Cardiovascular disease remains the leading cause of death in Western societies. Endothelial dysfunction is one of the initiating steps in the development of atherosclerosis. While there is a strong correlation with a person’s genetics, lifestyle factors including smoking, physical activity, and diet can significantly increase a person’s susceptibility to the development of atherosclerosis. In addition to these lifestyle factors, there is a strong body of evidence linking exposure to environmental pollutants including persistent organic pollutants such as polychlorinated biphenyls to increased cardiovascular disease and mortality. It has been well-established that exercise protects against cardiovascular disease, but whether exercise can modulate PCB-induced cardiovascular inflammation and dysfunction is unknown. To investigate the effects of exercise on PCB-induced cardiovascular disease, two murine models of atherosclerosis, the ApoE-/- and the LDLr-/- mouse were utilized. Risk factors for cardiovascular disease including adiposity, glucose intolerance, hyperlipidemia, hypertension, oxidative stress, and inflammation, were assessed in these two models as well as mean atherosclerotic lesion size. Exercise positively modulates several risk factors associated with cardiovascular disease including hypertension, hyperlipidemia, adiposity and obesity, systemic levels of oxidative stress, inflammation, and glucose tolerance. Exercise significantly reduced mean lesion size in vehicle-treated animals. To assess the mechanism of protection of exercise in chapter 4, vascular reactivity studies were performed to measure endothelial function after exposure to PCB 77. Exercise prevented PCB-impaired endothelial function implicating the role of superoxide as a cause of impairment. Exercise upregulated phase II antioxidant enzymes. The work in this dissertation demonstrates several protective properties of exercise against PCB-induced cardiovascular disease; however, additional studies are needed to determine if exercise enhances metabolism and excretion of these environmental pollutants.

Previous studies demonstrated that coplanar PCBs promote inflammation by release of pro-inflammatory cytokines like TNF, MCP-1, and VCAM-1 from endothelial cells as well as adipocytes. Also these PCBs at small doses may contribute to the development of obesity by inducing adipocyte differentiation. Obesity is a known risk factor that promotes cardiovascular disorders like atherosclerosis and AAAs. Evidence shows Ang II, a component of the RAS, leads to the formation of atherosclerosis and AAAs in both normal as well as hyperlipidemic mice. Earlier studies in our laboratory have also shown that coplanar PCB-77 promotes atherosclerotic lesion formation in ApoE-/- mice. The purpose of this study was to define the effects of PCB77 on Ang II induced vascular diseases like atherosclerosis and AAAs. Two different hyperlipidemic mouse models, which require different diets to get atherosclerosis, the ApoE deficient mice (ApoE-/-) requiring the normal mouse diet (Chow diet) and the Low Density Lipoprotein Receptor deficient mice (LDLr-/-) requiring the Western diet, were used for this study as both are susceptible to Ang II induced vascular disorders. The timing of PCB administration was also studied in LDLr-/- mice to see the profound effects of PCB77 on atherosclerosis and AAAs.

This dissertation combines laboratory and field experiments to investigate the mechanisms of atropisomer enrichment for chiral polychlorinated biphenyls (PCBs) and their metabolites in organisms. Stereoselective biotransformation and bioaccumulation were identified as two major reasons for the different environmental fate of PCB atropisomers. Other affecting factors, such as presence of nanoparticles and changes in feeding ecology of organisms, also affect the fate of chiral contaminants. In vitro incubations of rat cytochrome P-450 2B1 (CYP2B1) isozyme with chiral PCBs indicated that different biotransformation kinetics and competition among PCB congeners or between atropisomers were two main factors affecting atropisomer enrichment. Different interactions between chiral PCB congeners or atropisomers with rat CYP2B1 may occur at the molecular level. Non-racemic meta-hydroxylated-PCBs (5-OH-PCBs) were the major metabolites. CYP-mediated stereoselective formation of dihydroxylated PCBs from OH-PCBs was observed. Gold nanoparticles affected biotransformation activity of rat CYP2B1 and changed PCB atropisomeric composition, directly by electrostatic interaction, or indirectly by changes to the surrounding ionic strength. Thus, stereoselective metabolism of chiral PCBs and OH-PCBs by CYPs is a major mechanism for atropisomer enrichment of PCBs and their metabolites in the environment, with the degree of enrichment dependent, at least in part, on charged nanoparticles and stereoselective interference of atropisomers with each other at the enzyme level. The atropisomer compositions of chiral PCBs were measured in the marine biota of Cumberland Sound (Canada) and Svalbard (Norway). High trophic level organisms, including harp seal, beluga, and narwhal reported for the first time, had species-specific atropisomer signatures, likely due to a combination of in vivo biotransformation and trophic transfer. PCB chiral signatures in Greenland sharks supported the hypothesis that some of these PCB atropisomer compositions shifted over time and space, possibly due to a change in feeding ecology. To our knowledge, this is the first report to investigate temporal trends of PCB atropisomer signatures in Arctic biota.

