Abstract
Long-term lead (Pb) exposure alters the normal development of the nervous system and physiology. It affects multiple organ systems, causing hypertension, cardiorespiratory dysfunction, being a well-known neurotoxin, inducing changes in neurogenesis, neurodegeneration, and glial cells. However, studies of the developmental effects of lead and its outcomes throughout life are lacking. Determine morphofunctional, behavioral, and cognitive developmental effects of long-term lead exposure at three different ages. Wistar rats were exposed to a Pb-acetate solution from fetal period until adulthood and compared to a non-exposed control group. General behavior and cognitive skills were evaluated by behavioral tests and physiological data and cardiorespiratory reflexes measured. Neurodegeneration, neuroinflammation, and synaptic activity were assessed by immunohistochemistry. Lead exposure caused long-lasting anxiety-like behavior and strong long-term memory impairment without changes in locomotor and exploratory activity. Hypertension was observed at all time points, concomitant with baroreflex impairment and increased chemoreflex sensitivity. Persistent neuroinflammation, transient synaptic overexcitation without neurodegeneration was observed. Long-term Pb exposure, since fetal period, causes long-lasting anxiety-like behavior, concomitant with hypertension, without general motor skills impairment. Synaptic overexcitation, reactive astrogliosis, and microgliosis could underlie behavioral and long-term memory changes, which might have been caused during developmental phases and consolidated during adulthood. Also, alterations observed in the cardiorespiratory reflexes can explain persistent hypertension. This longitudinal study identifies and characterizes lead toxicity nature and magnitude, important to devise and test potential interventions to attenuate the long-term harmful effects of lead on the nervous and cardiovascular systems.
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References
Abadin H, Ashizawa A, Stevens Y-W et al (2007) Toxicological profile for lead. US Public Heal Serv Agency Toxic Subst Dis Regist 582. https://doi.org/10.1201/9781420061888_ch106
Alfano DP, Petit TL (1982) Neonatal lead exposure alters the dendritic development of hippocampal dentate granule cells. Exp Neurol 75:275–288
Altmann L, Weinsberg F, Sveinsson K, Lilienthal H, Wiegand H, Winneke G (1993) Impairment of long-term potentiation and learning following chronic lead exposure. Toxicol Lett 66:105–112. https://doi.org/10.1016/0378-4274(93)90085-C
Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13:93–110. https://doi.org/10.1007/s10339-011-0430-z
Basha DC, Basha SS, Reddy GR (2012) Lead-induced cardiac and hematological alterations in aging Wistar male rats: alleviating effects of nutrient metal mixture. Biogerontology 13:359–368. https://doi.org/10.1007/s10522-012-9380-9
Bellinger DC (2008) Very low lead exposures and children’s neurodevelopment. Curr Opin Pediatr 20:172–177. https://doi.org/10.1097/MOP.0b013e3282f4f97b
Bielarczyk H, Tian X, Suszkiw JB (1996) Cholinergic denervation-like changes in rat hippocampus following developmental lead exposure. Brain Res 708:108–115
Braun JM, Kahn RS, Froehlich T et al (2006) Exposures to environmental toxicants and attention deficit hyperactivity disorder in US children. Environ Health Perspect 114:1904
Brockel BJ, Cory-slechta DA (1999) Lead-induced decrements in waiting behavior : involvement of D 2 -like dopamine receptors. Science (80- ) 63:423–434
Buccafusco JJ (2001) Methods of behavior analysis in neurosciences. CRC Tress LLC
