LIST OF FIGURES AND TABLES

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Christal Patterson
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1 ii LIST OF FIGURES AND TABLES GENERAL INTRODUCTION Fig. 1 Effect of Pb on antioxidant enzymes and cofactors leading to inactivation of enzyme activity Fig. 2 Rationale between Pb exposures among low SES population. Influence of nutritional stress on HPA axis function Fig. 3 Effects of protein malnutrition Table 1 Effects of Pb in in vitro models Table 2 Some recent publications on epidemiological evidence of Pb exposure Table 3 Chelators in the treatment of Pb poisoning Table 4 Antioxidants and Pb toxicity Table 5 Antioxidant nutrients against Pb toxicity MATERIALS AND METHODS Fig. 1 Life cycle of Drosophila melanogaster Fig. 2 Drosophila husbandry and experimental protocol Fig. 3 Hyperactivity (Speed) Fig. 4 Open field locomotor activity Fig. 5 T-Maze continuous alternation task Fig. 6 Motor coordination test Table 2.1 Composition of normo protein diet Table 2.2 Composition of low protein diet

2 iii CHAPTER 1 Fig. 1.1 Lethality response (A) and hyperactivity phenotype (flying speed) (B) among Drosophila melanogaster (Young/adult) exposed to varying concentrations of lead (Pb) acetate in culture media Fig. 1.2 Oxidative stress response measured as reactive oxygen species formation and hydroperoxide levels in cytosol of head/body regions of young/adult Drosophila melanogaster exposed to lead (Pb) acetate Fig. 1.3 Effect of lead (Pb) acetate on redox status (GSH and total thiols) and nitric oxide levels in cytosol of head and body regions of young and adult Drosophila melanogaster Fig. 1.4 Effect of lead (Pb) acetate on the activity levels of catalase and superoxide dismutase activity in head and body regions among young and adult male Drosophila melanogaster Fig. 1.5 Effect of lead (Pb) acetate on the activity levels of thioredoxin reductase and glutathione-stransferase in head and body regions among young and adult male Drosophila melanogaster Fig. 1.6 Mitochondrial complex I-III activity in head and body regions among young and adult male Drosophila melanogaster exposed to lead (Pb) acetate (5 d) Fig. 1.7 Cholinergic function and dopamine levels in head/ body regions among young/ adult male Drosophila melanogaster exposed to lead (Pb) acetate Fig. 1.8 Lethality response (Young vs adult, male), gender differences (young male and female) and flying speed (young) in Drosophila melanogaster exposed to lead (Pb) acetate in sucrose media for 7 days Fig. 1.9 Effect of Pb acetate on cholinergic function and dopamine levels in head region among young male Drosophila melanogaster Fig Protein enrichment as a response modifier of Pb-induced (10mM) lethality among young male Drosophila melanogaster in a 7 day treatment protocol Fig Modulatory effect Casein enrichment (1 & 2%) on Pb acetate (10mM) induced lethality and incidence of hyperactivity phenotype (speed) among young male Drosophila melanogaster Fig Modulatory effect of Casein enrichment on Pb acetate (5mM) induced perturbations in antioxidant enzymes in young Drosophila melanogaster

