Molecular neurotoxicology: environmental agents and transcription-transduction coupling

Book Cover......Page 1
Half-Title......Page 2
Title......Page 3
Copyright......Page 4
Preface......Page 6
The Editor......Page 7
Contributors......Page 8
Contents......Page 11
1.1 INTRODUCTION......Page 12
1.2 GENE EXPRESSION IN THE BRAIN: THEN AND NOW......Page 13
1.3 REGULATION OF GENE EXPRESSION......Page 14
1.5 TRANSCRIPTIONAL TARGETS IN NEUROTOXICITY......Page 17
REFERENCES......Page 19
CHAPTER 2 Introduction to Molecular Biology and Its Techniques......Page 22
2.1 CELLS, GENOMES, AND GENES......Page 23
2.2 BASAL TRANSCRIPTIONAL MACHINERY......Page 28
2.3 REGULATION OF GENE EXPRESSION......Page 30
2.4 MONITORING OF GENE EXPRESSION......Page 32
2.4.2 DNase I Footprinting......Page 33
2.4.4 Chromatin Immunoprecipitation Assay......Page 34
2.4.7 Blotting Analyses......Page 35
2.4.8 DNA Microarray......Page 36
2.4.10 Reverse Transcription Coupled Polymerase Chain Reaction (RT-PCR)......Page 37
2.4.12 Determination of Protein Levels......Page 38
2.5 RECOMBINANT DNA TECHNOLOGY......Page 41
2.5.2 Vector......Page 42
2.5.3 Library Screening......Page 43
2.5.4 Generation of Deletion and Point Mutants......Page 44
2.5.5 Production of Recombinant Proteins......Page 45
2.5.7 Purification of Recombinant Proteins......Page 46
2.6.1 Transgenics......Page 48
2.6.3 Conditional Knockout......Page 49
2.6.4 Application of Genetically Modified Animals......Page 50
2.6.5 Toxicological Models......Page 51
2.6.7 Disease Models......Page 52
REFERENCES......Page 53
CHAPTER 3 Zinc Finger Transcription Factors Mediate Perturbations of Brain Gene Expression......Page 56
3.2 TOXIC RESPONSES OF THE NERVOUS SYSTEM AFTER EXPOSURE TO HEAVY METALS......Page 57
3.3 METAL-INDUCED PERTURBATIONS IN THE Sp FAMILY OF TRANSCRIPTION FACTORS......Page 58
3.3.1 Direct Interactions by Heavy Metals at the Zinc Finger Domain......Page 61
3.3.2 Indirect Perturbations of Sp1 by Metals via Cell Signaling Pathways......Page 63
3.3.3 Metal-Induced Disturbances in a Sp1-Driven Promoter......Page 66
3.4 THE Egr FAMILY OF TRANSCRIPTION FACTORS AND HEAVY METALS......Page 68
3.6 CONCLUSIONS......Page 71
REFERENCES......Page 72
4.1 INTRODUCTION TO NF-κB......Page 79
4.2 NF-κB AND THE BRAIN......Page 85
4.3 THE TRIMETHYLTIN MODEL OF BRAIN INJURY......Page 87
4.5 SUMMARY......Page 91
REFERENCES......Page 92
CHAPTER 5 Functional Implications of NMDA Receptor Subunit Expression in the Rat Brain Following elopmental Pb2+ Exposure......Page 102
5.1 DEVELOPMENTAL LEAD EXPOSURE: A GLOBAL PROBLEM......Page 103
5.2 NMDA RECEPTOR FUNCTION IN SYNAPTIC PLASTICITY AND COGNITIVE FUNCTION......Page 104
5.3 DEVELOPMENTAL EXPRESSION OF NMDA RECEPTOR SUBUNIT GENES......Page 105
5.4 ACTIVITY-DEPENDENT REGULATION OF NMDA RECEPTOR SUBUNIT EXPRESSION......Page 106
