 72:70–78. https://doi.org/10.1080/19338244.2016.1157454

    Article  CAS  Google Scholar 

  2. Bodeau-Livinec F, Glorennec P, Cot M et al (2016) Elevated blood lead levels in infants and mothers in benin and potential sources of exposure. Int J Environ Res Public Health 13:1–14. https://doi.org/10.3390/ijerph13030316

    Article  CAS  Google Scholar 

  3. Olympio KPK, Gonçalves CG, Salles FJ et al (2017) What are the blood lead levels of children living in Latin America and the Caribbean? Environ Int 101:46–58. https://doi.org/10.1016/j.envint.2016.12.022

    Article  CAS  PubMed  Google Scholar 

  4. Pelc W, Pawlas N, Dobrakowski M, Kasperczyk S (2016) Environmental and socioeconomic factors contributing to elevated blood lead levels in children from an industrial area of Upper Silesia. Environ Toxicol Chem 35:2597–2603. https://doi.org/10.1002/etc.3429

    Article  CAS  PubMed  Google Scholar 

  5. Cecil KM, Brubaker CJ, Adler CM et al (2008) Decreased brain volume in adults with childhood lead exposure. PLoS Med 5:0741–0749. https://doi.org/10.1371/journal.pmed.0050112

    Article  CAS  Google Scholar 

  6. Garza A, Vega R, Soto E (2006) Cellular mechanisms of lead neurotoxicity. Med Sci Monit 12:57–65

    Google Scholar 

  7. Lidsky TI, Schneider JS (2003) Lead neurotoxicity in children: basic mechanisms and clinical correlates. Brain 126:5–19. https://doi.org/10.1093/brain/awg014

    Article  PubMed  Google Scholar 

  8. Toscano CD, Guilarte TR (2005) Lead neurotoxicity: from exposure to molecular effects. Brain Res Rev 49:529–554. https://doi.org/10.1016/j.brainresrev.2005.02.004

    Article  CAS  PubMed  Google Scholar 

  9. Costa LG, Aschner M, Vitalone A et al (2004) Developmental neuropathology of environmental agents. Annu Rev Pharmacol Toxicol 44:87–110. https://doi.org/10.1146/annurev.pharmtox.44.101802.121424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fenga C, Gangemi S, Alibrandi A et al (2016) Relationship between lead exposure and mild cognitive impairment. J Prev Med Hyg 57:205–210

    Google Scholar 

  11. Murata K, Iwata T, Dakeishi M, Karita K (2009) Lead toxicity: does the critical level of lead resulting in adverse effects differ between adults and children? J Occup Health 51:1–12. https://doi.org/10.1539/joh.k8003

    Article  CAS  PubMed  Google Scholar 

  12. Shih RA, Hu H, Weisskopf MG, Schwartz BS (2007) Cumulative lead dose and cognitive function in adults: a review of studies that measured both blood lead and bone lead. Environ Health Perspect 115:483–492. https://doi.org/10.1289/ehp.9786

    Article  CAS  PubMed  Google Scholar 

  13. Kazi TG, Shah F, Afridi HI (2015) Occupational and environmental lead exposure to adolescent workers in battery recycling workshops. Toxicol Ind Health 31:1288–1295. https://doi.org/10.1177/0748233713485883

    Article  CAS  PubMed  Google Scholar 

  14. La-Llave-León O, Salas Pacheco JM, Estrada Martínez S et al (2016) The relationship between blood lead levels and occupational exposure in a pregnant population. BMC Public Health 16:1–9. https://doi.org/10.1186/s12889-016-3902-3

    Article  Google Scholar 

  15. Laidlaw MAS, Filippelli G, Mielke H et al (2017) Lead exposure at firing ranges - a review. Environ Heal A Glob Access Sci Source 16:1–15. https://doi.org/10.1186/s12940-017-0246-0

