Submitted by Biblioteca de Pós-Graduação em Geoquímica BGQ (bgq@ndc.uff.br) on 2016-05-02T17:17:55Z No. of bitstreams: 1 Tese final toda (11_agosto_2015).pdf: 3292855 bytes, checksum: bbd17ebdbe647b364c4a07ba7475191a (MD5) / Made available in DSpace on 2016-05-02T17:17:56Z (GMT). No. of bitstreams: 1 Tese final toda (11_agosto_2015).pdf: 3292855 bytes, checksum: bbd17ebdbe647b364c4a07ba7475191a (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Geociências-Geoquímica. Niterói, RJ / As baías do Estado do Rio de Janeiro são ecossistemas de grande importância econômica, ecológica e social. Entretanto, estes ambientes vêm sofrendo impactos antropogênicos, oriundo de diversas origens. Dentre as diversas fontes de poluição dos ecossistemas de baías, pode-se destacar a contaminação por hidrocarbonetos policíclicos aromáticos (HPA), uma vez que estes compostos estão presentes em grande parte das atividades urbano-industriais, atingindo os ambientes aquáticos após derramamentos acidentais de petróleo. Os HPA são carcinogênicos, mutagênicos e genotóxicos. Desta forma são considerados poluentes prioritários em monitoramentos ambientais. Para avaliação da contaminação de ambientes aquáticos por HPA como parte de programas de monitoramentos ambientais do EUA e de alguns países da Europa têm sido utilizados, de forma crescente, os chamados biomarcadores. Estes podem ser definidos como alterações bioquímicas, celulares, moleculares ou mudanças fisiológicas nas células, fluidos corpóreos, tecidos ou órgãos de um organismo indicativos da exposição ou efeito de um xenobiótico. A utilização de biomarcadores em peixes tem se mostrado bastante eficaz na avaliação dos efeitos da contaminação por esta classe de compostos. Diante disso, o objetivo deste trabalho foi avaliar a contaminação por HPA em bagres (Genidens genidens) das baías de Guanabara (BG), Sepetiba (BS) e Ilha Grande (BIG) através do uso de biomarcadores. Para tanto, analisou-se uma série de biomarcadores em bagres coletados nas baías de Guanabara, Sepetiba e Ilha Grande, a saber: avaliação do fator de condição; determinação de metabólitos de HPA em bile; determinação de etoxireosrufina- O-desetilase (EROD) hepática; avaliação da frequência de micronúcleos (MN) e anormalidades nucleares eritrocitárias (ANE); avaliação das alterações histopatológicas hepáticas; e formação de adutos de HPA-DNA. O fator de condição evidenciou diferenças na saúde geral dos peixes nas áreas estudadas, tendo os peixes da BG os piores índices de saúde. Foi observada diferença estatisticamente significativa entre a BG e BIG e BS e BIG, para todos os metabólitos de HPA estudados. A indução de EROD também se mostrou mais elevada na BG comparativamente a BS e BIG, com diferenças estatisticamente significativas entre as áreas. Da mesma forma, o MN elucidou estas diferenças. Novamente, a BG mostrou os piores efeitos entre as áreas estudadas. No caso das alterações histopatológicas, a BS mostrou as maiores prevalências de injúrias. Na avaliação do aduto de BPDE-DNA, os peixes da BG possuíram os piores efeitos genotóxicos, com diferença estatisticamente significativa em relação a BIG. A realização de estudos que utilizam ferramentas de avaliação da contaminação em áreas de grande importância social, econômica e ecológica, como o litoral do estado do Rio de Janeiro, é fundamental para o real conhecimento dos impactos causados pelos poluentes, pré requisito essencial para um efetivo plano de conservação e restauração destes ecossistemas / The bays of the state of Rio de Janeiro are ecosystems of great economic, ecological and social importance. However, these environments are suffering anthropogenic impacts, arising from diverse backgrounds. Among the several pollution sources, the pollution caused by polycyclic aromatic hydrocarbons (PAH) is under concern since these compounds are present in many urban and industrial activities. This class of chemistry can cause severe damages in the aquatic biota and suggesting the necessity for environmental monitoring to assess the effects of PAH in fish. The PAH are carcinogenic, mutagenic and genotoxic, being considered priority pollutants in environmental monitoring. For evaluation of contamination by PAH in aquatic environments as part of environmental monitoring, US programs and of some countries in Europe has been used, increasingly, biomarkers. These can be defined as biochemical changes, cellular, molecular or physiological changes in cells, body fluids, tissues or organs of an organism indicative of exposure or effect of a xenobiotic. The use of biomarkers in fish has been shown quite effective in