Burdette LJ, Goldstein R (1986) Long-term behavioral and electrophysiological changes associated with lead exposure at different stages of brain development in the rat. Brain Res 394:101–110
Chen L-W, Dong M-H, Kuang F et al (2015) Microglia and astroglia: the role of neuroinflammation in lead toxicity and neuronal injury in the brain. Neuroimmunol Neuroinflamm 2:131. https://doi.org/10.4103/2347-8659.156980
Cory-Slechta DA (1995) Relationships between lead-induced learning impairments and changes in dopaminergic, cholinergic, and glutamatergic neurotransmitter system functions. Annu Rev Pharmacol Toxicol 35:391–415. https://doi.org/10.1146/annurev.pa.35.040195.002135
Costa R, Tamascia ML, Nogueira MD et al (2012) Handling of adolescent rats improves learning and memory and decreases anxiety. J Am Assoc Lab Anim Sci 51:548–553
Cullen MR, Kayne RD, Robins JM (1984) Endocrine and reproductive dysfunction in men associated with occupational inorganic lead intoxication. Arch Environ Health An Int J 39:431–440. https://doi.org/10.1080/00039896.1984.10545877
Dobbs MR (2009) Clinical neurotoxicology : syndromes, substances, environments. Saunders/Elsevier
Finkelstein Y, Markowitz ME, Rosen JF (1998) Low-level lead-induced neurotoxicity in children: an update on central nervous system effects. Brain Res Rev 27:168–176. https://doi.org/10.1016/S0165-0173(98)00011-3
Froehlich TE, Lanphear BP, Auinger P et al (2009) Association of tobacco and lead exposures with attention-deficit/hyperactivity disorder. Pediatrics 124:e1054–e1063
Geraldes V, Carvalho M, Goncalves-Rosa N et al (2016) Lead toxicity promotes autonomic dysfunction with increased chemoreceptor sensitivity. Neurotoxicology 54:170–177. https://doi.org/10.1016/j.neuro.2016.04.016
Gilbert ME, Kelly ME, Samsam TE, Goodman JH (2005) Chronic developmental lead exposure reduces neurogenesis in adult rat hippocampus but does not impair spatial learning. Toxicol Sci 86:365–374. https://doi.org/10.1093/toxsci/kfi156
Goyer RA (1990) Lead toxicity: from overt to subclinical to subtle health effects. Environ Health Perspect 86:177–181. https://doi.org/10.1289/ehp.9086177
Grizzo LT, Cordellini S (2008) Perinatal lead exposure affects nitric oxide and cyclooxygenase pathways in aorta of weaned rats. Toxicol Sci 103:207–214
Guimarães D, Carvalho ML, Geraldes V, Rocha I, Alves LC, Santos JP (2012) Lead in liver and kidney of exposed rats: aging accumulation study. J Trace Elem Med Biol 26:285–290. https://doi.org/10.1016/j.jtemb.2012.02.006
Hinwood M, Morandini J, Day TA, Walker FR (2012) Evidence that microglia mediate the neurobiological effects of chronic psychological stress on the medial prefrontal cortex. Cereb Cortex 22:1442–1454. https://doi.org/10.1093/cercor/bhr229
Hol EM, Pekny M (2015) Glial fibrillary acidic protein (GFAP) and the astrocyte intermediate filament system in diseases of the central nervous system. Curr Opin Cell Biol 32:121–130. https://doi.org/10.1016/j.ceb.2015.02.004
Hu F, Xu L, Liu Z-H et al (2014) Developmental lead exposure alters synaptogenesis through inhibiting canonical Wnt pathway in vivo and in vitro. PLoS One 9:e101894
Jaishankar M, Tseten T, Anbalagan N, Mathew BB, Beeregowda KN (2014) Toxicity, mechanism and health effects of some heavy metals. Interdiscip Toxicol 7:60–72. https://doi.org/10.2478/intox-2014-0009
Janak PH, Tye KM (2015) From circuits to behaviour in the amygdala. Nature 517:284–292. https://doi.org/10.1038/nature14188
Kara T, Narkiewicz K, Somers VK (2003) Chemoreflexes - physiology and clinical implications. Acta Physiol Scand 177:377–384. https://doi.org/10.1046/j.1365-201X.2003.01083.x
