No description available.

No description available.

Acrylamide (AA) is a vinyl monomer that has many applications in chemical industries. The aim of this work was to assess the reproductive toxicity of AA and clarity its underlying mechanism of action in rat; in particular, whether AA or its reactive metabolite glycidamide is responsible for the majority of the noted adverse effects. Moreover, the protective effect of 5-aminosalicylic acid (5-ASA) against AA testicular and genotoxicity was investigated. Acrylamide gavaged at doses from 5-60mg/kg daily for 5 consecutive days caused dose- dependent toxicity. Light microscopy examination showed multinucleated giant cells and tubular atrophy in the testis. In addition, electron microscopy showed Leydig cell atrophy and Sertoli cell toxicity. Epididymal sperm count showed a significant reduction in caudal sperm count in particular at higher concentrations. Despite these microscopic effects on the testis, this work also showed that AA has no toxic effects on absolute or relative testis or cauda weight, and no toxic effect on seminiferous tubule diameter. Outside of the testis, COMET assay undertaken on peripheral blood leukocytes showed genotoxicity in the form of COMET cells with increased Tail moment, while ELISA of serum testosterone showed severe reduction in testosterone level after AA treatment, which was reversed by concomitant ASA treatment. ELISA of CYP2El showed a 2-fold higher concentration in control liver S9 when compared to control testis S9. Further, 5-ASA (50mg/kg) induced the level of liver CYP2El, potentially increasing AA metabolism and clearance; this induction was accompanied by an improvement of testicular pathology and reduction in COMET Tail moments. Together, these data are consistent with AA being the main causative agent responsible for the toxicity noted in the testis and genotoxicity in blood. Moreover, 5-ASA could potentially offer a protective mechanism against AA- mediated toxicity, by increasing AA clearance. In conclusion, at the used dose, AA caused toxic effects in male rat that can be reduced by concomitant treatment with 5-ASA, which might be considered as an antidote to AA toxicity in victims of AA poisoning.

Organophosphate pesticides (OPs) are used globally to control pests on crops and animals. At high exposure levels, several toxic syndromes can occur due to significant acetylcholinesterase (AChE) inhibition. As a result, an acceptable threshold level for human exposure has been established based upon the lack of significant AChE inhibition. However, there has been limited investigation ofthe effects of OP exposure below the acceptable threshold, particularly in adults, despite the many opportunities for long term sub-threshold OP exposure in an occupational setting. The purpose of this thesis was to expand knowledge of the consequences of sub-threshold OP exposure during adulthood on gene expression, behaviour and neurochemistry. Initial studies were performed in adult male rats to develop short term administration models below the threshold for significant AChE inhibition for two commonly used OPs, diazinon and chlorpyrifos. These models were then used to investigate the potential for sub-threshold OP exposure to cause changes in behaviour, neurochemistry and gene expression. Neither OP caused significant changes to working memory, anxiety-like behaviour, locomotor activity and anhedonia (a symptom of depression). However sub-chronic exposure to both OPs caused a marked reduction in marble burying behaviour. Subsequent investigation of diazinon's effects over chronic exposure revealed that marble burying behaviour was affected throughout exposure. Further, diazinon treated rats took longer to bury marbles over sessions, suggesting repetitive/perseverative behaviour may be affected. As for neurochemistry, overall diazinon and chlorpyrifos had no effect on 5-HT levels in the prefrontal cortex, hippocampus, dorsal raphe nucleus and cerebellum. Similarly, overall DA levels in the prefrontal cortex, caudate putamen, hippocampus, substantia nigra and cerebellum were unaffected. However, microarray analysis ofthe hippocampus and dorsal raphe nucleus after chronic diazinon exposure revealed that overall there were changes in genes responsible for synaptic plasticity and synaptic signalling and there may be reorganisation of the synapse. - These data clearly demonstrate that sub-threshold OP exposure alters behaviour and gene expression and suggest a more comprehensive assessment of the risk posed by sub-threshold OP exposure to human health is warranted.

No description available.

- / -

Appendix 7, (3 leaves) in pocket / Includes bibliography / 1 v. (various foliations) : ill ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1984