evaluation of the contamination effects by this class compounds. Thus, the objective of this study was evaluate the PAH contamination in fish from Guanabara, Sepetiba and Ilha Grande Bay, using biomarkers. Therefore, we analyzed a series of biomarkers in catfish collected in these bays, namely: assessment of the condition factor; determination of PAH metabolites in bile; determination of the activity of O – ethoxy- resorufin - deetilase (EROD) in fish liver; evaluation of the frequency of micronucleus (MN) and erithrocytic nuclear abnormalities (ENA); evaluation of histopathological hepatic injuries and; formation of PAH-DNA adducts. The condition factor demonstrated differences in the general health of fish arising distinct studied areas. Fish from BG showed the worst health index. There was a statistically significant difference between BG and BS and BG and BIG for all PAH metabolites analyzed. The EROD induction was also higher in BG compared to BS and BIG, with statistically significant differences between areas. Likewise, the micronucleus elucidated these differences. Again, BG showed the worst effects of the studied areas. In the case of the histopathological changes, BS revealed the highest prevalence of injuries. In assessing the BPDE-DNA adduct, fish BG possessed the worst genotoxic effects, with statistically significant difference from BIG. The knowledge of the impacts of pollutants in aquatic biota, based on use of biomarkers in areas with significant social, economic and ecological importance, like Rio de Janeiro cost, is essential for effective conservation and restoration plan of these ecosystems.

The 5-HTT gene (SLC6A4) is regulated by a common polymorphism in the promoter region (5-HTTLPR), which has functional consequences. Two major alleles have been observed and shown to have differential transcriptional activity with the long (L) allele having greater gene expression than the short (S) allele. 5-HTTLPR appears to modulate depression, anxiety and personality traits such as neuroticism. Additionally, a significant influence of 5-HTTLPR genotype on amygdala reactivity in response to fearful stimuli has been reported. Moreover, 5-HTTLPR seems to impact on the role of stressful life events (SLEs) in the development of depression. An elevated risk of depression and suicidal behaviors has been found in carriers of at least one low expressing S allele who had experienced SLEs, suggesting a gene x environment interaction. However, a recent meta-analysis showed that several findings failed to replicate this finding. Since genetic polymorphisms of the dopaminergic and serotonergic neurotransmission interact at the molecular, analyses with another polymorphism of the dopaminergic system, the dopamine D4 receptor (DRD4) was included to consider these likely gene-gene interactions (epistasis). The aim of this series of studies was to investigate the role 5-HTTLPR and SLEs on the endocrine stress response in different age samples. While newborns have been examined by a heel prick, stress responses were provoked in children (8-12 yrs) and younger adults (19-31 yrs) and older adults (54-68 yrs.) with the Trier Social Stress Test (TSST). The Life History Calendar (LHC) and Life Events Questionnaire (LEQ) were used to acquire data on SLEs. While in newborns the S/S genotype showed a significantly higher acute endocrine stress response than L/L or S/L genotypes, no significant difference between genotype groups was found in children. In the younger adult sample, the genotype impacted on cortisol stress responsiveness was reversed. Adults carrying the more active L allele of the 5-HTTLPR polymorphism showed a significantly larger cortisol response to the TSST than individuals carrying at least one of the lower expressing S allele. In older adults, no significant difference between genotype groups was found. However, results point in the same direction with showing highest cortisol response in individuals with L/L genotype. These data suggest that the association between 5-HTTLPR and endocrine stress reactivity seems to alter across lifespan, more specific the effects of genotype turns around. In addition, a significant interaction effect of 5-HTTLPR and SLEs has been found in the sample of younger adults, i.e. that early SLE as well as a severe number SLEs across the entire lifespan seem to modulate the interaction between HPA axis activity and 5-HTTLPR genotype. Additionally, a DRD4 by 5-HTTLPR interaction emerged which point to independent and joint effects of these polymorphisms on stress responsivity with regard to the concept of genegene interaction.

