Methylmercury (MeHg) is a neurotoxic global pollutant that accumulates at high levels in predatory fish and marine mammals. The dietary intake of these animals is the main source of MeHg exposure in humans. At high levels, MeHg is known to damage the sensory and motor systems in both adults and children. Due to the complexity and inaccessibility of the central nervous system (CNS), early dysfunction is difficult to detect. Biochemical markers in the CNS have been used to identify MeHg neurotoxicity in animal models. Analogues of these biochemical targets are also present in peripheral blood tissue and may reflect early CNS dysfunction in human populations. The proposed peripheral biomarkers include (1) lymphocyte muscarinic acetylcholine (mACh) receptor, (2) serum cholinesterase (ChE) and (3) platelet monoamine oxidase (MAO). This thesis evaluates the effects of mercury (Hg) compounds on these CNS and peripheral biochemical markers in laboratory and epidemiological studies. In vitro studies showed that inorganic Hg (HgCl2) and MeHg inhibited mACh receptor binding in human, rat, and mouse brain tissue. Additionally, studies demonstrated that a low-level gestational exposure to MeHg reduced MAO activity in the developing embryo and in adult female offspring. Combined, these studies provide a framework for the assessment of biochemical targets of Hg compounds in humans. A cross sectional study was conducted to evaluate the association between peripheral biochemical markers and MeHg exposure in fish-eating adults (n=129) from Lac St-Pierre, Quebec. Blood-Hg concentrations were used as a marker of exposure and ranged from 0.2 to 17.0 mug/L. Multiple linear regression analysis demonstrated that both blood-Hg (p=0.011) and heavy smoking (p=0.001) were associated with reduced platelet-MAO activity. However, neither lymphocyte mACh receptor nor serum ChE was related to blood-Hg. These results suggest that exposure to MeHg may result in reduced plat

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 6 uppsatser.

Thesis (M. Phil.)--University of Hong Kong, 2005. / Title proper from title frame. Also available in printed format.

No description available.

Chlorpyrifos (CPF) is one of the most widely used organophosphorus insecticides (OPs). The developmental exposure to low levels of CPF results in the inhibition of the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) and in altered emotional behavior (increased social play) without affecting the acetylcholinesterase, the canonical target of OPs. However, the molecular mechanisms responsible for this increased social play are not known. In this study, male rat pups were exposed orally to either corn oil, 0.75 mg/kg CPF, or 0.02 mg/kg PF-04457845 (PF; a specific inhibitor of FAAH) daily from postnatal day 10 (PND10) - PND16. This dosage of CPF does not alter brain cholinergic activity but inhibits FAAH. Once these rats reached adolescence (PND38), they were divided into two cohorts and each cohort contained all treatments. One cohort underwent social behavior testing and the other cohort remained naïve to behavioral testing. Following testing, the amygdala was collected from each cohort and protein expression was determined using a labelree shotgun proteomic approach. The obtained differentially expressed proteins from the different cohorts were analyzed by DAVID and Ingenuity Pathway Analysis software. Comparison of control non-behavior and control behavior rats suggests that social play altered the systems involved in the regulation of reward such as the opioid, dopaminergic, and serotonergic systems. These data also suggest that synaptic levels of GABA and glutamate increased during play. Comparison of non-behavior control and treated rats suggests that FAAH inhibition resulting from developmental exposure to CPF and PF persistently affects glutamatergic and GABAergic signaling. These data also suggest that there is a similar pattern of protein expression between CPF and PF. Comparison of the data from the behavioral groups of rats suggests that alterations in glutamatergic and GABAergic signaling and improper activation of opioid signaling could be responsible for the increased social play behavior. These alterations in the neurotransmitter signaling were observed in both CPF and PF treated rats. Overall, the results suggest that FAAH inhibition by either CPF or PF leads to alterations in opioid, glutamatergic, and GABAergic signaling that could be responsible for increased levels of social play.

No description available.

published_or_final_version / abstract / Anatomy / Master / Master of Philosophy

published_or_final_version / abstract / Pharmacology / Master / Master of Philosophy

