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<p dir="ltr">Neurodegenerative disease (ND) is a debilitating neurological disorder characterized by progressive loss of neurons in central nervous system (CNS), resulting in the decline in memory, cognition and motor functions. Alzheimer's disease (AD) and Parkinson's disease (PD) are the two of the most prevalent NDs, affecting millions of individuals in the United States. While hundreds of genetic risk factors have been identified in association with ND, familial cases with genetic origin only account for 10% and 15% of diagnosed AD and PD incidences, respectively. The majority of ND cases occur sporadically. Mounting evidence from epidemiology studies suggests that environmental stressors are one of the key ND associated risk factors where exposure to environmental stressors leads to the on-set of ND years or decades later. Little is known about the molecular mechanism facilitating the establishment of the persistent and potentially permanent neurotoxic state after exposures, particularly at a developmental stage. Hence, there is a pressing need in understanding the cellular machineries involved in establishment of a persistent neurotoxic state resulting from early-life exposure to environmental toxins. Subcellular compartments are crucial for the maintenance of neuronal homeostasis. Alterations in various subcellular compartments, including the nucleus, mitochondria, and lysosomes, have been commonly noted in cases of AD and PD; and are believed to play a crucial role in the establishment of a persistent neurotoxic state. The primary goal of my thesis is thus to uncover the dysregulation in multiple subcellular compartments and their contributes to ND pathogenesis induced by early-in-life exposure to environmental stressors, including atrazine (ATZ), per-and polyfluoroalkyl substances (PFAS), and neurofibrillary tangles.</p><p dir="ltr">I started by developing live-cell compatible tools to track cellular and sub-cellular changes. Mitochondria DNA methylation is of particular interest, due to its potential regulatory role in the expression of electron transport chain (ETC) subunits and thus mitochondrial activity. Thus, I started expanding the mitochondria probe tool set by designing a novel probe targeting methylated CpGs of mitochondrial DNA (mtDNA). We demonstrated the capability of our probe to reveal spatial distribution of methylated mtDNA and capture mtDNA methylation change at single cell level. Combined with our previously developed probe for nuclear DNA methylation, we monitored mtDNA and nuclear DNA methylation simultaneously on the single-cell level where unsynchronized dynamics of DNA methylation from nucleus and mitochondria were discovered.</p><p dir="ltr">Our tool offers a unique opportunity to understand epigenetic regulation of mtDNA and its dynamic response to microenvironment and cellular changes. Later, I further extended these efforts to develop in situ probes for tracking the formation of tau aggregates based on fluorescence resonance energy transfer (FRET); and demonstrated the superior performance of our engineered probes compared to the current state-of-the-art.</p><p dir="ltr">I explored two neuronal culture systems, namely SH-SY5Y- and human induced pluripotent stem cell (hiPSC)-derived neurons; and their feasibility in studying neurotoxic effects of developmental exposure to environmental stressors. Specifically, I used SH-SY5Y derived neuron-like cells to study the impact of pre-differentiation exposure to PFOA, abundant chemical in environment due to its historical uses in consumer products and industrial applications. hiPSC-derived neurons were used to study the effects of developmental exposure to ATZ. Both studies identified cellular changes, for example neurite morphology and expression of enzyme catalyzing the production of neurotransmitters, that last after completion of differentiation. We also identified changes of pathogenic markers aligning with increased PD risks associated with developmental PFOA and ATZ exposure. Compared to SH-SY5Y, hiPSC-derived neurons were more advantageous due to their ability to recapitulate neuronal activity and pathogenic changes related to ND, and thus were used in my follow-up studies.</p><p dir="ltr">I adopted hiPSC derived neuron model to study the molecular mechanism of ND using established ND etiology. Patients with neurodegenerative disorders (ND) exhibit varying levels and temporal patterns of aggregated β-amyloid (Aβ) and tau protein. We exposed neurons derived from hiPSC with preformed fibrils (PFFs) of Aβ, tau and Aβ+tau, respectively. These treatments result in significant alterations in neurite network morphology, nuclear morphology, chromatin compactness and synaptic density. Interestingly, Aβ and tau fibrils seem to have opposite effects on mitochondrial membrane potential on neurites. Increased quantity of lysosomes was found in neurons treated with Aβ, tau and Aβ+tau, while decrease of lysosomal acidity was only observed in neurons treated with Aβ and tau sequentially. Collectively, our data suggests the potential synergy between Aβ and tau in establishing a neurotoxic state.</p><p dir="ltr">In summary, my thesis work has developed enabling engineering tools to monitor cellular and subcellular changes in neurons; identified hiPSC-derived neurons as a promising platform for studying developmental neurotoxicity; and paved the way towards understanding multi-etiology and its molecular underpinning for ND.</p>