3 iv Fig Modulatory effect of Casein enrichment on Pb acetate (5mM) induced perturbations in antioxidant enzymes in young Drosophila melanogaster Fig Modulatory effect Casein enrichment on Pb acetate (5mM) induced effect on acetylcholinesterase activity levels in young male Drosophila melanogaster Fig Modulatory effect Casein enrichment on Pb acetate (5mM) induced mitochondrial dysfunctions in young male Drosophila melanogaster Table 1.1 Status of oxidative stress markers in young male Drosophila melanogaster exposed to lead (Pb) acetate in sucrose media. Table 1.2 Redox status (GSH and thiol levels) and nitric oxide levels in young male Drosophila melanogaster exposed to lead (Pb) acetate in sucrose media Table 1.3 Effect of lead (Pb) acetate on activity levels of enzymic antioxidant defenses and glutathione-s-transferase activity in young male Drosophila melanogaster Table 1.4 Activity of complex I-III and MTT reduction in young male Drosophila melanogaster exposed to lead (Pb) acetate Table 1.5 Status of oxidative markers in head and body regions of young male Drosophila melanogaster maintained on casein-enriched medium Table 1.6 Status of Glutathione and protein carbonyl levels in head and body regions of young male Drosophila melanogaster maintained on casein-enriched medium Table 1.7 Status of antioxidant defenses in head and body regions of young male Drosophila melanogaster maintained on casein-enriched medium Table 1.8 Modulatory effect of casein-enriched diet on lead (Pb) acetate induced oxidative perturbations in head and body regions of young male Drosophila melanogaster CHAPTER 2 Fig. 2.1 Absolute body weights of prepubertal rats administered with lead (Pb) acetate in drinking water for 5 weeks. Fig. 2.2 Locomotor phenotype measured as number of crossings and rearing activity in open field box among prepubertal rats administered with lead acetate in drinking water

4 v Fig. 2.3 Effect of Pb acetate on hemoglobin and activity levels of ALAD in prepubertal rats Fig. 2.4 Activity levels of antioxidant enzymes in cortex and cerebellum of prepubertal rats administered with Pb acetate in drinking water Fig. 2.5 Activity levels of antioxidant enzymes in hippocampus and striatum of prepubertal rats administered with Pb acetate in drinking water Fig. 2.6 Activity levels of mitochondrial complex enzymes and MTT reduction in cortex and cerebellum of prepubertal rats administered with Pb acetate in drinking water Fig. 2.7 Cholinergic function and dopamine (striatum) levels in brain regions of prepubertal rats administered with Pb acetate in drinking water Fig. 2.8 Histoarchitecture of hippocampus CA1 region in prepubertal rats administered with Pb acetate in drinking water Fig. 2.9 Histoarchitecture of hippocampus dentate gyrus region in prepubertal rats administered with Pb acetate in drinking water Fig Body weights of prepubertal rats fed on either normo- or low -protein diet and administered with lead (Pb) acetate in drinking water for 5 weeks. Fig Activity of ALAD enzyme in blood and blood lead (Pb) levels of prepubertal rats exposed to lead (Pb) acetate in drinking water fed with normo or low protein diet for 5 weeks. Fig Effect of Pb exposure on open field locomotor activity among PP rats exposed to Pb acetate in drinking water fed with Normo or low protein diet Ambulatory counts (A), rearing activity (B), grooming activity (C) sniffing activity (D) and T-Maze alternation task (E) Fig Status of oxidative stress markers in cytosolic brain regions of cortex and cerebellum of prepubertal rats fed either normo or low protein diet and administered with lead (Pb) acetate in drinking water Fig Status of oxidative stress markers in cytosolic brain regions of hippocampus and straitum of prepubertal rats fed either normo or low protein diet and administered with lead (Pb) acetate in drinking water Fig Antioxidant enzyme activities in cytosol of cortex and cerebellum among prepubertal rats fed on normo and low protein diet and administered with lead (Pb) acetate in drinking water

