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Statins are the mainstay of cholesterol-lowering therapy and are taken by millions of people worldwide. These drugs are generally well-tolerated but can cause myopathy ranging from mild muscle pain to fatal rhabdomyolysis. The mechanism of statin-induced myopathy (SIM) is not fully understood and there is currently no convenient and reliable marker of SIM, but mitochondrial dysfunction has been implicated. We sought to investigate the effect of statins on mitochondrial DNA (mtDNA) levels in order to gain information on the mechanism of SIM and to explore the possibility of utilizing changing mtDNA levels as a marker of SIM. Several approaches were used. First, mtDNA levels were quantified in skeletal muscle biopsies collected from a previously published 8-week clinical trial of high-dose simvastatin or atorvastatin versus placebo. Forty-eight hypercholesterolemic subjects were randomly assigned to receive placebo (N=16), high dose atorvastatin 40mg/day (N=16), or high dose simvastatin 80mg/day (N=16) for 8 weeks. Muscle mtDNA content was assessed by real-time PCR atbaseline and after 8-weeks on statin treatment and found to be significantly reduced in the groupreceiving simvastatin (P=0.005) but not the other two. In addition, a significant positive correlation was observed between mtDNA and muscle ubiquinone in all groups (R=0.63, P<0.01), with the strongest association found in the simvastatin-treated subjects (R=0.75, P=0.002). Next, in an attempt to determine whether statin-induced muscle pain may be associated with muscle mtDNA depletion, archived muscle biopsies collected from statin users with muscle complaints were sought through a review of a muscle biopsy database and possible study samples were identified; however, this was put on hold as too much information was missing from the pathology reports. Third, a series of cell culture experiments were carried out in which human skeletal muscle myotubes were exposed to various concentrations of simvastatin or atorvastatin, in order to determine an appropriate dose range for subsequent mitochondrial toxicity experiments. Lastly, mtDNA content and expression was quantified in skeletal muscle biopsies collected from 10 patients with statin-induced rhabdomyolysis (SIR) and compared to 8 healthy controls to investigate whether muscle mtDNA is altered in rhabdomyolysis. No differences in mtDNA content or expression were observed between the two study groups, but this may have been be due to the SIR subjects' marked heterogeneity. Statin therapy can be associated with considerable alterations in mtDNA content, which may play a role in the aetiology of SIM. MtDNA levels alterations with statin exposure should be investigated further to explore the involvement of mitochondrial alterations in the mechanism of SIM, and determine whether these may represent a useful clinical tool for assessing statin-induced muscle toxicity.

Background: A third of HIV-infected patients are co-infected with HCV in the developed world, and more of co-infected patients than ever before are dying because of liver related diseases today. Drug-related hepatotoxicity is a growing concern among human immunodeficiency virus (HIV) / hepatitis C virus (HCV) co-infected population. Nucleotide analogues containing HIV antiretroviral therapy, namely highly active anti-retroviral therapy (HAART), can induce mitochondrial toxicity. However, little is known about the effect of nucleotide analogues on the liver at the cellular and molecular level, and how it may affect treatment. Objective: To investigate whether liver tissue from HIV/HCV co-infected individuals will show greater liver mitochondrial toxicity if currently receiving antiviral HIV medication, compared to those who are not taking it. Methods: Liver biopsies were collected from 23 HIV/HCV co-infected males. Fourteen patients were on stable HAART (ON-HAART) and 9 were OFF-HAART, including 4 who stopped HAART >6 months prior and 5 who were HAART-nave. Liver mitochondrial toxicity was assessed by transmission electron microscopy-based quantitative stereological analyses of hepatocyte and mitochondrial morphometry, as well as by mitochondrial DNA (mtDNA) and mtRNA (COX1/(ß-actin) real-time-PCR quantification. Results: Hepatocytes tended to be larger in the ON-HAART group than in the OFF-HAART group (p=0.05), but they both showed similar mitochondrial volume fraction of the cell and mitochondrial crista density. Liver mtDNA and mtRNA levels were not significantly differentbetween ON-HAART and OFF-HAART. Hepatocyte lipid accumulation was significantly higher in HCV genotype 3 compared to genotype 1 infection ()=0.002), but was not associated with HAART status. Conclusions: We found no evidence or trend of increased mitochondrial toxicity in HIV/HCV co-infected individuals currently on HAART compared to those who are not. This finding could be relevant to the decision-making process with respect to initiating HCV therapy in this population.