No description available.

La sécurité d’attachement joue un rôle significatif dans la gestion du stress. En effet, elle permet à l’enfant de se réguler, tant sur le plan comportemental, émotionnel que physiologique. Le présent mémoire, qui s’inscrit dans une optique de valorisation des données de recherche, vise à investiguer, d’un point de vue longitudinal, le lien entre la sécurité d’attachement et la synchronisation physiologique des mécanismes de stress chez les dyades mère-enfant. En étudiant la réactivité de l’axe hypothalamo-pituito-surrénalien (HPS) qui régule le cortisol, souvent désigné comme l’hormone du stress, cette étude cherche à comprendre les mécanismes d’harmonisation physiologique de la réponse de stress chez les dyades. Les données qui ont servi à ce projet de mémoire proviennent d’une étude longitudinale de 1995 qui portait sur des mères adolescentes. Bien que les résultats des analyses corrélationnelles ne permettent pas d’identifier des différences significatives entre les différents types d’attachement, les résultats des analyses de variances mixtes à mesures répétées suggèrent que chez les dyades mères-enfants, l’harmonisation du cortisol salivaire se développerait de façon significative entre le 9e et 15e mois, et ce, indépendamment du type d’attachement de l’enfant. Ces résultats suggèrent que, dans les contextes de réactivité au stress, l’harmonisation de l’axe HPS des dyades mères-enfants serait un mécanisme physiologique normatif qui se développe à travers le temps. / Attachment security plays a significant role in stress management. Indeed, it allows the child to regulate his behavior, emotions and physiology. The present dissertation, which is part of a research data valuation approach, aims to investigate, from a longitudinal point of view, the link between attachment security and the physiological synchronization of stress mechanisms in mother-child dyads. By studying the reactivity of the hypothalamo-pituitary-adrenal (HPA) axis that regulates cortisol, often referred to as the stress hormone, this study seeks to understand the mechanisms of physiological attunement of the stress response in dyads. The data for this dissertation project came from a 1995 longitudinal study of adolescent mothers. Although the results of the correlational analyses did not identify significant differences between the different types of attachment, the results of the repeated measures analysis of variance using mixed models, suggest that within mother-child dyads, the attunement of salivary cortisol would develop significantly between the 9th and 15th month of age, independently of the child's type of attachment. These results suggest that, in contexts of stress reactivity, the attunement of the HPS axis of mother-infant dyads would be a normative physiological mechanism that develops over time.

<p>  </p> <p>Heat stress affects breeder ducks raised in North America and other parts of the world, but the effects of such stress on the progenies is not known. Therefore, the objectives of this study were to investigate: 1) The objectives of this thesis were to first investigate the effect of heat stress or exposure to exogenous glucocorticoid (GC) on fertility, production performance, egg biochemistry, egg quality, and welfare of breeder Pekin ducks. 2) the effects of maternal GC on phenotypic plasticity and behavior of the F1 generation. Three studies were carried out to investigate these objectives.</p> <p>The first experiment was conducted to test the hypothesis that chronic treatment with low levels of either corticosterone or cortisol would alter heterophil to lymphocyte ratio (HLR) and immune organ morphometrics. Further, we wanted to determine if chronic treatment with either GC would elicit an increase in cortisol levels in egg albumen. To test our hypotheses, we implanted silastic capsules subcutaneously under the skin of the neck of adult ducks (n = 5/sex/dose) using propofol anesthesia. Capsules contained corticosterone, cortisol, or empty capsules as controls. Over the course of 2 weeks, blood serum, blood smears, body weights, and egg quality data were collected. After 2 weeks, ducks were euthanized using pentobarbital (FatalPlus, 396 mg/ml/kg) and body weight, weights of spleens, livers, and the number of active follicles were recorded. Blood smears were analyzed for HLR by a lab unaware of the treatment groups. Albumen GC levels were assessed using mass spectrometry. Data were analyzed using a 2- or 3-way ANOVA as appropriate and <em>post hoc </em>with Fishers protected least squares difference (PLSD). There were no treatment effects on egg quality measures or body weight. Corticosterone treatment did elicit an increase in serum corticosterone (p < 0.05), but not cortisol levels, compared to controls in both sexes. Both cortisol and corticosterone treatments increased (p < 0.05) serum levels of cortisol compared to controls. Relative spleen weights were higher (p < 0.05) in hens following corticosterone but not cortisol treatment. No other organs showed any differences among the treatment groups. Both GCs elicited an increase (p < 0.001) in HLR in hens at all time-points over the 2-week treatment period compared to controls. Cortisol, not corticosterone, elicited an increase in HLR for drakes (p < 0.05) compared to controls at day 1 after implants. Chronic treatment with cortisol, but not corticosterone, elicited an increase (p < 0.01) in egg albumen cortisol levels compared to other groups. Corticosterone was not detected in any albumen samples.