5 vi Fig Antioxidant enzyme activities in cytosol of hippocampus and striatum among prepubertal rats fed on normo and low protein diet and administered with lead (Pb) acetate in drinking water Fig Activity of Acetylcholinesterase (A-cortex; cerebellum); (B-hippocampus; striatum) and striatal dopamine levels (C) among prepubertal rats fed on normo and low protein diet administered with lead (Pb) acetate Fig Activity of mitochondrial complex I-III (A), succinate dehydrogenase (B) and MTT reduction (C) in brain regions of prepubertal rats fed on normo and low protein diet administered with lead (Pb) acetate in drinking water Fig Histoarchitecture of hippocampus dentate gyrus region in prepubertal rats fed on normo and low protein diet administered with lead (Pb) acetate in drinking water Fig Histoarchitecture of hippocampus CA1 region in prepubertal rats fed on normo and low protein diet administered with lead (Pb) acetate in drinking water Table 2.1 Induction of oxidative stress measured as ROS generation, lipid peroxidation and hydroperoxide levels in cytosol of cortex and cerebellum in prepubertal rats administered with lead (Pb) acetate in drinking water Table 2.2 Induction of oxidative stress measured as ROS generation and lipid peroxidation and hydroperoxide levels in cytosol of hippocampus and striatum in prepubertal rats administered with lead (Pb) acetate Table 2.3 Status of oxidative markers in mitochondria of cortex and cerebellum regions of prepubertal rats exposed to lead (Pb) acetate in drinking water for 5 weeks Table 2.4 Status of oxidative markers in mitochondria of hippocampus and striatal brain regions of prepubertal rats exposed to lead (Pb) acetate in drinking water for 5 weeks CHAPTER 3 Fig. 3.1 Modulatory efficacy of ferulic acid (FA) supplements on Pb-induced effects on crossings and rearing activity among rats Fig. 3.2 Modulatory effect of FA supplements on hemoglobin levels and activity of ALAD in prepubertal rats exposed to lead (3000 ppm in drinking water) Fig. 3.3 Effect of Ferulic acid supplements on oxidative stress markers of PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD.

6 vii Fig. 3.4 Modulatory effect of Ferulic acid (FA) supplements on antioxidant enzyme activities in PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Fig. 3.5 Modulatory effect of Ferulic acid (FA) supplements on NADH- cyt C reductase, succinatecyt C reductase and MTT reduction in mitochondria of brain regions PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Fig. 3.6 Modulatory effect of Ferulic acid supplements on activity levels of AChE, BChE and dopamine levels in striatum PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Fig. 3.7 Modulatory effect of Ferulic acid (FA) supplements on the histoarchitecture of hippocampus in PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Fig. 3.8 Modulatory effect of Ferulic acid (FA) supplements on the histoarchitecture of hippocampus in PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Fig. 3.9 Efficacy of ferulic acid supplements on crossings and rearing activity of PP rats exposed to lead (Pb) acetate (2000ppm) and maintained on low protein diet (LPD) Fig Efficacy of ferulic acid supplements on hemoglobin levels, ALAD activity and blood Pb levels in of PP rats exposed to lead (Pb) acetate (2000ppm) and maintained on LPD Fig Modulatory effect of ferulic acid (FA) supplements on oxidative stress markers in cortex and cerebellum of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD Fig Modulatory effect of ferulic acid (FA) supplements on oxidative stress markers in hippocampus and striatum of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD Fig Modulatory efficacy of ferulic acid supplements on catalase, SOD and GPx activities in cortex and cerebellum of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD Fig Modulatory efficacy of ferulic acid supplements on SOD and GPx activity in hippocampus and striatum of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD Fig Effect of ferulic acid supplements acetylcholinesterase and dopamine levels (Striatum) in of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD

7 viii Fig Effect of ferulic acid supplements on mitochondrial complex-i-iii activity and MTT reduction in cortex and cerebellum of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD Fig Hematoxylin and eosin stained sections of hippocampi of rats (4 week study). The number of degenerating neurons with shrunken and dark nuclei in cornu ammonis CA1 region was decreased among LPD+Pb+FA group Fig Hematoxylin and eosin stained sections of hippocampi of rats (4 week study). The number of degenerating neurons with shrunken and dark nuclei in cornu ammonis CA3 region was decreased among LPD+Pb+FA group Fig Hematoxylin and eosin stained sections of hippocampi of rats (4 week study). The number of degenerating neurons with shrunken and dark nuclei in dentate gyrus region was decreased among LPD+Pb+FA group Table 3.1 Modulatory effect of ferulic acid on the activities of antioxidant enzymes in cortex and striatum of PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Table 3.2 Modulatory effect of ferulic acid on the status of oxidative stress markers and reduced glutathione in cortex and striatum of m PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Table 3.3 Modulatory effect of ferulic acid on the mitochondrial function in cortex and striatum of PP rats exposed to lead (Pb) acetate (3000ppm in drinking water) maintained on NPD Table 3.4 Modulatory effect of ferulic acid (FA) supplements on oxidative stress markers in mitochondria of cortex and cerebellum of PP rats exposed to lead (Pb) acetate (2000ppm in drinking water) maintained on LPD CHAPTER 4 Fig. 4.1 Effect of lead (Pb) acetate exposure during gestation (GD-1-19) on Hb, ALAD, blood lead level and open field activity among rats fed either on Normoprotein (NPD) or low protein (LPD) diets Fig. 4.2 Effect of gestational lead (Pb) exposure on the status of antioxidant enzyme activities in brain regions (maternal) of rats on either normo (NPD) or low protein (LPD) diet Fig. 4.3 Effect of gestational Pb exposure on the status of antioxidant enzyme activities in brain regions (maternal) of rats fed on either normo (NPD) or low protein (LPD) diet