Kasparov S, Butcher JW, Paton JFR (1998) Angiotensin II receptors within the nucleus of the solitary tract mediate the developmental attenuation of the baroreceptor vagal reflex in pre-weaned rats. J Auton Nerv Syst 74:160–168. https://doi.org/10.1016/S0165-1838(98)00149-0
Khalil-Manesh F, Gonick HC, Weiler EWJ, Prins B, Weber MA, Purdy RE (1993) Lead-induced hypertension: possible role of endothelial factors. Am J Hypertens 6:723–729
Kim JJ, Song EY, Kim JJ et al (2006) Stress effects in the hippocampus: synaptic plasticity and memory. Stress 9:1–11. https://doi.org/10.1080/10253890600678004
Kim S, Arora M, Fernandez C, Landero J, Caruso J, Chen A (2013) Lead, mercury, and cadmium exposure and attention deficit hyperactivity disorder in children. Environ Res 126:105–110
Kuhlmann AC, McGlothan JL, Guilarte TR (1997) Developmental lead exposure causes spatial learning deficits in adult rats. Neurosci Lett 233:101–104. https://doi.org/10.1016/S0304-3940(97)00633-2
Lantelme P, Khettab F, Custaud M, et al (2002) Pierre Lantelme
Lasley SM, Gilbert ME (1996) Presynaptic glutamatergic function in dentate gyrus in vivo is diminished by chronic exposure to inorganic lead. Brain Res 736:125–134. https://doi.org/10.1016/0006-8993(96)00666-X
Lasley SM, Gilbert ME (2000) Glutamatergic components underlying lead-induced impairments in hippocampal synaptic plasticity. Neurotoxicology 21:1057–1068
Liu J, Gao D, Chen Y, Jing J, Hu Q, Chen Y (2014) Lead exposure at each stage of pregnancy and neurobehavioral development of neonates. Neurotoxicology 44:1–7. https://doi.org/10.1016/j.neuro.2014.03.003
Liu JT, Chen BY, Zhang JQ, Kuang F, Chen LW (2015) Lead exposure induced microgliosis and astrogliosis in hippocampus of young mice potentially by triggering TLR4-MyD88-NFκB signaling cascades. Toxicol Lett 239:97–107. https://doi.org/10.1016/j.toxlet.2015.09.015
Liu MC, Xu Y, Chen YM, Li J, Zhao F, Zheng G, Jing JF, Ke T, Chen JY, Luo WJ (2013) The effect of sodium selenite on lead induced cognitive dysfunction. Neurotoxicology 36:82–88. https://doi.org/10.1016/j.neuro.2013.03.008
Loghman-Adham M (2008) Renal effects of environmental and occupational lead exposure. Environ Health Perspect 105:103–106. https://doi.org/10.4103/0019-5278.44689
McQuirter JL, Rothenberg SJ, Dinkins GA et al (2013) Lead and lead poisoning from antiquity to modern times. Environ Health Perspect 115:1–2. https://doi.org/10.2106/JBJS.H.01077
Mendola P, Selevan SG, Gutter S, Rice D (2002) Environmental factors associated with a spectrum of neurodevelopmental deficits. Ment Retard Dev Disabil Res Rev 8:188–197. https://doi.org/10.1002/mrdd.10033
Misselwitz B, MÜhler A, Weinmann H (1995) A toxicologic risk for using manganese complexes?: a literature survey of existing data through several medical specialties. Investig Radiol 30:611–620
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
Mouro FM, Batalha VL, Ferreira DG, Coelho JE, Baqi Y, Müller CE, Lopes LV, Ribeiro JA, Sebastião AM (2017) Chronic and acute adenosine A2A receptor blockade prevents long-term episodic memory disruption caused by acute cannabinoid CB1 receptor activation. Neuropharmacology 117:316–327. https://doi.org/10.1016/j.neuropharm.2017.02.021
Naganuma A, Koyama Y, Imura N (1980) Behavior of methylmercury in mammalian erythrocytes. Toxicol Appl Pharmacol 54:405–410
Naolapo OJO, Naolapo AYO, Josiah T et al (2012) Elevated plus maze and Y-maze behavioral effects of subchronic , oral low dose monosodium glutamate in Swiss albino mice. J Pharm Biol Sci 3:21–27. https://doi.org/10.9790/3008-0342127