Persistent organic pollutants (POPs) have been contaminating the marine environment since the mid 2Oth Century and continue to do so today. The polychlorinated biphenyls (PCBs) are of particular concern, since they are found at high concentrations in marine mammals throughout the Northern Hemisphere, and have been associated with endocrine disruption, reproductive impairment, immunotoxicity, and outbreaks of disease. In this study, samples were obtained from free-ranging harbour seal (Phoca vituilna) pups, which were live-captured in British Columbia, Canada, and Washington State, USA, in order to assess adverse health effects associated with POPs on the immune system of these mammals. PCBs were the most abundant of the 31 POPs measured in seals, and represented the greatest toxicological concern on the basis of established reference values for laboratory rodents and aquatic wildlife consumers. Seal immune function was assessed using traditional measures of immunotoxicity, including hematology, innate immune function, and adaptive immune function, and related to PCB concentrations while carefully controlling for confounding factors such as age, sex and condition. PCB concentrations negatively correlated to phagocytosis, T lymphocyte proliferative responses, (thymosin-a1-induced) lymphocyte signalling, and lymphocyte counts, and positively associated with the respiratory burst of phagocytes and aryl hydrocarbon receptor (AhR) expression of white blood cells, suggesting chemical-associated immunotoxicity. Parallel experiments, in which harbour seal white blood cells were exposed in vitro to 2,3,7,8-tetrachlorodibenzo-p-dioxin, a potent immunotoxicant, further supported the hypothesis that the observed reduction in immunocompetence in free-ranging seals may be due to an AhR-mediated mechanism of immunotoxicity. Principal component analysis (PCA) of immunological endpoints combined evidence of PCB-associated effects on the immune system as a whole. However, PCA also identified a difference between the immunological profiles of urban seals and those from remote sites, consistent with elevated pathogen abundance due to biological pollution at urban sites. In a second approach, PCB concentrations were related to concentrations of vitamin A and expression levels of its receptor, the retinoic acid receptor alpha (RARa), which are known to be sensitive to PCB exposure. More contaminated seals were characterised by lower vitamin A concentrations in circulation and in the blubber, as well as higher RARa expression in the blubber. AhR expression and concentrations of thymosin-a1 (a thymic hormone important in lymphocyte development and immune function) did not relate to contaminants when their levels were investigated in seal tissues (blubber, skin), contrasting their sensitivity in white blood cells. These results implied that PCB-associated toxicity may be reflected if a biomarker represents a primary lesion, but might not be extrapolated among tissues in all cases. Secondly, although blubber represents the primary site of PCB storage, it is not necessarily the site of the highest toxicity. In summary, significant evidence of immunotoxicity and disruption of immune function-related biomarkers has been provided in a healthy group of free-ranging marine mammals which contributes to the weight of evidence that environmental contaminants may render marine mammal populations more vulnerable to disease through immunotoxicity. Immune function measures in free-ranging harbour seal pups exposed to contaminants in vivo, in combination with harbour seal white blood cells in vitro, furthermore suggested that immunotoxicity may take place through an AhR-mediated mechanism of action. An unexpected finding was the evidence of a second, independent, impact on the immune system of seals, consisting of biological pollution. The combination of both chemical and biological pollution, that would imply both diminished immune responses and increased pathogen loads, may represent the largest threat to the health of marine mammals in many parts of the world.

The fate and bioaccumulation of a contaminant entering the marine environment through wastewater outfalls depends on the contaminant’s persistence and affinity for particles. The physical characteristics of the receiving environment, e.g. current velocity, sedimentary processes, and the availability of organic carbon are also important. However, these latter effects are not usually evaluated quantitatively. This thesis investigates the near-field accumulation in sediment and biota of particle-reactive polybrominated diphenyl ethers (PBDEs) entering coastal waters via two municipal outfalls: one discharging into a high energy, low sedimentation environment near Victoria, B.C., Canada; the other into a low energy, high sedimentation environment near Vancouver, B.C. We used 210Pb profiles in sediment box cores together with an advection-diffusion model to determine surface mixing and sedimentation rates, and to model the depositional history of PBDEs at these sites. A particularly important finding of this study is that the very high energy environment to the southeast of the Victoria outfall accumulates PBDEs despite not having net sediment accumulation. Although the discharge of PBDEs was much lower from the Victoria outfall than from Vancouver, some sediment PBDE concentrations were higher near Victoria. Most PBDEs were dispersed beyond the near-field at both sites, but a greater proportion was captured in the sediment near the Vancouver outfall where rapid burial was facilitated by inorganic sediment supplied from the nearby Fraser River. Clearly, treating wastewater to the same level, regardless of local oceanographic conditions, will not result in a uniform environmental footprint. Total PBDE concentrations in benthic invertebrate communities were higher near Vancouver than Victoria, despite lower concentrations in sediments, and correlated with organic carbon normalized sediment concentrations. Principal Components Analysis suggested uptake of individual PBDE congeners was determined by sediment properties (TOC, grain size), whereas PCB congener uptake was governed by physico-chemical properties (octanol-water partitioning coefficient). Our results suggest that sediment quality guidelines for PBDEs and likely PCBs may be more relevant if corrected to TOC content in sediment. In addition, where enhanced wastewater treatment increases the ratio of PBDEs to particulate organic carbon in effluent, nearfield benthic invertebrates may face increased PBDE accumulation. This underlines the need for source control of persistent organic contaminants, which cannot be broken down by conventional wastewater treatment. / Graduate

