Elsevier

Neuroscience Research

Volume 78, January 2014, Pages 81-89
Neuroscience Research

Age related changes in aminergic system and behavior following lead exposure: Protection with essential metal supplements

https://doi.org/10.1016/j.neures.2013.09.007Get rights and content

Highlights

  • Early life exposure to Pb significantly altered the aminergic system in rat brain.

  • The alterations persisted in late life.

  • Developing rats at PND 45 were found to be more vulnerable to Pb than aged rats.

  • Nutrient mixture reversed Pb-induced perturbations in aminergic system and behavior.

  • Adequate intake of essential nutrients may be beneficial in reversing Pb-toxicity.

Abstract

Age related impairments in behavioral functions following lead (Pb) exposure have been linked to changes in neurotransmitter levels in brain regions. In the present study, we have evaluated the protective effect of a mixture of essential elements containing calcium, zinc and iron against Pb-induced long-term effects on aminergic system and behavior of rats. Rats were lactationally exposed to Pb (0.2%) or Pb acetate together with nutrient metal mixture (0.02% Ca, Zn and Fe) in drinking water of the mother from postnatal day (PND) 1 to PND 21. Increases in synaptosomal dopamine, epinephrine, norepinephrine and serotonin levels and decrease in mitochondrial monoamine oxidase (MAO) in cortex, cerebellum, and hippocampus regions were observed following Pb exposure in different age groups (PND 45, 4, 12 and 18 months) of rats. The alterations were greater in hippocampus than cortex and cerebellum. Total locomotor activity, exploratory and open field behaviors were also altered following Pb exposure. However, the alterations were maximum in PND 45 coinciding with greater blood Pb levels observed in PND 45. These data suggest that, Pb exposure induced age dependent alterations in motor behavior and synaptosomal aminergic system were significantly reversed with the supplementation of nutrient metal mixture suggesting therapeutic nature of essential metal supplements against Pb-induced toxicity.

Introduction

Recent studies suggested that exposure to environmental toxic agents during early life has been linked to neurodegenerative diseases and deficits in cognitive and motor functions in later life (Landrigan et al., 2005, Basha et al., 2005, Lahiri et al., 2008, Weuve et al., 2009). Lead (Pb) is a pervasive and persistent environmental toxic metal and the adverse health effects of Pb have been known for centuries (Zbakh and El Abbassi, 2012). Exposure to Pb at any age can be harmful and has shown demonstrable effects including neurological (Reddy et al., 2003), cardiac (Basha et al., 2012a, Basha et al., 2012b), hepatic (Patra et al., 2001), behavioral (Prasanthi et al., 2006), renal and hematological dysfunctions (Rastogi, 2008). Several experimental and epidemiological studies suggest that the neurotoxic effects of Pb are mediated through interference with the cholinergic and aminergic systems (Xu et al., 2009, El-Ansary et al., 2011). Oxidative stress has been proposed to be another mechanism involved in Pb toxicity (Franco et al., 2009, Dewanjee et al., 2013). Our earlier studies showed that the gestational and/or lactational exposure to Pb perturbs the cholinergic, aminergic and antioxidant systems in different brain regions of developing rats even though blood Pb (PbB) levels have declined (Devi et al., 2005, Basha et al., 2005, Verina et al., 2007, Reddy et al., 2007, Prasanthi et al., 2010, Basha et al., 2012a, Basha et al., 2012b). Bolin et al. (2006) also reported that Pb exposure during development have shown a continuation of neurological deficits that remain well into adult hood when blood levels are undetectable. The behavioral abnormalities, particularly those associated with the cognitive and motor functions, normally manifested in Pb-exposed rats have been attributed to the toxic effects of Pb on cholinergic and aminergic transmission (De la Fuente et al., 2003, Verina et al., 2007). Therefore, in the present study, we wanted to examine whether early exposure to Pb can manifest latent effects in old age and such effects can be reversed with essential elements calcium, zinc, and iron. Nutritional status is often mentioned as an important modifier of the metabolism of Pb toxicity (Ahamed and Siddiqui, 2007). Low dietary intake of iron, zinc, calcium has been associated with increased blood Pb levels and neurotoxicity of Pb (Prasanthi et al., 2010). We have previously reported that calcium and zinc supplementation significantly reversed the Pb-induced perturbations in mitochondrial antioxidant enzymes, and neurotransmitter levels in different brain regions of rats (Prasanthi et al., 2005, Basha et al., 2012a, Basha et al., 2012b). In the present study, we examined the therapeutic efficacy of nutritional supplement containing a mixture of essential elements calcium, zinc and iron against Pb-induced alterations in brain aminergic transmitter system and behavior.