    Article  CAS  Google Scholar 

  16. Nie LH, Wright RO, Bellinger DC et al (2011) Blood lead levels and cumulative blood lead index (CBLI) as predictors of late neurodevelopment in lead poisoned children. Biomarkers 16:517–524. https://doi.org/10.3109/1354750X.2011.604133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Santa Maria MP, Hill BD, Kline J (2018) Lead (Pb) neurotoxicology and cognition. Appl Neuropsychol Child. https://doi.org/10.1080/21622965.2018.1428803

    Article  PubMed  Google Scholar 

  18. Bellinger DC (2008) Lead neurotoxicity and socioeconomic status: Conceptual and analytical issues. Neurotoxicology 29:828–832. https://doi.org/10.1016/j.neuro.2008.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Healey N (2009) Lead toxicity, vulnerable subpopulations and emergency preparedness. Radiat Prot Dosimetry 134:1–9. https://doi.org/10.1093/rpd/ncp068

    Article  CAS  Google Scholar 

  20. Peters JL, Kubzansky L, McNeely E et al (2007) Stress as a potential modifier of the impact of lead levels on blood pressure: the normative aging study. Environ Health Perspect 115:1154–1159. https://doi.org/10.1289/ehp.10002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rice DC (2006) Animal models of cognitive impairment produced by developmental lead exposure. In: Levin ED, Buccafusco JJ (eds) Animal models of cognitive impairment. CRC Press/Taylor and Francis Group LLC., Boca Raton

    Google Scholar 

  22. Cory-Slechta DA, Virgolini MB, Rossi-George A et al (2008) Lifetime consequences of combined maternal lead and stress. Basic Clin Pharmacol Toxicol 102:218–227. https://doi.org/10.1111/j.1742-7843.2007.00189.x

    Article  CAS  PubMed  Google Scholar 

  23. Glass TA, Bandeen-Roche K, McAtee M et al (2009) Neighborhood psychosocial hazards and the association of cumulative lead dose with cognitive function in older adults. Am J Epidemiol 169:683–692. https://doi.org/10.1093/aje/kwn390

    Article  PubMed  PubMed Central  Google Scholar 

  24. Virgolini MB, Chen K, Weston DD et al (2005) Interactions of chronic lead exposure and intermittent stress: consequences for brain catecholamine systems and associated behaviors and HPA axis function. Toxicol Sci 87:469–482. https://doi.org/10.1093/toxsci/kfi269

    Article  CAS  PubMed  Google Scholar 

  25. Yamamoto BK, Kutscher CL (2002) Drug and food-deprivation modulation of activity in rats given chronic dietary lead: significance of type of activity measure. Pharmacol Biochem Behav 15:505–512. https://doi.org/10.1016/0091-3057(81)90285-9

    Article  Google Scholar 

  26. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    Article  CAS  Google Scholar 

  27. 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

    Article  CAS  PubMed  Google Scholar 

  28. Bulduk S, Canbeyli R (2004) Effect of inescapable tones on behavioral despair in Wistar rats. Prog Neuro-Psychopharmacol Biol Psychiatry 28:471–475. https://doi.org/10.1016/j.pnpbp.2003.11.012

    Article  Google Scholar 

  29. Christianson JP, Drugan RC (2005) Intermittent cold water swim stress increases immobility and interferes with escape performance in rat. Behav Brain Res 165:58–62. https://doi.org/10.1016/j.bbr.2005.06.028

    Article  PubMed  Google Scholar 

  30. Drugan RC, Eren S, Hazi A et al (2005) Impact of water temperature and stressor controllability on swim stress-induced changes in body temperature, serum corticosterone, and immobility in rats. Pharmacol Biochem Behav 82:397–403. https://doi.org/10.1016/j.pbb.2005.09.011

    Article  CAS  PubMed  Google Scholar 

  31. Filgueiras CC, Abreu-Villaça Y, Krahe TE, Manhães AC (2006) Unilateral hemispherectomy at adulthood asymmetrically affects immobile behavior of male Swiss mice. Behav Brain Res 172:33–38. https://doi.org/10.1016/j.bbr.2006.04.015