Background: Platinum refinery workers are exposed to various elements during the refining process, with soluble platinum salts posing a potential health risk. Platinum salts are extremely potent sensitisers that can result in the clinical syndrome of platinum salt sensitivity (PSS) that leads to skin and respiratory hypersensitivity in refinery workers. Several published research articles document refinery workers’ exposure levels to soluble platinum salts during production. However, the exposure levels to soluble platinum salts during non–routine stock take activities are unknown although cases of sensitisation have been diagnosed following these nonoperational periods. Stock take for the platinum refinery under study commenced on 18 January 2010 and ended 22 February 2010. Increased emphasis was placed on flushing plant equipment rather than dismantling it. The aim was to dismantle 10% of what previously was dismantled to reduce the risk of exposing employees to soluble platinum salts, to reduce the chance of damaging plant equipment and for cost and time saving purposes. Aim: The objectives of this study are to: (i) quantify work area and personal exposure levels; (ii) identify work areas and work practices with exposure levels exceeding the occupational exposure limit (OEL) (>2 ug/m3); (iii) determine whether exposure levels differ significantly between: a) personal sampling groups (engineering versus production), b) area sampling groups (open versus closed–face sampling), c) work areas, d) total area and total personal sampling groups and to (iv) evaluate the efficiency of the current control measures utilised. Design and Method: A total of 58 platinum samples were collected, consisting of 38 personal and 20 area samples. Personal sampling consisted of Institute of Occupational Medicine (IOM) samplers housing reusable 25 mm filter cassettes with mixed cellulose ester (MCE) membrane filters for the collection of inhalable airborne particles. Because both the cassette and the filter were pre and post–weighed as a single unit, all particles collected (even those against the walls of the cassette) were included in the analysis. Sampling was conducted in accordance with the stock take schedule and scope and included a roster for the systematic dismantling and cleaning of the refinery, following the process flow. A target population of maximum five fitters and five operators per area were identified, responsible for dismantling and cleaning plant equipment respectively. The sampling strategy was based on the identification and sampling of employees presumed to have the highest exposure risk. The Occupational Exposure Sampling Strategy Manual (OESSM) refers to this as the “maximum risk employees” (Liedel et al., 1977). The selection of the maximum risk employees was done with reasonable certainty since the employees sampled were working closest to the source of exposure. Sampling was conducted for the total duration of the task consisting of single sample measurements. Area sampling was conducted by means of BUCKAir high volume samplers fitted with preweighed 47 mm MCE filter cassettes to show the spread of the contaminant in the work area. The high volume samplers were calibrated to operate at a sampling volume of 20 L/min. The sampling heads were positioned 1.5 m from the ground surface and as near as possible to the work location or failing this as near as is possible to major sources of exposure. Samples were collected and analysed according to the method for the determination of hazardous substances 46/2 (MDHS 46/2). This is an advanced sampling and analysis standard which enables detection of low levels of soluble platinum (0.01 ug/m3). Results: Thirty eight personal platinum samples were collected, consisting of a sampled engineering (n=15) and production (n=23) subgroup. Out of the thirty eight personal samples taken in total, 21% of the samples’ concentrations exceeded the OEL of 2 ug/m3 and ranged between 0.004–20.479 ug/m3. Twenty area platinum samples were collected, consisting of open (n=10) and closed face (n=10) sampling. Out of the twenty area samples taken in total, 10% of the samples’ concentrations exceeded the OEL of 2 ug/m3 and ranged between 0.0004–5.752 ug/m3. The mean personal exposure levels for the production subgroup (2.739 ug/m3) were significantly higher compared to the engineering subgroup’s mean personal exposure levels (0.393 ug/m3). This significant difference (p=0.033) was expected since the production subgroup was more exposed and involved in the digging out of residues and the cleaning of plant equipment compared to the engineering subgroup with limited exposure and involved in the opening of plant equipment. Although the mean exposure levels for open face sampling (0.725 ug/m3) were higher compared to the mean exposure levels for closed face sampling (0.441 ug/m3) no significant difference (p=0.579) were noted. The mean area exposure levels (0.583 ug/m3) were significantly lower (p=0.004) compared to the mean personal exposure levels (1.813 ug/m3) for