</p> <p>The goal of our second experiment was to test the hypothesis that heat stress (HS) would alter welfare, egg quality, and morphometrics of breeder ducks. Furthermore, we wanted to test if HS would increase cortisol levels in egg albumen due to recent exciting findings that cortisol, not corticosterone, is isolated in egg albumen. To test our hypothesis, adult Pekin ducks were randomly assigned to two different rooms at 85% lay with 60 hens and 20 drakes per room. Baseline data including body weight, body condition scores (BCS) (such as footpad quality, eyes, nostrils, feather cleanliness, and feather quality scores), and egg production/quality were collected the week preceding heat treatment. Ducks were subjected to cyclic HS of 350C for 10h/day and to 29.50C for the remaining 14h/day for 3 weeks while the control room was maintained at 220C. Eggs were collected daily, and body weights were taken on days 0 and 21 relative to the onset of heat treatment. BCS were collected weekly. Eggs were collected weekly for quality assessment and albumen glucocorticoid (GCs) levels assessment using mass spectrometry. One week before the exposure to HS, 10 hens and 5 drakes were euthanized and the same number again after 3 weeks of HS or control exposures using pentobarbital and birds necropsied. Body weight, weights of the liver, spleen, and the number of maturing follicles were recorded. Data analyses were done by 2- or 3-way ANOVA as appropriate with a Tukey-Kramer post hoc test. BCS were analyzed using a chi-squared test. A p value ≤ 0.05 was considered significant. Circulating levels of corticosterone were significantly (p < 0.01) elevated at week 1 only in the HS hens while there was no significant difference in the circulating levels of corticosterone in drakes compared to the controls. The circulating levels of cortisol increased significantly at week 1 (p < 0.05), week 2 (p < 0.05), and week 3 (p < 0.01) in the hens and at week 2 and 3 only (p < 0.05) in the drakes compared to the controls. Feather quality scores (p < 0.01), feather cleanliness scores (p < 0.001) and footpad quality scores (p < 0.05) increased significantly in the HS group compared to controls, higher BCS indicate a decline in welfare. HS elicited a significant (p < 0.001) decrease in egg production at weeks 1 and 3 and a descriptive decrease in the number of fertile eggs upon candling at 10 days of incubation, numeric decrease hatchability and increase in the number of dead embryos in the HS group after the incubation period. Hens in the HS group showed a significantly decreased BW (p < 0.001), and number of ovarian follicles (p < 0.05) compared to controls. Shell weight decreased significantly at week 1 (p < 0.05) compared to controls. Yolk weight decreased significantly at week 3 (p < 0.01) compared to controls. HS elicited a significant increase in albumen cortisol levels at week 1 (p < 0.05) and week 3 (p < 0.05).</p> <p>The third experiment was conducted to determine if parental exposure to heat stress would impair performance, hypothalamic pituitary adrenal (HPA) axis response, welfare, or behavior of their offspring. To achieve these goals, we treated adult drakes and hens at peak lay to heat stress or control temperature for 3 weeks and incubated eggs collected from the last 3 days of the experiment. A total of 76 ducklings were placed into pens from each parental treatment group: control (CON-F1) and heat stress (HS-F1) and raised as grow-out ducks. Weekly data for body weights, body condition scores (BCS), and novel object test (NOT) were collected weekly. At 3 weeks of age, ducks (n = 6 per treatment group) were subjected to adrenocorticotropic hormone (ACTH) (ACTH/cosyntropin, 0.0625 mg/kg) challenge or vehicle as control. Blood samples were collected from the metatarsal vein into serum-separator tubes at 0, 1, 2, 3, and 4 hours relative to treatment for the determination of serum glucocorticoids. Blood smears were also produced from these same samples to determine heterophil to lymphocyte ratios (HLR). All injected birds were euthanized with pentobarbital on the second day relative to ACTH administration, spleen and bursa were removed and weighed immediately. Duck level analyses were completed using 1-, or 2 -way ANOVA as appropriate. BCS were analyzed using a chi-squared test. We observed that HS-F1 had a lower hatch weight (p < 0.05) compared to CON-F1. However, growth rates during the 5-week grow-out period were not significantly different between the two flocks. NOT (N = 4) analyses showed that the HS-F1 had a greater fear response (P< 0.001) compared to CON-F1. Similarly, an ACTH stimulation test showed that the HS-F1 ducks had significantly heightened corticosterone and HLR responses compared to CON-F1 ducks (p < 0.05). The HS-F1 showed altered baseline and ACTH-stimulated levels of cortisol compared to controls.