    Article  PubMed  Google Scholar 

  32. Krahe TE, Filgueiras CC, Schmidt SL (2002) Effects of rotational side preferences on immobile behavior of normal mice in the forced swimming test. Prog Neuro-Psychopharmacol Biol Psychiatry 26:169–176. https://doi.org/10.1016/S0278-5846(01)00248-2

    Article  Google Scholar 

  33. Thierry B, Steru L, Chermat R, Simon P (1984) Searching-waiting strategy: a candidate for an evolutionary model of depression? Behav Neural Biol 41:180–189

    Article  CAS  Google Scholar 

  34. de Kloet ER, Molendijk ML (2016) Coping with the forced swim stressor: Towards understanding an adaptive mechanism. Neural Plast 2016:1–13. https://doi.org/10.1155/2016/6503162

    Article  CAS  Google Scholar 

  35. Leasure JL, Giddabasappa A, Chaney S et al (2008) Low-level human equivalent gestational lead exposure produces sex-specific motor and coordination abnormalities and late-onset obesity in year-old mice. Environ Health Perspect 116:355–361. https://doi.org/10.1289/ehp.10862

    Article  CAS  PubMed  Google Scholar 

  36. Moreira EG, Vassilieff I, Vassilieff VS (2001) Developmental lead exposure: Behavioral alterations in the short and long term. Neurotoxicol Teratol 23:489–495. https://doi.org/10.1016/S0892-0362(01)00159-3

    Article  CAS  PubMed  Google Scholar 

  37. Silbergeld EK, Goldberg AM (1974) Hyperactivity: a lead induced behavior disorder. Environ Health Perspect 7:227–232

    Article  CAS  Google Scholar 

  38. Szczerbak G, Nowak P, Kostrzewa RM, Brus R (2007) Maternal lead exposure produces long-term enhancement of dopaminergic reactivity in rat offspring. Neurochem Res 32:1791–1798. https://doi.org/10.1007/s11064-007-9306-0

    Article  CAS  PubMed  Google Scholar 

  39. Trombini TV, Pedroso CG, Ponce D et al (2001) Developmental lead exposure in rats: Is a behavioral sequel extended at F2 generation? Pharmacol Biochem Behav 68:743–751. https://doi.org/10.1016/S0091-3057(01)00473-7

    Article  CAS  PubMed  Google Scholar 

  40. Bains JS, Shaw CA (1997) Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Rev 25:335–358. https://doi.org/10.1016/S0165-0173(97)00045-3

    Article  CAS  PubMed  Google Scholar 

  41. Coyle J, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 80(262):689–695

    Article  Google Scholar 

  42. Schulz JB, Lindenau J, Seyfried J, Dichgans J (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911

    Article  CAS  Google Scholar 

  43. Dobrakowski M, Pawlas N, Hudziec E et al (2016) Glutathione, glutathione-related enzymes, and oxidative stress in individuals with subacute occupational exposure to lead. Environ Toxicol Pharmacol 45:235–240. https://doi.org/10.1016/j.etap.2016.06.008

    Article  CAS  PubMed  Google Scholar 

  44. Engstrom AK, Xia Z (2017) Lead exposure in late adolescence through adulthood impairs short-term spatial memory and the neuronal differentiation of adult-born cells in C57BL/6 male mice. Neurosci Lett 661:108–113. https://doi.org/10.1016/j.neulet.2017.09.060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Fan Y, Zhao X, Yu J et al (2020) Lead-induced oxidative damage in rats/mice: a meta-analysis. J Trace Elem Med Biol 58:126443. https://doi.org/10.1016/j.jtemb.2019.126443

    Article  CAS  PubMed  Google Scholar 

  46. Carocci A, Catalano A, Lauria G et al (2016) Lead toxicity, antioxidant defense and environment. Rev Environ Contam Toxicol 238:45–67. https://doi.org/10.1007/398_2015_5003

    Article  CAS  PubMed  Google Scholar 

  47. Filgueiras CC, Ribeiro-Carvalho A, Nunes F et al (2009) Early ethanol exposure in mice increases laterality of rotational side preference in the free-swimming test. Pharmacol Biochem Behav 93:148–154. https://doi.org/10.1016/j.pbb.2009.04.023