similar areas and tasks performed and, therefore, not an effective indicator of personal exposure levels. Higher personal exposure levels were expected since the workers were closer to the source of exposure and since the platinum salts could have diluted in the workplace’s air resulting in lower area exposure levels. Conclusion: The research study addressed the problem statement, met the objectives set out in Chapter 1, hypotheses were accepted and rejected and future studies were recommended. It was hypothesised that: a) refinery workers are exposed to airborne soluble platinum during non–operational periods; b) exposure levels do not differ significantly between the personal sampling groups (engineering vs production); c) exposure levels do not differ significantly between the area sampling groups (open versus closed–face sampling); d) exposure levels do not differ significantly between work areas; e) exposure levels differ significantly between total personal and total area sampling groups. The results confirmed that refinery workers are exposed to airborne soluble platinum during non–operational periods and hypothesis a was accepted. The personal exposure levels of the engineering versus production sampling groups differed statistically (p=0.033) and hypothesis b was rejected. The exposure levels of the open and closed face sampling groups did not differ significantly (p=0.579) and hypothesis c was accepted. In addition no statistical difference (p>0.05) was indicated between the work areas and hypothesis d was accepted. Total personal versus total area exposure levels (p=0.004) differed statistically and hypothesis e was accepted. / Thesis (M.Sc. (Occupational Hygiene))--North-West University, Potchefstroom Campus, 2011.

Background: Platinum refinery workers are exposed to various elements during the refining process, with soluble platinum salts posing a potential health risk. Platinum salts are extremely potent sensitisers that can result in the clinical syndrome of platinum salt sensitivity (PSS) that leads to skin and respiratory hypersensitivity in refinery workers. Several published research articles document refinery workers’ exposure levels to soluble platinum salts during production. However, the exposure levels to soluble platinum salts during non–routine stock take activities are unknown although cases of sensitisation have been diagnosed following these nonoperational periods. Stock take for the platinum refinery under study commenced on 18 January 2010 and ended 22 February 2010. Increased emphasis was placed on flushing plant equipment rather than dismantling it. The aim was to dismantle 10% of what previously was dismantled to reduce the risk of exposing employees to soluble platinum salts, to reduce the chance of damaging plant equipment and for cost and time saving purposes. Aim: The objectives of this study are to: (i) quantify work area and personal exposure levels; (ii) identify work areas and work practices with exposure levels exceeding the occupational exposure limit (OEL) (>2 ug/m3); (iii) determine whether exposure levels differ significantly between: a) personal sampling groups (engineering versus production), b) area sampling groups (open versus closed–face sampling), c) work areas, d) total area and total personal sampling groups and to (iv) evaluate the efficiency of the current control measures utilised. Design and Method: A total of 58 platinum samples were collected, consisting of 38 personal and 20 area samples. Personal sampling consisted of Institute of Occupational Medicine (IOM) samplers housing reusable 25 mm filter cassettes with mixed cellulose ester (MCE) membrane filters for the collection of inhalable airborne particles. Because both the cassette and the filter were pre and post–weighed as a single unit, all particles collected (even those against the walls of the cassette) were included in the analysis. Sampling was conducted in accordance with the stock take schedule and scope and included a roster for the systematic dismantling and cleaning of the refinery, following the process flow. A target population of maximum five fitters and five operators per area were identified, responsible for dismantling and cleaning plant equipment respectively. The sampling strategy was based on the identification and sampling of employees presumed to have the highest exposure risk. The Occupational Exposure Sampling Strategy Manual (OESSM) refers to this as the “maximum risk employees” (Liedel et al., 1977). The selection of the maximum risk employees was done with reasonable certainty since the employees sampled were working closest to the source of exposure. Sampling was conducted for the total duration of the task consisting of single sample measurements. Area sampling was conducted by means of BUCKAir high volume samplers fitted with preweighed 47 mm MCE filter cassettes to show the spread of the contaminant in the work area. The high volume samplers were calibrated to operate at a sampling volume of 20 L/min. The sampling heads were positioned 1.5 m from the ground surface and as near as possible to the work location or failing this as near as is possible to major sources of exposure. Samples were collected and analysed according to the method for the determination of hazardous