</p> <p>In conclusion, GC elicit differential effects and although corticosterone has been stated to be the predominant GC in avian species, cortisol may provide critical information to further understand and improve welfare. HS decreased performance, fertility, and productivity of breeder ducks. In addition, HS and exogenous GC elicited a selective deposition of cortisol, not corticosterone, in the egg albumen. The maternal cortisol deposited in eggs alter the hypothalamic-pituitary adrenal (HPA) axis and behavioral responses of the F1 generation. This suggests that maternal hormones can alter the phenotypic plasticity of the offspring and can be used to produce offspring that have better adaptation to the rising temperatures as a result of climate change. Finally, the measure of cortisol in egg albumen can be used as a non-invasive marker of stress.</p>

Les différences sexuelles ne se limitent pas uniquement aux organes de reproduction, elles sont aussi très marquées dans plusieurs pathologies humaines. De ce fait, les études impliquant un seul sexe ne pourraient jamais permettre d’élucider les mécanismes qui sous-tendent ces pathologies. De plus, l’exclusion des femelles/filles/femmes des protocoles de recherche a des impacts négatifs sur la qualité de vie des patients, plus spécifiquement celle des filles et femmes. Des études récentes ont suggéré que la testostérone et ses métabolites affectent le développement de l’hippocampe aux niveaux biochimique, morphologique et fonctionnel. En revanche, les données ne sont pas aussi extensives que celles de leurs rôles chez les adultes. Ainsi, une meilleure compréhension des mécanismes par lesquels l’hormone stéroïdienne influence le développement du cerveau facilitera l’identification des cibles thérapeutiques de plusieurs maladies neurodéveloppementales qui affectent le fonctionnement de l’hippocampe. Afin de se développer adéquatement, le cerveau mâle requiert une exposition aux hormones sexuelles mâles pendant une période de temps donnée. En revanche, le cerveau femelle possède une phase critique peu après la naissance au cours de laquelle une exposition aux hormones sexuelles mâles le masculinise en produisant des caractéristiques comparables à celles rencontrées chez des mâles biologiques. Ainsi, la capacité de manipuler les cerveaux femelles dans le but de les masculiniser représente un outil expérimental important pour investiguer les différences sexuelles. Du fait que les hormones sexuelles telles que la testostérone et l’estradiol représentent respectivement l’élément caractéristique de chacun des sexes, cette thèse a pour objectif de disséquer l’implication de la testostérone dans le développement et le fonctionnement du cerveau en étudiant en plus des rats mâles et femelles, des femelles traitées avec la testostérone ainsi que des mâles rendus insensibles à la testostérone. En premier lieu, nous avons investigué sur un système de neurotransmission spécifique, à savoir le système GABAergique, qui est important pour le contrôle des convulsions communément observées dans l’épilepsie. Ce système possède des particularités notables en fonction du sexe, particularités qui pourraient être l’une des causes de la prédisposition des mâles à l’épilepsie. En effet, notre étude révèle qu’au niveau basal, les femelles ainsi que les mâles insensibles à la testostérone montrent très tôt au cours de leur développement une localisation à la membrane du co-transporteur KCC2 qui régule la force de la neurotransmission inhibitrice. Par ailleurs, nous avons aussi détecté des niveaux élevés du neurotrophine BDNF qui est un puissant modulateur du fonctionnement des cellules GABAergiques, ceci, au cours de la première semaine postnatale. Par ailleurs, chez les adultes, nous avons trouvé que les femelles ainsi que les mâles insensibles à la testostérone montrent une augmentation de la transmission GABergique spontanée comparativement aux mâles et aux femelles qui ont été exposées à la testostérone. En somme, ces données démontrent que le fonctionnement de la circuiterie GABAergique est modulé par le niveau de testostérone périnatal, ce qui suggère d’un rôle des hormones sexuelles dans la régulation de l’excitabilité cellulaire. De plus, les différences sexuelles dans le cerveau sont largement déterminées par des facteurs extrinsèques. Parmi ces derniers, le stress du début de la vie est un facteur extrinsèque puissant qui altère l’habileté à contrôler la rétroaction négative des glucocorticoïdes sur l’axe hypothalamo-hypophyso-surrénalien (HHS). Le stress est également connu pour affecter différentiellement les rats mâles comparativement aux femelles. Nous démontrons alors que la corticostérone rend l’hippocampe vulnérable à une seconde insulte, telle que les épilepsies induites par l’hyperthermie. En effet, chez les rats traités à la corticostérone, la latence d’induction