No description available.

Thesis (Master)--İzmir Institute of Technology, İzmir, 2004. / Includes bibliographical references (leaves 65-70).

No description available.

No description available.

No description available.

Endosulfan is a commonly used organochlorine in Durham Region, Ontario Canada which has known toxic effects on non-target organisms including fish. This research investigated the effects of endosulfan on Florida flagfish (Jordanella floridae), using both continuous and pulse-exposure. The 96 hour continuous exposure LC50 in larval flagfish was 4.35 μg/L; sub-lethal observations included hyperactivity, convulsions, and some axis malformation. The effects of a 4 hour endosulfan pulse-exposure on 7-8 day-old larval growth, reproduction, and survivability were investigated over one full life-cycle. The 4 hour pulse-exposure LC50 value for larval flagfish was 49.7 μg/L; there were no growth or reproductive effects of endosulfan pulse-exposure up to the highest exposure concentration of 10 μg/L. Thus, the life-cycle 4-h pulse-exposure no observed effect concentration (NOEC) and lowest observed effect concentration (LOEC) were 3.2 and 10 μg/L endosulfan, respectively, due to significantly higher mortality.

Organochlorine pesticides (OCs) are environmental toxicants with important links to human health. They have been found to activate signalling pathways within cells and thereby affect cell survival and proliferation. Receptor Activator of Nuclear Factor kB (RANK) ligand and its receptor RANK are crucial for mammary epithelial proliferation in pregnancy and have recently been linked to hormone induced breast cancers. The objectives of this study were to confirm the proliferative effects of an OC (endosulfan) on human MCF-7 breast cancer cells, identify activated intracellular signaling pathways and investigate changes in RANK and RANKL gene expression. This study showed that endosulfan has a stimulatory effect on human MCF-7 cell proliferation, which may be invoked through activated intracellular signaling pathways (JNK, ERK1/2 and p38). In addition, there was a down regulation of RANK and upregulation of RANKL gene expression suggesting endosulfan is capable of modulating both cellular behavior and gene expression. / UOIT

Thesis (MTech (Chemical Engineering))--Peninsula Technikon, 2003. / Word processed copy. Summary in English. Includes bibliographical references (leaves 93-96). Also available online.