substances 46/2 (MDHS 46/2). This is an advanced sampling and analysis standard which enables detection of low levels of soluble platinum (0.01 ug/m3). Results: Thirty eight personal platinum samples were collected, consisting of a sampled engineering (n=15) and production (n=23) subgroup. Out of the thirty eight personal samples taken in total, 21% of the samples’ concentrations exceeded the OEL of 2 ug/m3 and ranged between 0.004–20.479 ug/m3. Twenty area platinum samples were collected, consisting of open (n=10) and closed face (n=10) sampling. Out of the twenty area samples taken in total, 10% of the samples’ concentrations exceeded the OEL of 2 ug/m3 and ranged between 0.0004–5.752 ug/m3. The mean personal exposure levels for the production subgroup (2.739 ug/m3) were significantly higher compared to the engineering subgroup’s mean personal exposure levels (0.393 ug/m3). This significant difference (p=0.033) was expected since the production subgroup was more exposed and involved in the digging out of residues and the cleaning of plant equipment compared to the engineering subgroup with limited exposure and involved in the opening of plant equipment. Although the mean exposure levels for open face sampling (0.725 ug/m3) were higher compared to the mean exposure levels for closed face sampling (0.441 ug/m3) no significant difference (p=0.579) were noted. The mean area exposure levels (0.583 ug/m3) were significantly lower (p=0.004) compared to the mean personal exposure levels (1.813 ug/m3) for similar areas and tasks performed and, therefore, not an effective indicator of personal exposure levels. Higher personal exposure levels were expected since the workers were closer to the source of exposure and since the platinum salts could have diluted in the workplace’s air resulting in lower area exposure levels. Conclusion: The research study addressed the problem statement, met the objectives set out in Chapter 1, hypotheses were accepted and rejected and future studies were recommended. It was hypothesised that: a) refinery workers are exposed to airborne soluble platinum during non–operational periods; b) exposure levels do not differ significantly between the personal sampling groups (engineering vs production); c) exposure levels do not differ significantly between the area sampling groups (open versus closed–face sampling); d) exposure levels do not differ significantly between work areas; e) exposure levels differ significantly between total personal and total area sampling groups. The results confirmed that refinery workers are exposed to airborne soluble platinum during non–operational periods and hypothesis a was accepted. The personal exposure levels of the engineering versus production sampling groups differed statistically (p=0.033) and hypothesis b was rejected. The exposure levels of the open and closed face sampling groups did not differ significantly (p=0.579) and hypothesis c was accepted. In addition no statistical difference (p>0.05) was indicated between the work areas and hypothesis d was accepted. Total personal versus total area exposure levels (p=0.004) differed statistically and hypothesis e was accepted. / Thesis (M.Sc. (Occupational Hygiene))--North-West University, Potchefstroom Campus, 2011.

Problem background: This thesis in building technology at Mälardalen University examines the noise level of the constructions on Öster Mälarstrand. The area Öster Mälarstrand is in the eastern part of Västerås next to the water area Mälaren. This district began to build in the end of the 20th century, and the area went from an industrial field to become as described, one of the best places in Västerås to live at. The district is now an area with a large extent of residentials and other necessities such as banking, gym, cafes, restaurants, shops and a large marina. Öster Mälarstrand is still under constant construction of new buildings. The purpose of the survey is to investigate the noise level on Öster Mälarstrand, and if the construction sites are customised to the guidelines that exist regarding noise and noise levels outside in a residential area. The work is summarized and ends by giving examples of measures to reduce noise and noise levels in the area. The method is based on own noise measurements, calculations and interviews. The noise measurements carried out at three specific locations on Öster Mälarstrand during four working days when constructions were underway. Interviews have also been conducted with 50 people who live in the area. The calculations of the noise measurments showed several varying values, but one thing that is clear is that the noise calculations that was executed, exceeds the guideline values set for noise-levels in Öster Mälarstrand. The interviews that were conducted presents that a majority of the interviewees thought that the noise level of the constructions on Öster Mälarstrand was disturbing, especially now during the pandemic of Covid-19, when several people started working from home. The conclusion in this thesis is that noise levels exceeds the guideline values ​​that exist according to the Swedish Environmental Protection Agency. The interviews in the area show that the majority of the participants experience the noise from the construction site as a disturbance.