Sprague-Dawley rats were administered daily, subcutaneous injections of methylmercuric chloride at a dose of 5 mg/Hg/kg beginning on postnatal day 5. By their fourth postnatal week, animals exhibited a constellation of neurological signs of motor impairment which resembled the cerebral palsy syndrome of humans perinatally exposed to methylmercury. Routine histological examination of the brain revealed no gross differences between methylmercury-treated (MeHg), normal control (NC) or weight-matched littermates. The histochemical localization of the mitochondrial enzyme cytochrome oxidase (CO) was utilized in Experiment I to examine possible alterations in the metabolic activity of motor nuclei which might contribute to the observed movement and postural disorders. A population of intensely-staining cytochrome oxidase neurons (ICONs) in the magnocellular portion of the red nucleus (RMC) and interrubral mesencephalon (IRM) were conspicuously present in all MeHg animals at the onset of motor impairment. These morphologically, histochemically, and anatomically distinct neurons did not exhibit intense CO staining in control animals. Conversely, a significant decrease was demonstrated in the oxidative metabolic activity of many neurons in the substantia nigra, zona reticulata of MeHg animals. In Experiment II, the postnatal appearance of ICONs was morphometrically quantified in MeHg animals sacrificed at PND 14, 16, 18, 20, 22, or 25. The histochemically-defined onset of increased metabolic activity in ICONs was first observed on PND 16, at least one week before the onset of clinical signs of neurological impairment. This was the earliest manifestation of methylmercury neurotoxicity yet described in this animal model. A subsequent four-fold increase in the total number of ICONs at PND 18 was followed by a gradual decrease in number to PND 25. Significantly more of the ICONs were found in the IRM than in the RMC at PND 18 & 20. The possibility that the increased activity of ICONs may result from disinhibition of specific afferents to the red nucleus was addressed by introducing either hemidecortication or hemicerebellectomy on PND 10 and then morphometrically determining the deviation from symmetry in the bilateral distribution of the total number of ICONs in the RMC and IRM at PND 22. The distribution of ICONs was symmetrical and not different in either hemidecorticate or unoperated controls. A significant (36%) decrease in the total number of ICONs was observed in both the RMC and IRM contralateral to hemicerebellectomy. The identical ipsilateral regions did not differ from control or hemidecorticate MeHg animals. In Experiment III, the anatomical distribution of major histocompatability complex antigens (MHC) in the brain of MeHg animals was examined using immunohistochemical methods. MHC immunoreactivity was widely distributed throughout the brain of MeHg animals. Areas with low immunoreactivity, or lack of it, stand out and include all of the hippocampus, thalamus, pyriform and entorhinal cortex, and lateral cerebellar hemispheres. Moderate staining intensity was observed in neocortical areas, basal forebrain, caudate-putamen and cerebellar vermis. Strong immunoreactivity was found in red nucleus, substantia nigra, cingulate cortex, retrosplenial cortex, presubiculum, parasubiculum and vestibular nuclei. It was suggested that the increased activity of ICONs likely contributes to the movement and postural disorders resulting from methylmercury intoxication. The increased activity in ICONs was determined to be, at least partially, dependent upon cerebellar input. The results are discussed with reference to the toxic effects of methylmercury and specifically to the susceptibility of GABAergic interneurons in perinatal trauma. Possible analogies are drawn between the mechanisms of methylmercury-induced cerebral palsy syndrome and those of other developmental movement and postural disorders. / Medicine, Faculty of / Graduate