8 ix Fig. 4.4 Effect of gestational Pb exposure on the mitochondrial function in maternal brain regions of rats fed on either normo (NPD) or low protein (LPD) diet Fig. 4.5 Effect of gestational Pb exposure on oxidative stress markers in maternal and fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig. 4.6 Effect of gestational Pb exposure on oxidative stress markers in maternal and fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig. 4.7 Effect of gestational Pb exposure on antioxidant enzyme activities in maternal and fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig. 4.8 Effect of gestational Pb exposure on antioxidant enzyme activities in maternal and fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig. 4.9 Effect of gestational Pb exposure on mitochondrial complex activities in maternal and fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig Effect of gestational Pb exposure on on AChE and dopamine levels in maternal and fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig Effect of gestational lead (Pb) acetate exposure on maternal hippocampal histoarchitecture of rats fed on low protein (LPD) diet Fig Effect of gestational lead (Pb) acetate exposure on maternal hippocampal histoarchitecture of rats fed either normo (NPD) diet Fig Effect of gestational lead (Pb) exposure on the expression of vascular endothelial growth factor and glial fibrillary acidic protein in GD19 fetal brain of rats fed on either normo (NPD) or low protein (LPD) diet Fig Effect of Pb acetate exposure on body weight gain of pups during postnatal period of 3 weeks Fig Effect of Pb acetate exposure on motor activity (open field) and motor coordination test (rotarod) measured among postnatal 21 d rats Fig Effect of Pb acetate exposure on hemoglobin, ALAD and blood Pb levels in maternal and PND 21 rats

9 x Fig Status of oxidative stress markers in brain regions of postnatal 21 d rats following perinatal Pb exposure Fig Effect of perinatal Pb exposure on glutathione levels, nitric oxide levels and protein carbonyls in brain regions of postnatal 21 d rats Fig Effect of perinatal Pb exposure on antioxidant enzyme activities in brain regions of postnatal 21 d rats Fig Effect of perinatal Pb exposure on antioxidant enzyme activities in brain regions of postnatal 21 d rats Fig Effect of perinatal Pb exposure on the oxidative stress markers in the mitochondrial brain regions of postnatal 21 d rats Fig Effect of perinatal Pb exposure on the mitochondrial complex I-III activity and MTT reduction in brain regions of postnatal 21 d rats Fig Effect of perinatal Pb exposure on acetylcholinesterase activity and in brain regions of postnatal 21 d rats Fig Effect of Pb acetate exposure (drinking water) In PND 21 rats hippocampal histoarchitecture (H& E stain) Fig Effect of Pb acetate exposure (drinking water) In PND 21 rats hippocampal histoarchitecture (H& E stain) Table 4.1 Effect of gestational Pb exposure on body weight, fetal weights and placental weights of dams fed on either normo (NPD) or low protein (LPD) diet

Supplementary Materials

Supplementary Materials Fig. S1. Weights of full-dose treatment groups comparing 1 st, 2 nd, and 3 rd generation gene replacement therapy. Mice were treated at p1 with 4x10 11 GC of the three different