L’impact de l’environnement dans le développement de certaines pathologies est avéré bien qu’il soit difficile à évaluer. L’Homme est chroniquement exposé à des cocktails de xénobiotiques -des molécules étrangères à l’organisme- dont la nature, la concentration et les interactions sont variables avec des effets néfastes ou bénéfiques pour la santé humaine. Parmi ceux-ci, les polluants environnementaux jouent un rôle non négligeable dans l’apparition de certains cancers. Au contraire, des molécules naturelles comme le resvératrol, possède des propriétés anti-cancéreuses. Au cours de la cancérogenèse, les cellules tumorales acquièrent un phénotype métabolique réversible caractérisé par une glycolyse et une production de lactate élevées en présence ou non d’oxygène (effet Warburg). La flexibilité du métabolisme permet aux cellules cancéreuses d’assurer des niveaux d’énergie et de métabolites et de co-facteurs suffisants pour maintenir leur phénotype tumoral dans un microenvironnement qui fluctue. Dans cette étude, les effets de différents xénobiotiques seuls ou en mélange ont été évalués sur la progression du phénotype tumoral dans des cellules tumorales humaines. Dans une 1ère partie, les effets de 2 polluants organiques persistants agissant via des voies de signalisation différentes, la tétrachlorodibenzo-para-dioxine (TCDD) et l’a-endosulfan, un pesticide organochloré, ont été étudiés, seuls ou en mélange, sur le phénotype tumoral des cellules tumorales coliques humaines (Caco2). Nous avons montré que la TCDD (25 nM) et l’a-endosulfan (10µM) diminuent les capacités oxydatives des cellules tumorales. Cet effet est plus marqué lorsque les cellules sont exposées au mélange des 2 polluants, suggérant un effet synergique. Ces altérations sont associées à une diminution drastique de la respiration mitochondriale, corrélée à une forte réduction de l’activité du complexe I de la chaine respiratoire des mitochondries. Ces observations sont en partie liées à une diminution de l’expression de NDUFS3, l’une des sous unité du complexe I. Parallèlement, nous avons mis en évidence que l’exposition aux polluants entraine l’engagement des cellules tumorales vers une transition épithélio-mésenchymateuse (EMT). Ces données suggèrent que les polluants favorisent la progression tumorale en altérant le métabolisme énergétique des cellules tumorales coliques humaines et en favorisant la mise en place d’une EMT. Le lien entre ces 2 processus ainsi que les voies de signalisation impliquées restent à élucider. Dans une 2ème partie, nous avons évalué les effets du resvératrol (RSV), un composé naturel présent entre autre dans le vin, sur sur la progression du phénotype tumoral. Ce polyphénol a été largement décrit pour ses effets bénéfiques sur le cancer et pour ses capacités à modifier le métabolisme, notamment en mimant la restriction calorique. Nous avons montré que le RSV, à une concentration proche des doses sériques mesurées chez l’Homme (10 µM), diminue la prolifération cellulaire sans affecter la viabilité. Le RSV réoriente le métabolisme énergétique des cellules tumorales en augmentant leurs capacités oxydatives et en diminuant leurs capacités glycolytiques et l’activité de la voie des pentoses phosphates. Nous avons identifié le complexe pyruvate déshydrogénase comme une cible du RSV, mis en évidence que le calcium est impliqué dans cette régulation et que les effets métaboliques induits par le RSV sont relayés en partie par la voie CamKKß/AMPK. L’ensemble de ces résultats démontre que l’environnement, via les xénobiotiques, peut moduler le phénotype tumoral, et que le métabolisme tumoral, en raison de son extrême flexibilité, est une cible majeure de ces modulations. / The impact of the environment in the development of several human diseases is well established but difficult to evaluate. Humans are chronically exposed to xenobiotics mixture - foreign chemicals substances which are not normally present within the organism – with different nature, concentration and interactions leading to deleterious or beneficial effects on human health. Among these xenobiotics, environmental pollutants play a significant role in the development of some cancers. On the contrary, a natural molecule like resveratrol has anti-cancer properties. During carcinogenesis, tumor cells acquire a reversible metabolic phenotype characterized by a high glycolysis and a massive lactate production with or without oxygen (Warburg effect). The flexibility of the metabolism allows cancer cells to provide sufficient levels of energy, metabolites and cofactors to maintain their tumor phenotype in a fluctuating microenvironment. In this study, the effects of several xenobiotics alone or in a mixture were assessed on human cancer cell progression. In the first part, the effects of 2 persistent organic pollutants acting by different signaling pathways, tetrachlorodibenzo-para-dioxin (TCDD) and a-endosulfan, an organochlorine pesticide, were studied alone or in a mixture, on human colonic cancer cells (Caco2) progression. We have shown that TCDD (25 nM) and a-endosulfan (10µM) decrease the oxidative capacity of tumor cells. This effect is more pronounced when cells are exposed to the mixture, suggesting a synergistic effect. These alterations are associated with a drastic decrease in mitochondrial respiration, correlated with a strong reduction in the activity of the mitochondrial respiratory chain complex I. These observations are in part linked to a decrease of NDUFS3 gene expression, one of the subunit of the complex I. We have also found that the dysregulation of tumor cell metabolism was associated with an epithelial-mesenchymal transition (EMT). Our data show that pollutants strengthen the Warburg effect associated with an EMT, which suggests that the pollutants affect the progression of the tumor phenotype. The signaling pathways involved in these observations are under investigation. In the second part, we assessed the effects of resveratrol (RSV), a natural compound present among other in wine, on cancer cell progression. This polyphenol has been widely described for its benefits on cancer and its ability to mimic caloric restriction. We have shown that the RSV, with a close concentration of serum doses measured in humans (10 µM), decreases cell proliferation without modulate cell viability. RSV redirects the energy metabolism of tumor cells by increasing their oxidative capacity, decreasing their glycolytic capacity and reducing the activity of the pentose phosphate pathway. We have identified the complex pyruvate dehydrogenase as a target of the RSV and highlighted that the calcium is involved in the regulation of PDH activity. We have also shown that the RSV induces its metabolic effects in part through CamKKß/AMPK signaling pathway. These results demonstrate that the xenobiotics can modulate tumor phenotype, and tumor metabolism, because of its extreme flexibility, is a major target of these modulations.

The organochlorine pesticide endosulfan has been shown to be highly toxic to fish and there is some evidence to support that it may act as an endocrine disrupting chemical. Juvenile rainbow trout (Oncorhynchus mykiss) were caged at 4 sites in Oshawa Creek during the fall and spring of 2008 and 2009 while another group was intra-peritoneal injected in the laboratory with varying concentrations (ppm) of endosulfan. Plasma vitellogenin (VTG) levels, liver ethoxyresorufin-O-deethylase (EROD), citrate synthase (CS), lactate dehydrogenase (LDH), and brain acetylcholine esterase (AChE) (caged fish only) enzymatic activities were measured. Trout injected with endosulfan experienced an increase of the anaerobic (LDH activity) and a decrease of the aerobic (CS activity) metabolic pathways, while male VTG levels increased. Since it was a singular injection, VTG results have to be confirmed. Fall caged trout showed increased EROD activity and inhibited AChE activity while those caged in the spring experienced an unexpected exposure to the lampricide 3-Trifluoro-Methyl-4-Nitro-Phenol (TFM) which disrupted metabolic parameters (inhibited CS and increased LDH activity). Both fall and spring caged trout experienced no induction of VTG activity. Further research is needed since the spring exposure was altered due to the unplanned TFM treatment and thus did not represent a valid temporal replicate.