Kwok, Ka Ming. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 124-146). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT / In English --- p.ii / In Chinese --- p.v / LIST OF TABLES --- p.vii / LIST OF FIGURE --- p.ix / ABBREVIATIONS / For Units --- p.x / For Prefixes of the International System of Units --- p.x / For Terms Commonly Used --- p.xi / Role of research workers --- p.xv / Chapter CHAPTER 1 --- Overview of methylmercury / Chapter 1.1 --- Source of methylmercury --- p.1 / Chapter 1.2 --- Toxicokinetics --- p.3 / Chapter 1.2.1 --- Absorption and distribution --- p.3 / Chapter 1.2.2 --- Half-life --- p.5 / Chapter 1.2.3 --- Metabolism/Biotransformation --- p.5 / Chapter 1.2.4 --- Biochemical mechanism of toxicity --- p.7 / Chapter 1.3 --- Health effects of mercury exposure --- p.9 / Chapter 1.3.1 --- Adult central nervous system --- p.10 / Chapter 1.3.2 --- The developing central nervous system --- p.11 / Chapter 1.3.3 --- Cardiovascular effects --- p.13 / Chapter 1.3.4 --- Immunotoxicity --- p.14 / Chapter 1.4 --- Biomarkers for prenatal exposure --- p.15 / Chapter 1.5 --- MeHg exposure in high risk populations in Hong Kong --- p.17 / Chapter CHAPTER 2 --- Neurocognitive performance / Chapter 2.1 --- Introduction --- p.19 / Chapter 2.1.1 --- New Zealand --- p.20 / Chapter 2.1.2 --- Seychelles --- p.21 / Chapter 2.1.3 --- Faroe Islands --- p.22 / Chapter 2.1.4 --- The Hong Kong situation --- p.23 / Chapter 2.2 --- Method --- p.23 / Chapter 2.2.1 --- Subjects and study design --- p.23 / Chapter 2.2.2 --- Questionnaires --- p.24 / Chapter 2.2.3 --- Hg concentration measurement --- p.25 / Chapter 2.2.4 --- Neurocognitive measurements --- p.26 / Chapter 2.2.4.1 --- Hong Kong - Wechsler Intelligence Scale for Children --- p.27 / Chapter 2.2.4.2 --- Hong King List Learning Test --- p.28 / Chapter 2.2.4.3 --- Test of Everyday Attention for Children --- p.29 / Chapter 2.2.4.4 --- Boston Naming Test --- p.31 / Chapter 2.2.4.5 --- Grooved Pegboard Test --- p.31 / Chapter 2.2.5 --- Statistical analysis --- p.32 / Chapter 2.3 --- Results --- p.33 / Chapter 2.3.1 --- Subject characteristic --- p.33 / Chapter 2.3.2 --- Test results --- p.34 / Chapter 2.3.3 --- Statistical analysis results --- p.35 / Chapter 2.4 --- Discussion --- p.36 / Chapter CHAPTER 3 --- Cardiac autonomic function / Chapter 3.1 --- Introduction --- p.60 / Chapter 3.1.1 --- Mechanism --- p.60 / Chapter 3.1.2 --- The association between HRV and the ANS --- p.61 / Chapter 3.1.3 --- Clinical applications and related studies --- p.63 / Chapter 3.1.4 --- Associations between MeHg exposure & HRV --- p.64 / Chapter 3.2 --- Methods --- p.65 / Chapter 3.2.1 --- Subjects and study design --- p.65 / Chapter 3.2.2 --- Physical and HRV measurement --- p.66 / Chapter 3.2.3 --- Time domain analysis --- p.68 / Chapter 3.2.4 --- Frequency domain analysis --- p.68 / Chapter 3.2.5 --- Non-linear method --- p.69 / Chapter 3.2.6 --- Statistical analysis --- p.70 / Chapter 3.3 --- Results --- p.71 / Chapter 3.3.1 --- Subjects characteristics --- p.71 / Chapter 3.3.2 --- HRV and statistical analysis results --- p.71 / Chapter 3.4 --- Discussion --- p.73 / Chapter CHAPTER 4 --- Immuno-toxicity / Chapter 4.1 --- Introduction --- p.91 / Chapter 4.2 --- Methods --- p.96 / Chapter 4.2.1 --- Subjects and Study Design --- p.96 / Chapter 4.2.2 --- Cytokine measurement --- p.96 / Chapter 4.2.3 --- Reversibility --- p.98 / Chapter 4.2.4 --- Statistical Analysis --- p.99 / Chapter 4.3 --- Results --- p.101 / Chapter 4.3.1 --- Subject Characteristics --- p.101 / Chapter 4.3.2 --- Atopic and non-atopic diseases group --- p.101 / Chapter 4.3.3 --- Cytokine profiles --- p.102 / Chapter 4.3.4 --- Reversibility --- p.103 / Chapter 4.4 --- Discussion --- p.104 / Chapter CHAPTER 5 --- Conclusion --- p.119 / Reference List --- p.124