Ligand I- along with nonionic surfactant, Triton X-100 or anionic surfactant, sodium dodecyl sulfate (SDS) were applied as soil washing agents to desorb Cd from both naturally and artificially contaminated soils. After seven consecutive washings, up to 90% of Cd was desorbed from both soils. Triton X-100 with I- showed a higher capacity to desorbing Cd than did SDS with I-. The increase of ligand concentration was a critical factor for increasing leaching capacity. Without the ligand, surfactant alone could not desorb Cd effectively from either soil. After seven consecutive washings, a sequential extraction experiment was performed for soil residuals to define the soil fraction of Cd removed by the washing agent. Among the washing agents, only Triton X-100/I- could remove Cd from the exchangeable fraction of both soils. / Various ligands including I-, SCN-, and I-/SCN- in combination with Triton X-100 were tested for their efficacy in desorbing heavy metals such as Cd, Zn, Cu, and Pb from a field contaminated soil. Cadmium was preferentially desorbed by Triton X-100/I- whereas Zn and Cu were preferentially desorbed by Triton X-100/SCN-. The mixture of I- and SCN- with Triton X-100 desorbed the most Cd and Cu, but not for Zn, as I- inhibited Zn desorption. Sequential extraction experiments after seven washings showed that metals held in the exchangeable fraction can be desorbed only by a combination of ligand and surfactant. / Nonionic surfactants having different alkyl chain lengths in combination with ligand I- were tested for the desorption of Cd and PCBs from soil. Cadmium desorption was increased at the lower surfactant concentration and higher ligand concentration. The increase in the hydrophilic alkyl chain length of the surfactant adversely affected Cd desorption. Up to 100% of PCBs were successfully removed by most of surfactant-ligand combinations and the desorption was less dependent, compared to heavy metals, on the concentration of washing agents and length of alkyl chain. The linear relationships between number of washings and Cd desorption, and between alkyl chain length and Cd desorption was defined. (Abstract shortened by UMI.)

Chlorinated paraffins (CPs) are ubiquitous environmental contaminants. They fulfill all of the criteria (persistent, toxic, and subject to long-range transport) for persistent organic pollutants (POPs) according to the United Nations Economic Commission for Europe (UNECE). CPs are also under consideration for inclusion in the Stockholm Convention on POPs. Their presence has been shown in various environmental matrices in the industrialized parts of the world, as well as in remote regions such as the Arctic. The aim of this thesis was to increase the limited knowledge of the presence of CPs in the environment, their sources to the environment, and the resulting human exposure. An analytical procedure for the determination of CPs in environmental samples based on gas chromatography coupled to electron capture detection (GC-ECD) has been developed. GC-ECD is a relatively inexpensive instrument that is fast and easy to operate. These advantages open up the possibility for a comprehensive screening of the occurrence of CPs in the environment, including developing countries. Furthermore, the occurrence of CPs in ambient air and in indoor air and dust was studied. Elevated CP concentrations in indoor air (<5-210 ng/m3) were observed compared to ambient air (0.7-33 ng/m3), which is indicative of the presence of indoor emission sources. Indoor air and dust concentrations were used to estimate the human exposure to CPs via the indoor environment. Comparison of the estimates to available dietary intake estimates indicated that the indoor exposure pathways are not negligible. CP concentrations in ambient air from urban Stockholm were higher than in rural Aspvreten, Sweden. This indicates the presence of additional (emission) sources in urban areas compared to rural sites. Additionally, a seasonal variation of air concentrations was observed at both locations, suggesting temperature dependent emission sources for CPs. These observations were supported by a substance flow analysis of CPs performed for Stockholm. This study estimated the major emission sources of CPs to the Stockholm environment to be emissions from painted surfaces and in-place sealants. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript. Paper 4: Manuscript.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning). Uppsala : Sveriges lantbruksuniv., 2003. / Härtill 4 uppsatser.