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Protein as a response modifier of lead (Pb)-induced neurotoxic implications

Lalith Kumar, V. (2015) Protein as a response modifier of lead (Pb)-induced neurotoxic implications. PhD thesis, University of Mysore.

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Abstract

(Pb) is a ubiquitous, persistent and non-essential toxic heavy metal which can be detected in almost all phases of the environment and biological systems. Pb is known to induce a broad range of physiological, biochemical, and behavioral/ cognitive dysfunctions in humans and animals. Nervous system is the primary target for the low levels of Pb-exposure, and the developing brain is highly vulnerable to Pb toxicity than the mature brain. One of the major mechanism involved in the pathogenesis of Pb-induced neurotoxicity, is the disruption of the prooxidant/antioxidant balance. Pb exposure has been shown to cause generation of excessive amount of ROS and alteration of antioxidant defense systems in animals and in occupationally exposed workers. Pb poisoning has been recognized as a major public health risk, particularly in developing countries. To alleviate Pb associated neurotoxic effects, various strategies such as chelators, antioxidants, their combination and phytoconstituents (e.g. phenolic compounds) have been attempted. Understanding the interaction between dietary protein deficits and neurotoxicants such as lead (Pb) is critical since oxidative stress is a common denominator under such conditions. Accordingly, the hypothesis examined in this proposal is whether low protein acts as a response modifier of Pb-induced neurotoxic implications in vivo and was tested employing Drosophila system, prepubertal and gestational rat models. In the first series of investigations, we tested the hypothesis that casein (CSN) enrichment has the propensity to attenuate Pb-associated phenotype, oxidative stress and neurotoxicity in Drosophila melanogaster. CSN markedly offset Pb-induced lethality and diminished the hyperactivity response. While CSN enrichment among Pb (5 mM) treated flies caused further elevation in ROS levels and thioredoxin reductase activity, the SOD levels were restored to normalcy. Further, CSN improved the activity levels of complex I–III and restored the dopamine levels. Further, the possibilities of alleviating the Pb induced Abstract xii neurotoxicity in the fly model by enriching the low protein diet with Ferulic acid (FA), a commonly consumed polyphenol was also investigated in young flies. In the prepubertal rat model, the potential of dietary casein and FA to abrogate such responses, the pattern of susceptibility to Pb exposure under low as well as normo protein condition was investigated in terms of behavioral deficits, effect on Pb toxicity markers, histopathologic analysis of hippocampus, brain oxidative stress, mitochondrial function, and neurotoxicity employing a prepubertal (PP) rat model. In the gestational model, we investigated whether gestational protein restriction acts as a response modifier of Pb-induced oxidative dysfunctions in maternal and fetal brain. Further, protein restriction and Pb exposure during postnatal development (PND21) was also studied in terms of behavioral impairments, extent of oxidative stress and hippocampal pathology. Collectively these research findings demonstrate the propensity of casein in Drosophila to ameliorate Pb-induced neurotoxicity. Further data obtained in the rat model, clearly suggest that low protein diet acts as a response modifier of Pb-induced neurotoxicity and the efficacy of FA enrichment to alleviate Pbneurotoxicity under both normo and low protein situations. Similar results were also demonstrable in the gestational rat model of Pb neurotoxicity. Hence, we propose that enrichment of diet with protein such as casein and antioxidants such as FA may be a useful approach to alleviate Pb associated adverse effects in children.

Item Type: Thesis (PhD)
Uncontrolled Keywords: heavy metal, lead, neurotoxicity, toxicity
Subjects: 600 Technology > 01 Medical sciences > 17 Toxicology
600 Technology > 01 Medical sciences > 09 Human Physiology
Divisions: Dept. of Biochemistry
Depositing User: Food Sci. & Technol. Information Services
Date Deposited: 19 May 2016 05:54
Last Modified: 19 May 2016 05:54
URI: http://ir.cftri.com/id/eprint/12172

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