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Developmental 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure can permanently alter immune system ontogeny, resulting in the dysregulation of a number of vital immune pathways. We hypothesized that developmental exposure to TCDD may also impair the establishment of self-tolerance, resulting in an increased risk of autoimmunity. For example, we observed that a single prenatal TCDD exposure given to non-autoimmune-prone high affinity aryl hydrocarbon receptor (AhR) C57BL/6 mice resulted in an immune complex-mediated autoimmune disease during the adult stage. Further using a similar TCDD exposure protocol, autoimmune-prone low affinity AhR SNF1 mice exhibited acceleration and exacerbation of lupus-like nephritis in adulthood. Examination of these mice showed that perinatal TCDD exposure adversely affected both primary immune organs of the adaptive immune system. In the thymic compartment, prenatal TCDD affected thymocyte cellularity, differentiation and maturation as well as central tolerance as indicated by high levels of autoreactive Vβ TCR T cells in the periphery. Prenatal TCDD also altered bone marrow B lymphopoiesis and B cell maturation and differentiation in the spleen. Functionally, these B cell changes resulted in high serum autoantibodies titers to dsDNA, ssDNA and cardiolipin suggesting a loss in central B cell tolerance. The functional assessment of T cells, via cytokine production showed that prenatal TCDD mice altered Th1/Th2 levels. As a result, significant changes were detected in the kidney characterized by increased immune complex deposition in the glomeruli, lymphocytic infiltration and general pathologic changes. This would suggest that multiple immune pathways are affected by prenatal TCDD and work either independently or synergistically to display immune-mediated disease during aging. Importantly, this study has also shown that the sex of an individual appears to influence both the type of immune pathways affected by TCDD as well as the progression and severity of the autoimmunity. In summary, these studies clearly demonstrate that postnatal immune system impairment due to prenatal TCDD exposure is not limited to immunosuppression but also can include inappropriate immune activation manifested as a hypersensitivity that can lead to the onset of autoimmune disease. / Ph. D.