Navas-Acien A, Guallar E, Silbergeld EK, Rothenberg SJ (2007) Lead exposure and cardiovascular disease - a systematic review. Environ Health Perspect 115:472–482. https://doi.org/10.1289/ehp.9785
Neal AP, Worley PF, Guilarte TR (2011) Lead exposure during synaptogenesis alters NMDA receptor targeting via NMDA receptor inhibition. Neurotoxicology 32:281–289
Nigg JT, Knottnerus GM, Martel MM, Nikolas M, Cavanagh K, Karmaus W, Rappley MD (2008) Low blood lead levels associated with clinically diagnosed attention-deficit/hyperactivity disorder and mediated by weak cognitive control. Biol Psychiatry 63:325–331
Nigg JT, Nikolas M, Mark Knottnerus G et al (2010) Confirmation and extension of association of blood lead with attention-deficit/hyperactivity disorder (ADHD) and ADHD symptom domains at population-typical exposure levels. J Child Psychol Psychiatry 51:58–65
Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR (2000) N-methyl-D-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning. Neuroscience 99:233–242
O’Regan RG, Majcherczyk S (1982) Role of peripheral chemoreceptors and central chemosensitivity in the regulation of respiration and circulation. J Exp Biol 100
Ordemann JM, Austin RN (2016) Lead neurotoxicity: exploring the potential impact of lead substitution in zinc-finger proteins on mental health. Metallomics 8:579–588. https://doi.org/10.1039/C5MT00300H
Paton JFR, Wang S, Polson JW, Kasparov S (2008) Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension. J Mol Med 86:705
Petit TL, Alfano DP, LeBoutillier JC (1983) Early lead exposure and the hippocampus: a review and recent advances. Neurotoxicology 4:79–94
Prabhakar NR, Peng Y-J (2004) Peripheral chemoreceptors in health and disease. J Appl Physiol 96:359–366
Ramos A (2008) Animal models of anxiety: do I need multiple tests? Trends Pharmacol Sci 29:493–498. https://doi.org/10.1016/j.tips.2008.07.005
dos Santos Alves R, de Souza AS et al (2014) The open field test. Igarss 2014:1–5. https://doi.org/10.1007/s13398-014-0173-7.2
Roy A, Queirolo E, Peregalli F, Mañay N, Martínez G, Kordas K (2015) Association of blood lead levels with urinary F2-8alfa isoprostane and 8-hydroxy-2-deoxy-guanosine concentrations in first-grade Uruguayan children. Environ Res 140:127–135. https://doi.org/10.1016/j.envres.2015.03.001
Schindelin J, Arganda-Carreras I, Frise E et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Meth 9:676–682
Schneider P, Ho Y-J, Spanagel R, Pawlak CR (2011) A novel elevated plus-maze procedure to avoid the one-trial tolerance problem. Front Behav Neurosci 5:1–8. https://doi.org/10.3389/fnbeh.2011.00043
Schnur J, John RM (2014) Childhood lead poisoning and the new centers for disease control and prevention guidelines for lead exposure. J Am Assoc Nurse Pract 26:238–247. https://doi.org/10.1002/2327-6924.12112
Shvachiy L, Geraldes V, Amaro-Leal Â, Rocha I (2018) Intermittent low-level lead exposure provokes anxiety, hypertension, autonomic dysfunction and neuroinflammation. Neurotoxicology 69:307–319. https://doi.org/10.1016/J.NEURO.2018.08.001
Silva-Carvalho L, Dawid-Milner MS, Goldsmith GE, Spyer KM (1995) Hypothalamic modulation of the arterial chemoreceptor reflex in the anaesthetized cat: role of the nucleus tractus solitarii. J Physiol 487:751–760. https://doi.org/10.1113/jphysiol.1995.sp020915
Simon P, Dupuis R, Costentin J (1994) Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions. Behav Brain Res 61:59–64. https://doi.org/10.1016/0166-4328(94)90008-6
