Call number: LD2668 .T4 1984 C68 / Master of Science

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As soon as the building of the body is completed, the ageing process begins. In the natural course of events, the functioning of some organ systems finally ebbs below the threshold necessary to maintain the body, resulting in death. This occurrence is relatively rare, because diseases superimpose themselves upon the ageing process, bringing premature death resulting from pathological causes. This study focused on the cholinergic system of the rat forebrain. The cholinergic neurons in the brain are said to be involved in memory and learning, and a decrease in the activity of its enzymes has been reported in certain diseases, such as Alzheimer's disease. In the present study, the in vitro effects on the cholinergic system, of aluminium and mercury and tryptophan metabolites, kynurenic acid and quinolinic acid, are determined. Aluminium has been considered as a possible factor in Alzheimer's disease. Mercury in high concentrations is toxic, and its use in amalgam for dental treatment is under consideration with regard to its possible role in promoting neurological disease. The tryptophan metabolites increase in the brain with age and may have a role in pathological diseases. Quinolinic acid, when administered in toxic concentrations produces a possible model for Huntington's disease. This study investigated the effects of the above mentioned toxins on: (1) The synthesis of acetylcholine by choline acetyltransferase; (2) The specific binding of acetylcholine muscarinic receptors; (3) The degradation of acetylcholine by acetyl cholinesterase, Choline acetyltransferase activity did not change in the presence of aluminium chloride, kynurenic acid and quinolinic acid from 1 nM to 1 mM. Mercuric chloride had no significant effect on the enzymes activity from a concentration of 1 nM- 1 pM. At 10 pM there was a significant decrease in cholineacetyltransferase activity (P < 0.001). Enzyme activity continued to decrease at 100 pM (P < 0.0002). At 1 mM, enzyme activity was virtually non existent (P < 0.0001). Acetyl cholinesterase activity was not affected by aluminium chloride, kynurenic acid and quinolinic acid. Mercuric chloride from 1 pM - 1 mM significantly reduced the enzyme activity (P < 0.05). The binding of the antagonist, [³H] quinuclidinyl benzilate (QNB), to acetylcholine muscarinic receptors, revealed that aluminium chloride did not affect the binding of the antagonist, in the concentration range of 1 nM - 100 pM, to the receptors. At 1 mM, aluminium chloride appears to increase the sensitivity of the receptors for the ligand (P < 0.01). Mercuric chloride also does not appear to have any significant effect on receptor binding in this range. However, at 1 mM there appears to be a very significant decrease in receptor binding (P < 0.01). This decrease may be attributed to the interaction of mercury with the sulfhydryl groups in muscarinic receptors. Kynurenic acid had no effect on the receptor binding. Quinolinic acid, in the concentration range from 10 nM - 1 mM increased the binding ofthe receptor to [3Hi QNB significantly (P < 0.001). The study also investigated the effect of the tryptophan metabolites of the kynurenine pathway on pineal indole metabolism. The kynurenine pathway is a major route of tryptophan metabolism in the pineal gland, along with indole metabolism. Investigations showed that kynurenic acid produced a decrease in N-acetylserotonin concentrations ( P < 0.001) and melatonin concentrations (P < 0.003). Further experiments using quinolinic acid produced a similar decrease in N-acetylserotonin (P < 0.001) and melatonin (P < 0.015). A decrease was also noted in the level of 5-methoxytryptophol (P < 0.0005). These findings suggest that aluminium chloride, kynurenic acid and quinolinic acid have no possible role in the decrease of activity of cholinergic enzymes which is observered in diseases such as Alzheimer's disease. The results regarding the effect of mercury chloride on the cholinergic system suggest that low exposure to the toxin will not adversely effect the enzymes. The decrease in N-acetylserotonin and melatonin concentrations reported here, may be a result of kynurenic acid and quinolinic acid having an inhibitory effect on the enzyme, serotonin Nacetyltransferase, which is responsible for the conversion of serotonin to N-acety/serotonin.