by Choi, Heung Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 79-95). / Acknowledgement --- p.iv / Abstract --- p.vi / Chapter CHAPTER 1 --- INTRODUCTION / Chapter 1.1 --- Cocaine --- p.1 / Chapter 1.1.1 --- History --- p.1 / Chapter 1.1.2 --- Epidemiology --- p.2 / Chapter 1.1.3 --- Pharmacology --- p.3 / Chapter 1.2 --- Maternal Cocaine Abuse --- p.5 / Chapter 1.2.1 --- Human Studies --- p.5 / Chapter 1.2.1.1 --- Prevalence --- p.5 / Chapter 1.2.1.2 --- Effects of Cocaine on the Developing Fetus --- p.7 / Chapter 1.2.1.2.1 --- Fetal Mortality --- p.8 / Chapter 1.2.1.2.2 --- Placental Abruption --- p.9 / Chapter 1.2.1.2.3 --- Premature Birth --- p.9 / Chapter 1.2.1.2.4 --- Neonatal Effects --- p.10 / Chapter 1.2.1.3 --- Congenital Abnormalities --- p.11 / Chapter 1.2.1.3.1 --- Cardiovascular Abnormality --- p.11 / Chapter 1.2.1.3.2 --- Genitourinary Tract Malformation --- p.12 / Chapter 1.2.1.3.3 --- Gastrointestinal Abnormality --- p.12 / Chapter 1.2.1.3.4 --- Respiratory Disorders --- p.13 / Chapter 1.2.1.3.5 --- Visual and Hearing Disorders --- p.14 / Chapter 1.2.1.3.6 --- CNS and Behavioural Abnormalities --- p.15 / Chapter 1.2.2 --- Animal Studies --- p.17 / Chapter 1.2.2.1 --- "Routes of Administration, Dosage and Tissue Distribution " --- p.18 / Chapter 1.2.2.2 --- Maternal and Offspring Effects --- p.21 / Chapter 1.2.2.2.1 --- Fetal and Maternal Mortality --- p.22 / Chapter 1.2.2.2.2 --- Gestational Length --- p.22 / Chapter 1.2.2.2.3 --- Maternal Weight Gain and Fetal Weight --- p.23 / Chapter 1.2.2.2.4 --- Little Size --- p.24 / Chapter 1.2.2.3 --- Congenital Abnormalities --- p.24 / Chapter 1.2.2.4 --- Behavioral Changes --- p.26 / Chapter 1.2.2.5 --- Neurochemical Changes --- p.28 / Chapter 1.2.2.5.1 --- Glucose Metabolism --- p.28 / Chapter 1.2.2.5.2 --- Dopamine Transporter --- p.29 / Chapter 1.2.2.5.3 --- Dopamine D1 Receptor --- p.29 / Chapter 1.2.2.5.4 --- Dopamine D2 Receptor --- p.30 / Chapter 1.2.2.5.5 --- Tyrosine Hydroxylase --- p.30 / Chapter 1.2.2.5.6 --- Other Changes --- p.31 / Chapter 1.3 --- The Aim of the Study --- p.31 / Chapter CHAPTER II --- MATERIALS AND METHODS / Chapter 2.1 --- Administration of Cocaine --- p.34 / Chapter 2.2 --- Biochemical Studies --- p.35 / Chapter 2.2.1 --- Receptor Binding Assays --- p.36 / Chapter 2.2.1.1 --- Dopamine Transporter --- p.37 / Chapter 2.2.1.1.1 --- Specific Binding Assay and Scatchard Analysis --- p.37 / Chapter 2.2.1.2 --- Dopamine D1 Receptor --- p.38 / Chapter 2.2.1.2.1 --- Association Curve --- p.38 / Chapter 2.2.1.2.2 --- Competition Assay --- p.39 / Chapter 2.2.1.2.3 --- Specific Binding Assay and Scatchard Analysis --- p.39 / Chapter 2.2.1.3 --- Dopamine D2 Receptor --- p.39 / Chapter 2.2.1.3.1 --- Association Curve --- p.40 / Chapter 2.2.1.3.2 --- Competition Assay --- p.40 / Chapter 2.2.1.3.3 --- Specific Binding Assay and Scatchard Analysis --- p.40 / Chapter 2.2.1.4 --- Assay for Residual Cocaine in Maternal Brain --- p.41 / Chapter 2.3 --- Statistics --- p.42 / Chapter 2.4 --- Morphological Studies --- p.42 / Chapter 2.4.1 --- Tyrosine Hydroxylase (TH) Immunocytochemical Staining --- p.42 / Chapter 2.5 --- Molecular Genetic Studies --- p.44 / Chapter 2.5.1 --- Material for DNA Insert --- p.44 / Chapter 2.5.1.1 --- "Dopamine Transporter, D2 receptor and β-actin cDNA Probe " --- p.44 / Chapter 2.5.2 --- Preparation for DNA Insert --- p.45 / Chapter 2.5.2.1 --- Competent Cells and Transformation of Plasmid --- p.45 / Chapter 2.5.2.2 --- Growth Transformed Bacteria and Isolation of DNA --- p.46 / Chapter 2.5.2.3 --- Purification of cDNA by Geneclean® II Kit --- p.47 / Chapter 2.5.3 --- Isolation of Total mRNA From Tissue --- p.47 / Chapter 2.5.4 --- Northern Blot Analysis --- p.48 / Chapter 2.5.4.1 --- Analysis of Northern Blots --- p.50 / Chapter 2.5.5 --- In Situ Hybridization --- p.50 / Chapter 2.5.5.1 --- Tissue Preparation --- p.50 / Chapter 2.5.5.2 --- Preparation of Dopamine Transporter Ribroprobe …… --- p.50 / Chapter 2.5.5.3 --- In Situ Hybridization Histochemistry --- p.51 / Chapter CHAPTER III --- RESULTS / Chapter 3.1 --- "Litter Size, Birth Weight and Maternal Weight Gain " --- p.53 / Chapter 3.2 --- Biochemical Studies --- p.53 / Chapter 3.2.1 --- Specific Binding --- p.53 / Chapter 3.2.2 --- Dopamine Transporter - Scatchard Analysis --- p.54 / Chapter 3.2.3 --- Dopamine Receptor --- p.55 / Chapter 3.2.3.1 --- Association Curve --- p.56 / Chapter 3.2.3.2 --- Competitive Curve --- p.57 / Chapter 3.2.3.3 --- Scatchard Analysis --- p.57 / Chapter 3.2.4 --- Dopamine D2 Receptor --- p.59 / Chapter 3.2.4.1 --- Association Curve --- p.59 / Chapter 3.2.4.2 --- Competitive Curve --- p.59 / Chapter 3.2.4.3 --- Scatchard Analysis --- p.59 / Chapter 3.2.5 --- Residual Cocaine Assay in Maternal Brain --- p.61 / Chapter 3.2.5.1 --- Specific Binding --- p.61 / Chapter 3.2.5.1.1 --- Dopamine Transporter --- p.61 / Chapter 3.3.5.1.2 --- Dopamine D1 Receptor --- p.62 / Chapter 3.3.5.1.3 --- Dopamine D2 Receptor --- p.62 / Chapter 3.3 --- Morphological Studies --- p.62 / Chapter 3.3.1 --- Tyrosine Hydroxylase (TH) Immunocytochemical Staining --- p.62 / Chapter 3.4 --- Molecular Genetic Studies --- p.63 / Chapter 3.4.1 --- Northern Blot Analysis --- p.63 / Chapter 3.4.1.1 --- Dopamine Transporter --- p.63 / Chapter 3.4.1.2 --- Dopamine D2 Receptor --- p.64 / Chapter 3.4.2 --- In Situ Hybridization --- p.64 / Chapter CHAPTER IV --- DISCUSSION AND CONCLUSION / Chapter 4.1 --- Discussion --- p.65 / Chapter 4.2 --- Conclusion --- p.77 / References --- p.79 / Publications --- p.95

Zhu Jian-hui. / "July 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 174-215). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xii, 150 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 131-150).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Lic.-avh. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 2 uppsatser.

Thesis (Ph.D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed on June 24, 2009). Includes bibliographical references (p. 97-104).

Thesis (M.S.)--University of Michigan, 1981.

Thesis (M.S.)--University of Michigan, 1981.