Sobin C, Montoya MGF, Parisi N, Schaub T, Cervantes M, Armijos RX (2013) Microglial disruption in young mice with early chronic lead exposure. Toxicol Lett 220:44–52. https://doi.org/10.1016/j.toxlet.2013.04.003
Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35. https://doi.org/10.1007/s00401-009-0619-8
Struzyńska L, Dabrowska-Bouta B, Koza K, Sulkowski G (2007) Inflammation-like glial response in lead-exposed immature rat brain. Toxicol Sci 95:156–162. https://doi.org/10.1093/toxsci/kfl134
Thome J, Pesold B, Baader M et al (2001) Stress differentially regulates synaptophysin and synaptotagmin expression in hippocampus. Biol Psychiatry 50:809–812. https://doi.org/10.1016/S0006-3223(01)01229-X
Timmers HJLM, Wieling W, Karemaker JM, Lenders JWM (2004) Baroreflex failure: a neglected type of secondary hypertension. Neth J Med 62:151–155
Tong S, Von Schirnding YE, Prapamontol T (2000) Environmental lead exposure: a public health problem of global dimensions. Bull World Health Organ 78:1068–1077. https://doi.org/10.1590/S0042-96862000000900003
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
Toscano CM, Simões MR, Alonso MJ, Salaices M, Vassallo DV, Fioresi M (2017) Sub-chronic lead exposure produces β1-adrenoceptor downregulation decreasing arterial pressure reactivity in rats. Life Sci 180:93–101. https://doi.org/10.1016/j.lfs.2017.05.009
Trzebski A, Tafil M, Zoltowski M, Przybylski J (1983) Central and peripheral chemosensitivity in early essential hypertension in man. In: Central Neurone Environment and the Control Systems of Breathing and Circulation. Springer, pp 204–213
Vaziri ND (2008) Mechanisms of lead-induced hypertension and cardiovascular disease. Am J Physiol Heart Circ Physiol 295:H454–H465. https://doi.org/10.1152/ajpheart.00158.2008
Walberer M, Jantzen SU, Backes H, Rueger MA, Keuters MH, Neumaier B, Hoehn M, Fink GR, Graf R, Schroeter M (2014) In-vivo detection of inflammation and neurodegeneration in the chronic phase after permanent embolic stroke in rats. Brain Res 1581:80–88. https://doi.org/10.1016/j.brainres.2014.05.030
Walker FR, Beynon SB, Jones KA et al (2014) Dynamic structural remodelling of microglia in health and disease: a review of the models, the signals and the mechanisms. Brain Behav Immun 37:1–14. https://doi.org/10.1016/j.bbi.2013.12.010
Waseem S, Bahmani A, Subaiea GM, Zawia NH (2014) Infantile exposure to lead and late-age cognitive decline : relevance to AD. Alzheimers Dement 10:187–195. https://doi.org/10.1016/j.jalz.2013.02.012
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
Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, Nelson RJ, Godbout JP, Sheridan JF (2011) β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci 31:6277–6288. https://doi.org/10.1523/JNEUROSCI.0450-11.2011
World Health Organization (2010) Exposure to lead: a major public health concern. World Health Organ 6. https://doi.org/10.1016/j.ecoenv.2011.12.007
Zhang D, Hu X, Qian L, O'Callaghan JP, Hong JS (2010) Astrogliosis in CNS pathologies: is there a role for microglia? Mol Neurobiol 41:232–241. https://doi.org/10.1007/s12035-010-8098-4
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Vera Geraldes received the post-doctoral fellowship given by the Fundação para a Ciência e Tecnologia (FCT) (Ref: SFRH/BPD/119315/2016).
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Shvachiy, L., Geraldes, V., Amaro-Leal, Â. et al. Persistent Effects on Cardiorespiratory and Nervous Systems Induced by Long-Term Lead Exposure: Results from a Longitudinal Study. Neurotox Res 37, 857–870 (2020). https://doi.org/10.1007/s12640-020-00162-8
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DOI: https://doi.org/10.1007/s12640-020-00162-8