Des études épidémiologiques ont montré que l’exposition à certains xénobiotiques est associée à une augmentation de la prévalence des maladies métaboliques. L’Homme est exposé à des mélanges de xénobiotiques de manière chronique et inévitable. Nous avons étudié les effets de l’interaction de deux xénobiotiques sur le métabolisme du foie, organe majeur de détoxification de l’organisme. Nous avons choisi deux perturbateurs endocriniens et polluants organiques persistants, qui activent des voies de signalisation différentes: la 2, 3, 7, 8 tétrachlorodibenzo-p-dioxine (TCDD), agissant via le récepteur aux hydrocarbures aromatiques (AhR), et l’α-endosulfan, un pesticide organochloré, qui peut agir via la voie du récepteur aux oestrogènes (ER) ou du récepteur X aux pregnanes (PXR). Notre objectif est de déterminer l’effet du mélange de ces polluants par rapport à chaque polluant isolé sur la régulation de certaines voies du métabolisme hépatique in vitro dans la lignée hépatocytaire humaine, HepaRG. Dans une première publication, une étude du transcriptome de cellules HepaRG différenciées a été effectuée. Ces cellules ont été exposées pendant 30 heures à 25nM de TCDD, 10μM d’α-endosulfan, ou au mélange. Nous avons observé que le mélange inhibe fortement l’expression de certains gènes impliqués dans le métabolisme glucidique et dans celui des alcools. Dans une seconde étude, nous avons donc étudié le mécanisme d’action du mélange sur le métabolisme glucidique. L’expression de deux gènes de la néoglucogenèse hépatique, le transporteur de glucose 2 (Glut2) et la glucose 6 phosphatase (G6Pc), est réduite de plus de 80% par le mélange. L’expression d’autres gènes du métabolisme glucidique (pyruvate kinase, glycogène synthase, glycogène phosphorylase, pyruvate déhydrogénase 2) est aussi diminuée, suggérant que le mélange peut affecter ce métabolisme de manière significative. De plus, la production de glucose diminue de 80% avec le mélange dans des conditions néoglucogéniques. En condition glycolytique, l’oxydation du glucose en CO2 diminue de 30% après 72 heures d’exposition au mélange. Un traitement à plus long terme (8 jours) avec des doses plus faibles des polluants (0.2 à 5nM de TCDD, 3μM d’α-endosulfan) diminue aussi l’expression de la G6Pc et de Glut2. Nous avons montré que la TCDD active bien la voie du AhR, et que le ER est impliqué dans l’action de l’α-endosulfan. Dans la troisième partie de cette thèse, nous avons étudié la régulation de plusieurs enzymes impliquées dans le métabolisme de l’alcool (alcool déshydrogénases, ADHs, cytochrome P450 2E1, CYP2E1) après l’activation du AhR. Les agonistes du AhR entrainent la diminution de l’expression des ARNm des ADH1, 4, 6 et du CYP2E1 et des protéines correspondantes. Nous avons montré que cette régulation utilise la voie génomique du AhR. De plus, cet effet est également observé après traitement de 8 jours par de faibles doses de TCDD. L’exposition chronique de l’Homme à de faibles doses de xénobiotiques en mélange pourrait affecter le métabolisme glucidique hépatique et contribuer, en partie, au développement du syndrome métabolique. / Epidemiological studies have shown that exposure to certain xenobiotics is associated with an increased prevalence of metabolic diseases. Humans are exposed to mixtures of xenobiotics in a chronic and inevitable way. We studied the effects of the interaction of two xenobiotics on metabolism in the liver, the major organ for detoxification in the body. We chose two endocrine disruptors and persistent organic pollutants which activate different signaling pathways: 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), which uses the AhR (Aryl hydrocarbon receptor) pathway, and α-endosulfan, an organochlorine pesticide, which acts via the PXR (pregnane X receptor) and/or the ER (estrogen receptor) pathway. Our aim was to determine the effects of this pollutant mixture, as compared to each pollutant alone, on the regulation in vitro of some hepatic metabolism pathways in the human hepatic cell line, HepaRG. In the first publication, a transcriptomic study of differentiated HepaRG cells was performed. The cells were exposed for 30h to 25nM TCDD, to 10 µM α-endosulfan or to the mixture. We observed that the mixture strongly inhibited the expression of some genes involved in the metabolism of glucose and alcohol. In the second study, we studied the mechanism of action of the mixture of pollutants on the metabolism of glucose. The expression of two genes involved in hepatic gluconeogenesis, glucose transporter 2 (GLUT2) and glucose-6-phosphatase (G6Pc), were reduced 80% by the mixture. The expression of other glucose metabolism genes (pyruvate kinase, glycogen synthase, glycogen phosphorylase, pyruvate dehydrogenase 2) also was decreased suggesting that the mixture might impact markedly carbohydrate metabolism. Furthermore, glucose production decreased 40% with the mixture under gluconeogenic conditions. Under glycolytic conditions, the oxidation of glucose into CO2 decreased 30% after 72h of exposure of the cells to the mixture. Long-term treatment (8 days) with lower doses (0.2 to 5 nM TCDD, 3 µM α-endosulfan) similarly decreased G6Pc and GLUT2 expression. We showed that TCDD activated the AhR pathway, and that ER was partly involved in the α-endosulfan effect. In the third part of this thesis, we studied the regulation of several enzymes involved in the metabolism of alcohol (alcohol dehydrogenase, ADH, cytochrome P450 2E1, CYP2E1) after activation of AhR. AhR agonists led to a decrease in the amounts of mRNAs for ADH1, 4, 6 and CYP2E1 and the corresponding proteins. We showed that this regulation uses the AhR genomic pathway. Furthermore, this effect was also observed after 8 days of treatment with lower doses of TCDD. Chronic exposure of individuals to low doses of xenobiotics in mixtures might significantly affect hepatic carbohydrate metabolism and be a contributing factor for the development of the metabolic syndrome.

Bibliography : leaves i-xxiii. / vi, 95, xxiii, [170] leaves, [4] leaves of plates : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1991

- / -