IntroductionEndocrine disrupting chemicals (EDCs) are agents, found either singly or used in mixtures, that disrupt the endocrine system or its production of hormones and may cause adverse effects in the exposed individuals or populations and, in the case of pregnant women, their offspring. It is presumed that maternal thyroid hormones contribute to fetal brain development. The EDCs that could impair maternal thyroid hormone function might result in subtle deficits in neurodevelopmental outcomes in children. Polychlorinated biphenyls (PCBs) are a class of EDCs produced in the past century and are still found in the environment. This dissertation aims to explore, elaborate, and embellish the associations between prenatal exposure to PCBs, the metabolites associated with PCBs, and child cognitive and motor development. The next aim of this dissertation is to explore the associations between prenatal exposure to PCBs, the metabolites associated with PCBs, and maternal thyroid hormones. Five chapters are included in this dissertation: First, an introduction to PCBs and specific aims; second, a systematic review of the literature, including the studies where prenatal exposure to PCBs or the hydroxylated PCB metabolites (OH-PCBs) and their relationship with various domains of children's neurodevelopment were investigated; third, an empirical study of exploring the associations between prenatal exposure to a mixture of PCB, OH-PCBs and children cognitive and motor skills measured in different ages; fourth, an empirical study of investigating the associations between prenatal exposure to a mixture of PCB, OH-PCBs and maternal thyroid hormones with potential for investigating the mediation of possible associations observed in the third chapter by maternal thyroid hormone concentrations; fifth, a discussion of the findings, implications for public health research, and practice and conclusions. Materials and Methods The systematic review included peer-reviewed studies indexed in several repositories (N=71 studies) from the inception of the repositories. This systematic review of the studies measured the PCBs directly in prenatal or immediately after delivery in maternal serum, cord blood, placenta, or breast milk. The empirical studies used the data available on mothers and children from "Child Health and Development Studies." Eleven PCB congeners and five OH-PCB metabolites were measured in the maternal serum post-partum among a random subset of the participants. I used a mixture analysis, Bayesian Kernel Machine Regression (BKMR), and generalized linear models (GLM) to assess the association between concentrations of PCB congeners and OH-PCB metabolites measured three days post-partum and children's cognitive and motor skills scores at age five, and cognitive skills measured at a follow-up at ages 9-11. BKMR and GLM were also used to explore the associations between PCB congeners and OH-PCB metabolites and maternal free thyroxine (FT4) and thyroid-stimulating hormone (TSH). Results The systematic review found that prenatal exposure to PCBs was possibly associated with poor cognitive development and poor attention in early and middle childhood. The evidence regarding motor development, behavior, and other neurodevelopmental outcomes were not conclusive at any stage in childhood. There was an indication for sex-specific associations with worse cognition and attention scores among boys. There was also evidence in individual studies regarding the possible association between prenatal exposure to OH-PCBs and neurodevelopmental outcomes. There were significant differences between the studies in markers of exposure, exposure assessment timing, outcome assessment, and the methodological approaches to assess the association. In the second empirical study, I found that in the crude and adjusted BKMR models among the OH-PCB metabolites, cognitive skills test scores at age five increased with each decile increase in the mixture of OH-PCB metabolites compared to when all of the metabolites were fixed at their 50th percentile among all the children and the boys and girls. These associations were largely driven by OH-PCB153 and OH-PCB146, metabolites associated with the congener PCB153. In the third empirical study, among OH-PCB metabolites attributed to PCB congeners, I observed suggestive evidence for a positive association with maternal FT4, particularly in the highest percentile of exposure to overall OH-PCB metabolites. I did not observe an association between exposure to the mixture of PCB congeners and Maternal FT4 or TSH. Nonetheless, the overall patterns suggested a positive association between exposure to PCB congeners and maternal FT4.No associations of the overall mixture of PCBs and OH-PCB metabolites were observed with maternal TSH concentrations in the BKMR models. Nonetheless, in single metabolite risk estimates, I found that 3’-OH-PCB138 was positively associated with maternal TSH values when the 3’-OH-PCB138 was fixed at its 90th percentile compared to when it was in its 10th percentile, fixing all the other congeners in their 10th, 50th, and 90th percentiles. Finally, there was an indication of a possible antagonistic interaction between 4-OH-PCB107 and 3’-OH-PCB-138 in the association of OH-PCBs with maternal FT4 such that 3’-OH-PCB138 tended to have a positive association with maternal FT4 when 4-OH-PCB107 was fixed in the 90th percentile and tended to have a negative association with maternal FT4 when 4-OH-PCB107 was fixed in their 10th percentile when all the other metabolites were fixed in their median value. Conclusions There were patterns of positive associations of OH-PCB metabolites with the children’s cognitive outcomes and maternal FT4 and maternal TSH. Nonetheless, the observed associations were weak in magnitude, often including the null value. The BKMR allowed me to explore and investigate the interactions between different components of the mixture and the overall mixture effect on the outcomes. My dissertation indicated the necessity of a holistic approach to address the impact of exposure to environmental toxins, specifically due to the detected findings regarding interactions between OH-PCB metabolites.

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