des épilepsies par hyperthermie est réduite, le temps de récupération plus long et le nombre d’évènements épileptiques plus nombreux. En outre, nous avons trouvé que tous ces effets sont plus proéminents chez les mâles que chez les femelles. Ces données confirment l’existence d’un lien entre le stress du début de la vie et la susceptibilité aux convulsions hyperthermiques chez les rats mâles et femelles. Une meilleure compréhension des conséquences des convulsions fébriles pourrait aider dans le pronostic et le traitement des patients souffrant d’épilepsie. Somme toute, cette thèse met en lumière le rôle complexe des hormones sexuelles dans la régulation des circuits GABAergiques, des réponses au stress et de l’hyperexcitabilité du cerveau en développement. Une meilleure compréhension des mécanismes pathologiques propres aux modèles animaux mâles et femelles résulterait en de meilleures interventions et thérapies aussi bien chez les hommes que les chez les femmes. / Sex differences extend far beyond reproductive health — there is a widespread prevalence of sex differences in many human diseases and conditions. Therefore, studies limited to a single-sex cannot fully give a comprehensive picture of the underlying disease mechanisms, and the neglect of females/girls/women in biological research negatively impacts patients' quality of life, especially women. Recent data suggest that testosterone and its metabolites affect the hippocampus during development at the biochemical, morphological, and functional levels, although the data are not nearly as extensive as what is known in adults. Therefore, a better understanding of these effects will elucidate steroid hormone-dependent mechanisms of brain development and, possibly, help identifying ways to mitigate the burden of the many neurodevelopmental disorders that involve hippocampal function. The male brain is unique in that it must be exposed to male sex hormones for a fixed period of time, which is so-called critical period. This is deemed a critical period because if androgens levels do not rise at this time in males, the brain will fail to be masculinized. The female brain, on the other hand, has a sensitive period shortly after birth, during which exposure to male sex hormones may masculinize the brain and produce features comparable to those seen in biological males. This capacity to manipulate females toward more masculinized brains represent an important experimental tool to investigate sex differences. Because sexual hormones, such as testosterone and estradiol, are a distinct point of divergence between sexes, my thesis proposes to study the implication of testosterone by using, in addition to male and female animals, females treated with testosterone as well as testosterone-insensitive male rats. First, we investigated a specific neurotransmitter system, the GABAergic system, which contributes to the control of seizures commonly observed in epilepsies. This system shows robust differences between males and females, which may be involved with the predisposition to epilepsy observed in males. Our study revealed that at baseline conditions female and testosterone-insensitive male rats show an earlier localization at the membrane of the chloride co-transporter KCC2, which regulates the strengths of inhibitory neurotransmission, and higher levels of the neurotrophin BDNF, which is a powerful modulator of GABAergic cell function, during the first postnatal week. In addition, we found that female and testosterone-insensitive male rats show enhanced spontaneous GABA synaptic transmission when compared to males and testosterone-exposed females in adults. Overall, these data show that perinatal testosterone levels modulate GABAergic circuit function, suggesting a role of sex hormones in regulating cell excitability. Second, sex differences in the brain are largely determined by extrinsic factors. Early-life stress is one such powerful extrinsic factor that impairs the ability to control glucocorticoid negative feedback on the HPA axis. Stress is also known to differentially affect male and female rats. Here, we show that corticosterone alone renders the hippocampus vulnerable to a second insult, namely hyperthermia-induced seizures, in fact in corticosterone-treated rats the latency to hyperthermia-induced seizures was shorter, the recovery time longer, and a larger number of hyperthermia-induced seizures. Further, these effects were a lot more prominent in males than in females. These findings support a link between early-life stress and hyperthermic seizure susceptibility in both male and female rats. A better understanding of the consequences of febrile seizures could help improve the prognosis and treatment of patients with epilepsy. Altogether, these findings shed light on the complex roles of sex hormones in regulating GABAergic circuits, stress responses and circuit hyper-excitability in the developing brain. A better understanding of disease-mechanisms underlying male and female animal models could lead to better interventions and therapeutics in both men and women.