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Heavy fuel oils (HFO) are produced from the refining of crude oils, and have high specific gravities and high viscosities. In recent years, spills of HFO have increased in the environment, and are of great concern because they are difficult to clean up. Spilled HFO is likely to become submerged, and can become stranded if fresh HFO coats benthic substrates or if weathered HFO sinks as tarballs. Conversely, lighter oils float on the surface and their components disperse and become diluted in the water column. There is a research need to assess the unique ecological risks of HFO that can sink and contaminate spawning shoals of fish. Chronic toxicity of HFO to fish embryos is correlated with exposure to polycyclic aromatic hydrocarbon (PAH) that become bioavailable from spilled HFO to identify under which spill conditions fish populations are at greatest risk. The results of this research demonstrate that: (1) Stranded HFO is a significant source of PAH to the receiving environment and causes chronic toxicity to embryonic fish; (2) Tarballs and weathered HFO cause less toxicity than fresh HFO, likely a consequence of physical limitations to PAH release; (3) HFO 7102 samples collected from an HFO spill in Wabamun Lake, Alberta, are less toxic than HFO 6303; (4) HFO is at least 2-fold more toxic than Medium South American (MESA), a well-studied reference crude oil, coincident with 3-fold higher concentrations of alkyl PAH, namely alkyl phenanthrenes. / Thesis (Master, Biology) -- Queen's University, 2011-07-25 10:43:05.759

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Selenium (Se) is an essential trace element to most living organisms, however when compared to other ingested essential trace elements Se has the lowest margin of safety between essential and toxic concentrations. Oviparous vertebrates, especially fishes, are highly susceptible to dietary Se toxicity. Greater incidences of deformities and/or mortalities have been observed in F1 generation larval fishes whose parents were exposed to excess dietary Se in the form of selenomethionine (SeMet), however little information is available on effects of chronic dietary SeMet exposure to adult fish and persistent effects of in ovo SeMet exposure to F1 generation fish. This thesis investigated effects of chronic dietary exposure of excess Se in the form of SeMet on swimming performance (Ucrit), oxygen consumption (MO2), stored energy (triglycerides and glycogen), and the physiological stress response (cortisol production) in adult zebrafish (Danio rerio), as well as immediate (incidence of deformities and mortality) and persistent (e.g. changes in Ucrit, MO2, bioenergetics, the physiological stress response and reproduction) effects of in ovo exposure to SeMet in F1 generation zebrafish. In addition, the study investigated potential underlying mechanisms of SeMet-induced developmental toxicities in early life stages of zebrafish using embryo microinjection. Two separate dietary SeMet exposure studies in adult zebrafish and two in ovo SeMet maternal transfer studies in F1 generation zebrafish were conducted. The first dietary or in ovo exposure study explored effects of excess SeMet exposure on adult zebrafish or the entire life cycle of F1 generation zebrafish. The second study investigated mechanisms of observed SeMet-induced effects on adult or F1 generation zebrafish. In the first feeding study, a significant reduction in Ucrit and greater accumulation of stored energy were observed in the excess dietary SeMet exposed groups when compared to the Se-sufficient dietary control group. The second feeding study showed a greater metabolic rate, and impaired aerobic energy metabolism and triglyceride homeostasis in adult fish fed excess dietary SeMet, which was associated with a reduction in swimming performance and accumulation of triglycerides. Embryos collected from adult zebrafish in both dietary SeMet exposure studies were used to investigate effects of in ovo SeMet exposure on the entire life cycle of F1 generation fish. The first study showed a greater incidence of mortality, an increasing trend for deformities in F1 generation larval zebrafish, and reduced Ucrit in F1 generation adult fish exposed to excess SeMet via in ovo maternal transfer. However, concentrations of stored energy, cortisol and reproduction were unaltered. The second study found that impaired aerobic performance might have been responsible for the reduction in Ucrit of F1 generation adult zebrafish exposed to excess SeMet. Since there is a high variability in Se deposition among eggs via natural maternal transfer, SeMet embryo microinjection was adopted to mimic maternal transfer and to investigate potential mechanisms of SeMet-induced developmental toxicities in early life stages of zebrafish. Greater gene expression of oxidant-inducible transcription factors and impairment in gene expression of an enzyme involved in methionine catabolism were observed in early life stages of zebrafish exposed to excess SeMet via in ovo microinjection. The research presented in this thesis suggests that environmentally relevant dietary SeMet exposure can alter physiological responses in adult fishes and reduce survivability of F1generation fishes, which could impact fitness and recruitment of wild fishes inhabiting Se-contaminated aquatic ecosystems. In addition, the study suggests that SeMet-induced developmental toxicities in early life stages of fishes might be related to oxidative stress or impaired methylation, or a combination of these mechanisms.