Section snippets

Chemicals

Chemicals (imidazole, heptane, cysteine, O-pthaladehyde, tyramine hydrochloride) used in this study were purchased from Sigma Chemicals (St. Louis, MO, USA) and all the remaining chemicals were from Merck, India.

Animal exposure

Pregnant rats were lactationally exposed to 0.2% Pb by adding Pb-acetate to deionized drinking water of the mother. All pups were pooled on postnatal day 1 (PND 1) and new litters consisting of eight males were randomly selected and placed with each dam. Pb-exposure commenced on PND 1,

Results

The specific activity of the mitochondrial MAO enzyme and synaptosomal catecholamines (dopamine, epinephrine, norepinephrine and serotonin) were determined in cerebral cortex, hippocampus and cerebellum at PND 45, 4 months, 12 months and 18 months of control, Pb-exposed and nutrient mixture supplemented rats (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5). As shown in Fig. 1, Fig. 2, Fig. 3, Fig. 4, in control rats, the catecholamine levels in general increased from early postnatal age (PND 45) to 12

Discussion

In the present study, we observed significant and brain region specific alterations in the synaptosomal dopamine, epinephrine, norephinephrine and serotonin levels as well as mitochondrial MAO activity in Pb-exposed rats. To date, numbers of studies have addressed the effects of Pb on cholinergic and aminergic systems and behavior in developing rats (Van Wijngaarden et al., 2009, Mansouri et al., 2013), but the present study focused on long term effects of Pb on behavior and aminergic system of

Acknowledgement

This research work was supported by Indian Council of Medical Research (ICMR) Grant No. 5/8/4-10(Env)/09-NCD-I.

References (54)

  • A.S. Ettinger et al.

    Dietary calcium supplementation to lower blood lead levels in pregnancy and lactation

    J. Nutr. Biochem.

    (2007)
  • S. Fraser et al.

    The relationship between lead exposure, motor function and behaviour in Inuit preschool children

    Neurotoxicol. Teratol.

    (2006)
  • H.A. Godwin

    The biological chemistry of lead

    Curr. Opin. Chem. Biol.

    (2001)
  • K. Jaako-Movits et al.

    Developmental lead exposure impairs contextual fear conditioning and reduces adult hippocampal neurogenesis in the rat brain

    Int. J. Dev. Neurosci.

    (2005)
  • O.H. Lowry et al.

    Protein measurement with Folin phenol reagent

    J. Biol. Chem.

    (1951)
  • J. Luthman et al.

    Postnatal lead exposure affects motor skills and exploratory behavior in rats

    Environ. Res.

    (1992)
  • M.T. Mansouri et al.

    Motor alterations induced by chronic lead exposure

    Environ. Toxicol. Pharmacol.

    (2009)
  • M.T. Mansouri et al.

    Behavioral deficits induced by lead exposure are accompanied by serotonergic and cholinergic alterations in the prefrontal cortex

    Neurochem. Int.

    (2013)
  • C.A. Netto et al.

    Differential effect of post-training naloxone, beta-endorphin, leu-enkephalin and electroconvulsive shock administration upon memory of an open-field habituation and of a water-finding task

    Psychoneuroendocrinology

    (1986)
  • R.C. Patra et al.

    Antioxidant effects of alpha tocopherol, ascorbic acid and l-methionine on lead-induced oxidative stress to the liver, kidney and brain in rats

    Toxicology

    (2001)
  • M. Payton et al.

    Relatons of bone and blood lead to cognitive function: The VA normative aging study

    Neurotoxicol. Teratol.

    (1998)
  • R.P.J. Prasanthi et al.

    Calcium and zinc supplementation protects lead (Pb)-induced perturbations in antioxidant enzymes and lipid peroxidation in developing mouse brain

    Int. J. Devlop. Neurosci.

    (2010)
  • R.P.J. Prasanthi et al.

    Calcium and zinc supplementation reduces lead toxicity: assessment of behavioral dysfunctions in young and adult mice

    Nutr. Res.

    (2006)
  • G.R. Reddy et al.

    Lead-induced effects on Acetylcholinesterase activity in cerebellum and hippocampus of developing rat brain

    Int. J. Devlop. Neurosci.

    (2003)
  • G.R. Reddy et al.

    Developmental lead neurotoxicity: alterations in brain cholinergic system

    NeuroToxicology

    (2007)
  • G.S. Roth

    Changes in tissue responsiveness to hormones and neurotransmitters during aging

    Exp. Gerontol.

    (1995)
  • E. Van Wijngaarden et al.

    Bone lead levels are associated with measures of memory impairment in older adults

    Neurotoxicology

    (2009)
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