    Article  CAS  PubMed  Google Scholar 

  48. Schmidt SL, Filgueiras CC, Krahe TE (1999) Effects of sex and laterality on the rotatory swimming behavior of normal mice. Physiol Behav 65:607–616. https://doi.org/10.1016/S0031-9384(98)00184-X

    Article  CAS  PubMed  Google Scholar 

  49. Dutra-Tavares AC, Manhães AC, Silva JO et al (2015) Locomotor response to acute nicotine in adolescent mice is altered by maternal undernutrition during lactation. Int J Dev Neurosci 47:278–285. https://doi.org/10.1016/j.ijdevneu.2015.10.002

    Article  CAS  PubMed  Google Scholar 

  50. Griffith OW (1999) Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 27:922–935. https://doi.org/10.1016/S0891-5849(99)00176-8

    Article  CAS  PubMed  Google Scholar 

  51. Correa M, Miquel M, Sanchis-Segura C, Aragon CMG (1999) Effects of chronic lead administration on ethanol-induced locomotor and brain catalase activity. Alcohol 19:43–49. https://doi.org/10.1016/S0741-8329(99)00023-3

    Article  CAS  PubMed  Google Scholar 

  52. Nieto-Fernandez FE, Ruiz A, Ntukogu N et al (2006) Short term lead exposure induces a stress-like response in adult mice. Med Sci Monit 12:325–329

    Google Scholar 

  53. Rice DC (1996) PCBs and behavioral impairment: are there lessons we can learn from lead? Neurotoxicol Teratol 18:229–232

    Article  CAS  Google Scholar 

  54. Salinas JA, Huff NC (2002) Lead and spatial vs. cued open field performance. Neurotoxicol Teratol 24:551–557. https://doi.org/10.1016/S0892-0362(02)00266-0

    Article  CAS  PubMed  Google Scholar 

  55. Abdulmajeed WI, Sulieman HB, Zubayr MO et al (2015) Honey prevents neurobehavioural deficit and oxidative stress induced by lead acetate exposure in male wistar rats- a preliminary study. Metab Brain Dis 31:37–44. https://doi.org/10.1007/s11011-015-9733-6

    Article  CAS  PubMed  Google Scholar 

  56. Villeda-Hernández J, Barroso-Moguel R, Méndez-Armenta M et al (2001) Enhanced brain regional lipid peroxidation in developing rats exposed to low level lead acetate. Brain Res Bull 55:247–251. https://doi.org/10.1016/S0361-9230(01)00512-3

    Article  PubMed  Google Scholar 

  57. Rodrigues ALS, Rocha JBT, Mello CF, Souza DO (1996) Effect of perinatal lead exposure on rat behaviour in open-field and two-way avoidance tasks. Pharmacol Toxicol 79:150–156. https://doi.org/10.1111/j.1600-0773.1996.tb00259.x

    Article  CAS  PubMed  Google Scholar 

  58. Ennaceur A, Michalikova S, Chazot PL (2009) Do rats really express neophobia towards novel objects? Experimental evidence from exposure to novelty and to an object recognition task in an open space and an enclosed space. Behav Brain Res 197:417–434. https://doi.org/10.1016/j.bbr.2008.10.007

    Article  CAS  PubMed  Google Scholar 

  59. Commons KG, Cholanians AB, Babb JA, Ehlinger DG (2017) The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci 8:955–960. https://doi.org/10.1021/acschemneuro.7b00042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cabib S, Puglisi-Allegra S (2012) The mesoaccumbens dopamine in coping with stress. Neurosci Biobehav Rev 36:79–89. https://doi.org/10.1016/j.neubiorev.2011.04.012

    Article  CAS  PubMed  Google Scholar 

  61. Tye KM, Mirzabekov JJ, Warden MR et al (2013) Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493:537–541. https://doi.org/10.1038/nature11740