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

Objetivo. Avaliar o campo visual em ex-trabalhadores de fábricas de lâmpadas fluorescentes com diagnóstico de mercurialismo metálico crônico ocupacional, através de testes psicofísicos de campimetria computadorizada e registros eletrofisiológicos da retina obtidos através do eletrorretinograma multifocal. Método. A avaliação psicofísica do campo visual foi realizada em 35 ex-trabalhadores (idade média = 44,2 ± 5,9 anos; 30 homens) no equipamento Humphrey Field Analyzer II (modelo 750i) em dois testes: acromático (standard automated perimetry) e azul-amarelo (short wavelength automated perimetry). O programa Visual Evoked Response Imaging System (VERISTM Science 5.0) permitiu o registro e análise dos sinais eletrofisiológicos da retina através do eletrorretinograma multifocal em 32 ex-trabalhadores (idade média = 44,6 ± 5,5 anos; 27 homens) dos 35 que realizaram os testes de campimetria computadorizada. Os resultados foram comparados com um grupo controle para o campo visual (n = 34; idade média = 43,3 ± 8,3 anos; 21 homens) e com outro grupo controle para o eletrorretinograma multifocal (n = 21; idade média = 43,5 ± 8,9 anos; 10 homens). Resultados. Os exames psicofísicos de campimetria computadorizada mostraram que há redução da sensibilidade visual em regiões centrais até 27? do campo visual. No exame acromático a diminuição da sensibilidade ocorreu, inclusive, na região foveal. O exame azul-amarelo confirmou a redução encontrada no exame acromático para regiões paracentrais até 27° de excentricidade. O eletrorretinograma multifocal apresentou redução nas amplitudes das respostas retinianas em regiões centrais até 25°, sem alteração no tempo implícito das respostas. As regiões paracentrais mostraram redução significativa para os valores de amplitude do primeiro componente negativo (N1) e do primeiro componente positivo (P1). Discussão. A redução na sensibilidade visual em diferentes regiões do campo visual, confirma que há prejuízos no sistema visual decorrentes da exposição crônica ao vapor de mercúrio. Nesse caso, não se pode especificar as regiões afetadas, porque a metodologia utilizada não permite isolar estruturas da via visual e, consequentemente, não permite localizar as regiões específicas que o mercúrio estaria prejudicando preferencialmente. Os prejuízos causados pela intoxicação ao vapor de mercúrio na retina parecem ser difusos, considerando que a redução de amplitude das respostas de N1 e P1 pode indicar prejuízos em diferentes grupos celulares da retina. Os resultados mostram que parte dos prejuízos de campo visual causados pelo vapor de mercúrio estão relacionados com alterações retinianas. Os resultados estão de acordo com trabalhos preliminares que monstraram alterações visuais que permanecem mesmo anos após o afastamento da fonte de exposição, sugerindo que a intoxicação por vapor de mercúrio pode não ser totalmente reversível. Conclusão. Os sujeitos expostos cronicamente ao vapor de mercúrio durante um período de 10 anos (em média) apresentam redução da sensibilidade visual em diferentes regiões do campo visual, mesmo após 7 anos (em média) de afastamento da fonte expositora. Pode haver prejuízos em diferentes regiões da via visual envolvidos nas alterações de campo visual, mas parte desses prejuízos causados pela exposição crônica ocupacional ao vapor de mercúrio possui origem retiniana. / Purpose. To analyse visual field sensitivity in a group of workers retired from thefluorescent lamp industry diagnosed with chronic occupational metallic mercurialism using psychophysical tests such as automated perimetry and measuring the retina cells\' electrical responses with the multifocal electroretinogram. Methods. The psychophysical evaluation of the visual field was performed in 35 retired workers (mean age = 44.2 ± 5.9 years; 30 males) using Humphrey Field Analyzer II (model 750i) device in two different tests: SAP (standard automated perimetry) and SWAP (short wavelength automated perimetry). The Visual Evoked Response Imaging System (VERISTM Science 5.0) provided us the electrophysiological recordings and analysis of the retina based on measurement data from the multifocal electroretinogram in 32 retired workers (mean age = 44.6 ± 5.5 years; 27 males) that were included in the 35 automated perimetry test subjects. The results were compared with an age-matched control group using the visual field tests (n = 34; mean age = 43.3 ± 8.3 years; 21 males) and to another age-matched control group at the multifocal electroretinogram (n = 21; mean age = 43.5 ± 8.9 years; 10 males). Results. The automated perimetry tests have shown visual sensitivity reductions in the central areas around 27° of eccentricity. In the SAP test sensitivity decrease was found even in the foveal region. The SWAP test results are in agreement with the reduction found around 27° in the SAP test at mid-peripheral areas. The multifocal electroretinogram has shown decreases in amplitude in the retina recordings in the central areas around 25° of eccentricity, but there were no implicit time reductions. The mid-peripheral areas have shown significant reductions in the amplitude values in the first negative component (N1) and in the first positive component (P1) as well. Discussion. The visual sensitivity reductions in the different visual field areas confirm the visual damages in patients with long-term mercury vapor exposure. In this case the affected visual pathway sections could not be determined since the applied psychophysical method does not allow us to indicate the specific visual structure principally damaged by the mercury vapor. The damages found in the retina due to mercury vapor intoxication can be considered broadly dispersed, since the reductions in N1 and P1 amplitudes might be the indications of damages in multiple retina cell groups. Our results show that some visual field losses are related to various retinal alterations caused by the mercury vapor. The results are in agreement with preliminary works that showed visual dysfunctions after several years away from the mercury vapor source suggesting that mercury vapor intoxication may not be completely reversible. Conclusion. The long-term (10 years in average) mercury vapor exposed workers have shown visual sensitivity reductions in different visual field areas after 7 years (in average) away from the mercury vapor source. In our present study we would like to indicate that visual field reductions cannot only be related to damages in the various sections of the visual pathway, but some of these visual field losses can occur due to retinal alterations caused by cronic mercury vapor exposure.