5.5 SYNAPTIC TARGETING OF NMDA RECEPTOR SUBUNITS......Page 107
5.6 EFFECT OF DEVELOPMENTAL EXPOSURE TO LEAD ON NMDA RECEPTOR SUBUNIT EXPRESSION......Page 109
5.7 FUNCTIONAL IMPLICATIONS AND CORRELATES OF NMDA RECEPTOR SUBUNIT CHANGES IN DEVELOPMENTAL Pb2+ NEUROTOXICITY......Page 111
5.8 ARE LEAD-INDUCED DEFICITS OF LEARNING AND MEMORY REVERSIBLE?......Page 114
ACKNOWLEDGMENTS......Page 115
REFERENCES......Page 116
6.1 INTRODUCTION......Page 122
6.2 MOLECULAR MODELS OF NEURODEGENERATIVE DISORDERS......Page 123
6.3 ENVIRONMENTAL TOXINS AS MODELS OF NEURODEGENERATION......Page 125
6.4 COMMON MECHANISTIC LINKS BETWEEN NEURODEGENERATIVE DISEASES......Page 128
6.5 CONCLUSION......Page 131
REFERENCES......Page 132
7.1 GENERAL INTRODUCTION TO DNA DAMAGE AND REPAIR......Page 138
7.2 OVERVIEW OF THE BASE EXCISION REPAIR PATHWAY......Page 142
7.3 NEURONAL VULNERABILITY ASSOCIATED WITH DEFECTIVE DNA REPAIR......Page 148
7.4 CHEMICAL EXPOSURES, OXIDATIVE STRESS, AND NEURODEGENERATION......Page 150
7.5 FUTURE PERSPECTIVES......Page 154
REFERENCES......Page 159
CHAPTER 8 Intracellular Signaling and Developmental Neurotoxicity......Page 166
8.1 INTRODUCTION......Page 167
8.2.1 Chronology of Nervous System Development......Page 168
8.2.2 Sensitivity of the Nervous System during Development......Page 170
8.3 INTRACELLULAR SIGNALING MECHANISMS......Page 171
8.3.1 Role in Nervous System Function......Page 172
8.3.2 Role in Nervous System Development......Page 174
8.3.3 Regulation of Downstream Molecular Events......Page 175
8.4 DEVELOPMENTAL NEUROTOXICANTS AND INTRACELLULAR SIGNALING......Page 176
8.4.1 Metals......Page 177
8.4.2 Alcohols......Page 178
8.4.3 Persistent Organic Pollutants......Page 179
8.5 EFFECTS OF PCBs ON INTRACELLULAR SIGNALING IN VITRO......Page 181
8.6 EFFECTS OF PCBs ON INTRACELLULAR SIGNALING IN VIVO......Page 183
8.7 CONCLUSIONS......Page 186
ACKNOWLEDGMENTS......Page 188
REFERENCES......Page 189
9.1 INTRODUCTION......Page 199
9.3 TRANSCRIPTIONAL TARGETS OF LEAD NEUROTOXICITY......Page 201
9.4 POU FAMILY OF TRANSCRIPTION FACTORS IN NEURAL DEVELOPMENT......Page 203
9.5 THE POU DOMAIN: A POTENTIAL NEW TARGET FOR LEAD NEUROTOXICITY......Page 205
9.6 GENES REGULATED BY OCT-2 AND THEIR TOXICOLOGICAL SIGNIFICANCE......Page 206
REFERENCES......Page 211
10.1 ETHANOL AND THE CENTRAL NERVOUS SYSTEM: AN OVERVIEW......Page 215
10.2 THE NEUROTOXICITY OF ETHANOL: FROM CELLS TO WHOLE ANIMALS......Page 217
10.3 MECHANISMS OF ETHANOL NEUROTOXICITY: APOPTOSIS VERSUS NECROSIS......Page 219
10.4 ALCOHOL NEUROTOXICOLOGY: NEW PERSPECTIVES FROM NEURAL STEM CELLS......Page 225
10.5 GENES AND ALCOHOLISM: MICROARRAYS AND THE “ALCOHOL CHIP”......Page 228
10.6 TRANSGENIC AND GENE KNOCKOUT STUDIES......Page 232
10.7 CONCLUDING REMARKS AND FUTURE DIRECTIONS......Page 235
REFERENCES......Page 236
Index......Page 242