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Di-2-ethylhexyl phthalate (DEHP) is an endocrine disruptor used as a plasticizer in industryas an additive to polyvinyl chloride commodities which include consumer and medical products.Developmental delay induced by exposure to chemicals such as DEHP has been a cause forconcern. In our work, we use a model in which pregnant dams are gavaged with DEHP fromgestational day 14 until birth. We have previously provided evidence that demonstrates theadverse effects of DEHP on the male endocrine system following in utero exposure; however,knowledge of analogous effects of DEHP in the female is lagging in comparison. In the presentstudy, we set out to characterize the anti-estrogenic effects of DEHP on the estrous cycle offemale offspring exposed to 1 - 300 mg DEHP/kg/day. In utero exposure to DEHP resulted in aperturbation of the ovarian steroids profiles as well as an underdevelopment of ovarian follicles.In the ovaries we reported a decrease in the expression of Cyp17a1, a gene that encodes for theenzyme necessary for androgen formation. Furthermore, pituitary-derived FSH serum levelswere significantly increased pre and post ovulation starting at the lowest dose. The feedbackmechanism in the hypothalamic-pituitary-gonadal axis was presumably not affected sincepituitary and hypothalamus expression of genes involved in the regulation of the axis was notaltered. Anti-Müllerian hormone gene expression was significantly decreased in the ovary.Mating studies showed a decrease in first cycle pregnancy. The data presented herein suggestthat in utero exposure to DEHP likely targets ovarian follicular development. / Di-2-ethylhexyl phthalate (DEHP) est un perturbateur endocrinien utilisé comme additif plastifiant dans la fabrication d'une variété de produits industriels, médicaux et de consommation courante. L'observation de retards développementaux suite à des expositions aux produits chimiques tels que le DEHP représente une source d'inquiétude depuis quelques décennies. Dans nos études, nous utilisons un modèle d'étude qui consiste à traiter des rattes gestantes par gavage avec du DEHP du quatorzième jour de gestation jusqu'au jour de la naissance, afin d'exposer les fétus au DEHP pendant une phase critique du développement reproductif. Nous avons préalablement fournis des évidences démontrant les effets adverses des expositions in utero au DEHP sur le système endocrinien masculin. Cependant, il y a un déficit de connaissance sur la possibilité que de tels effets prennent place chez les femelles exposées in utero au DEHP. De ce fait, le but de notre étude était de caractériser les effets potentiels anti-oestrogéniques de DEHP sur le cycle de l'œstrus des femelles rattes exposées en tant que fétus a des doses de DEHP variant de 1 à 300 mg/kg/jour. Nos résultats ont révélés que les expositions in utero au DEHP ont entrainé des perturbations dans les profiles des stéroïdes ovariens et dans le développement des follicules ovariens. Dans les ovaires, nous avons observé une diminution de l'expression de Cyp17a1, un gène codant pour une des enzymes nécessaires à la formation des androgènes. De plus, les niveaux sériques de l'hormone hypophysienne FSH étaient augmentés de façon significative aux périodes pré- et post- ovulatoires, y compris pour les faibles doses de DEHP. Il semble que le mécanisme de boucle de rétroaction de l'axe hypothalamo-hypophyso-gonadal n'ait pas été affecté par DEHP puisque nos études ont montré que les gènes hypothalamiques et hypophysaires impliqués dans ce processus n'aient pas été pas altérés par les traitements. L'expression du gène de l'hormone anti-mullerienne était diminuée de façon significative dans les ovaires. Des études d'accouplement ont montré un délai dans le succès des rattes à devenir gestantes. Les résultats présentés dans cette étude suggèrent que les expositions in utero au DEHP ciblent probablement le développement folliculaire ovarien.

This thesis sets out to examine the problems that have been associated with paraquat, both in relation to its occupational use as a herbicide and its misuse in cases of accidental or deliberate human poisoning. In order to provide a frame of reference for the later discussion, the general properties of paraquat are reviewed, together with its general toxic effects and possible mode of action in mammalian systems. The degree of risk associated with paraquat use in normal agricultural practice is examined. The available published literature is reviewed and the results of studies on both formulation workers and spraymen are discussed. It is concluded that the use of paraquat does not constitute a significant risk to health when sprayed at concentrations of up to 0.5% paraquat ion. Studies of situations in which low volume/high concentration application methods have been used would indicate that they are likely to produce an unacceptable level of risk and constitute dangerous agricultural practice. The problem of paraquat misuse is examined, both in regard to its extent and the effectiveness of treatment in cases of human poisoning. Treatment measures currently advocated are reviewed and their effectiveness discussed in relation to the series of 108 poisoning cases which is presented. On the basis of the data set out it is concluded that the treatment of paraquat poisoning is only likely to be effective in those cases who have, (a) ingested less than 5g of paraquat ion, (b) had treatment instituted within 2 hours of ingestion, and (c) show plasma paraquat levels in the order of 1-2mg/litre 2-4 hours after ingestion. It is also concluded that the only effective form of treatment is the vigorous and rapid removal of paraquat from the gut using Fuller's Earth and purgation or gut lavage. There is little clinical evidence to suggest that measures designed to remove paraquat from the circulation after absorption or block its action in the body have any effect on the clinical course of poisoning. Some general conclusions are drawn and a select bibliography is appended.

Staphylococcus aureus is a major human pathogen causing a wide range of illnesses from the trivial to the life-threatening. S. aureus produces many surface-associated and exoproteins, several of which have been implicated in its virulence. Production of these virulence determinants is co-ordinately controlled by several global regulatory elements in a growth phase dependent manner. The best characterised of these regulators are the accessory gene regulator (agr) and staphylococcal accessory regulator (sar). The agr locus comprises a quorum sensing system and encodes a signalling pheromone that autoregulates agr in a density dependent manner. Upregulation of agr expression leads to production of an mRNA transcript, RNAHI which is the actual effector of virulence gene expression. The RNAIII molecule upregulates several extracellular toxins including haemolysins, toxic shock syndrome toxin 1 (TSST-1) and epidermolytic toxin A (Eta), and down-regulates surface proteins such as protein A and fibronectin binding protein (FnBP) during late exponential growth and stationary phase. The regulation of toxin production by S. aureus is extremely complex and it is not yet understood exactly how this organism responds to environmental stimuli in order to mediate changes in virulence gene expression. In order to determine whether environmental signals are transduced via agr, the effect of several stimuli on both agr expression and a-haemolysin production was examined using a ß-galactosidase reporter gene fusion to the hid gene, which is encoded as part of the RNAIII transcript. A number of environmental stimuli were identified which led to changes in agr expression. Several of these stimuli resulted in different effects on a- haemolysin activity when compared to RNAIII levels. This suggests the presence of novel regulatory elements involved in the control of Hla production, independently of agr. In order to identify other novel regulators which interact with, or control, agr, transposon libraries have been created using Tn917 and Tn551. Two Tn917 transposon mutants were isolated as deficient in production of ß-haemolysin, which is also positively controlled by agr. These mutants were found to contain novel transposon insertions in the agr locus. Five Tn551 mutants were isolated which showed pleiotropic effects on virulence determinant levels and did not contain the transposon in previously mapped regulators. The Tn551 insertions may have therefore occurred in novel regulators of virulence determinant production. The regulation of toxin production by S. aureus in response to environmental stimuli is discussed.