    Article  CAS  PubMed  Google Scholar 

  62. Commissaris RL, Tavakoli-Nezhad M, Barron AJ, Pitts DK (2000) Effects of chronic low-level oral lead exposure on prepulse inhibition of acoustic startle in the rat. Neurotoxicol Teratol 22:55–60. https://doi.org/10.1016/S0892-0362(99)00042-2

    Article  CAS  PubMed  Google Scholar 

  63. Cory-Slechta DA, O’Mara DJ, Brockel BJ (1998) Nucleus accumbens dopaminergic medication of fixed interval schedule-controlled behavior and its modulation by low-level lead exposure. J Pharmacol Exp Ther 286:794–805

    CAS  PubMed  Google Scholar 

  64. McKlveen JM, Myers B, Flak JN et al (2013) Role of prefrontal cortex glucocorticoid receptors in stress and emotion. Biol Psychiatry 74:672–679. https://doi.org/10.1016/j.biopsych.2013.03.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Myers B, McKlveen JM, Herman JP (2014) Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front Neuroendocrinol 35:180–196. https://doi.org/10.1016/j.yfrne.2013.12.003

    Article  CAS  PubMed  Google Scholar 

  66. Virgolini MB, Bauter MR, Weston DD, Cory-Slechta DA (2006) Permanent alterations in stress responsivity in female offspring subjected to combined maternal lead exposure and/or stress. Neurotoxicology 27:11–21. https://doi.org/10.1016/j.neuro.2005.05.012

    Article  CAS  PubMed  Google Scholar 

  67. White LD, Cory-Slechta DA, Gilbert ME et al (2007) New and evolving concepts in the neurotoxicology of lead. Toxicol Appl Pharmacol 225:1–27. https://doi.org/10.1016/j.taap.2007.08.001

    Article  CAS  PubMed  Google Scholar 

  68. Servatius RJ, Ottenweller JE, Bergen MT et al (1994) Persistent stress-induced sensitization of adrenocortical and startle responses. Physiol Behav 56:945–954. https://doi.org/10.1016/0031-9384(94)90328-X

    Article  CAS  PubMed  Google Scholar 

  69. Gump BB, Stewart P, Reihman J et al (2008) Low-level prenatal and postnatal blood lead exposure and adrenocortical responses to acute stress in children. Environ Health Perspect 116:249–255. https://doi.org/10.1289/ehp.10391

    Article  CAS  PubMed  Google Scholar 

  70. Anyan J, Amir S (2018) Too depressed to swim or too afraid to stop? A reinterpretation of the forced swim test as a measure of anxiety-like behavior. Neuropsychopharmacology 43:931–933. https://doi.org/10.1038/npp.2017.260

    Article  PubMed  Google Scholar 

  71. Jozefczak M, Remans T, Vangronsveld J, Cuypers A (2012) Glutathione is a key player in metal-induced oxidative stress defenses. Int J Mol Sci 13:3145–3175. https://doi.org/10.3390/ijms13033145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ralf D (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671. https://doi.org/10.1016/s0301-0082(99)00060-x

    Article  Google Scholar 

  73. Hunaiti AA, Soud M (2000) Effect of lead concentration on the level of glutathione, glutathione S-transferase, reductase and peroxidase in human blood. Sci Total Environ 248:45–50

    Article  CAS  Google Scholar 

  74. Li XM, Gu Y, She JQ et al (2006) Lead inhibited N-methyl-d-aspartate receptor-independent long-term potentiation involved ryanodine-sensitive calcium stores in rat hippocampal area CA1. Neuroscience 139:463–473. https://doi.org/10.1016/j.neuroscience.2005.12.033

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from: Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ-BRAZIL), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-BRAZIL) and SR2-UERJ. The authors are thankful to to Ulisses Risso for animal care.

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Araujo, U.C., Krahe, T.E., Ribeiro-Carvalho, A. et al. Forced swimming stress increases natatory activity of lead-exposed mice. Toxicol Res. 37, 115–124 (2021). https://doi.org/10.1007/s43188-020-00045-2

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