Contexte : Bien qu’il ait été proposé que l’exposition à un faible statut socioéconomique (SSE) familial altère l’activité de l’axe hypothalamo-pituito-surrénalien et sa production de l’hormone cortisol, les résultats actuels sont incohérents et suggèrent la présence de facteurs supplémentaires susceptibles de modifier ces associations. Pourtant, peu d’études à ce jour ont adopté une approche développementale sensible au timing, à la stabilité et aux changements au sein du SSE familial lors de l’étude de l’association liant le SSE au cortisol. En outre, peu de travaux empiriques ont évalué si cette association est non linéaire ou si elle est modulée par le soutien social. Enfin, rares sont les études qui ont examiné dans quelle mesure cette association est affectée par les facteurs génétiques et par les processus gène-environnement, notamment à l’adolescence. Objectifs : Ancré dans une perspective de psychopathologie développementale, l’objectif principal de cette thèse est d’examiner les processus gène-environnement impliqués dans les associations entre le SSE et divers indicateurs de sécrétion cortisolaire mesurés à l’adolescence. Cette thèse a également examiné dans quelle mesure ces associations sont affectées par le timing, la chronicité et les changements au sein du SSE familial et sont atténuées par le soutien social. Méthodes : Les participants proviennent de l’Étude des jumeaux nouveau-nés du Québec, un échantillon populationnel de jumeaux recrutés à la naissance. Le SSE familial a été recueilli au cours de la petite enfance (0-5 ans) et à la mi-adolescence (14 ans). Le soutien social a été rapporté par les jumeaux à l’âge de 14 et de 19 ans. Le cortisol diurne (n=569) a été mesuré à l’âge de 14 ans au réveil, 30 minutes plus tard, l’après-midi et le soir pendant quatre jours non consécutifs. Le cortisol capillaire (n=704) a été mesuré à l’âge de 19 ans. Résultats : Cette thèse est composée de trois articles. Les résultats des deux premiers articles indiquent que l’étiologie génétique du cortisol au réveil et capillaire fluctuent au long du continuum du SSE mesuré à la petite enfance. Les formes que prennent ces interactions gène-environnement sont toutefois distinctes pour ces indicateurs. De plus, nos résultats révèlent la présence d’associations uniques entre le SSE familial mesuré à la mi-adolescence et la plupart des indicateurs cortisolaire, soit suivant une relation linéaire, ou non linéaire. Nous avons également trouvé que l’association liant le SSE au cortisol capillaire n’est pas expliquée par une étiologie génétique commune, mais semble refléter les effets de l’environnement partagé par les jumeaux. Enfin, les résultats du troisième article suggèrent que l’effet synergique du SES familial mesuré à la petite enfance et à la mi-adolescence prédisent la sécrétion cortisolaire. De plus, l’association concomitante entre le SSE et le cortisol au réveil est modulée par le soutien social. Conclusions : Collectivement, ces résultats soulignent l’importance d’adopter une approche développementale et génétiquement informative lors de l’étude de l’association liant l’adversité aux systèmes physiologiques de stress. Un tel examen pourrait contribuer à une meilleure compréhension des mécanismes sous-tendant les disparités socioéconomiques précoces documentées en matière de santé, d’apprentissage et de comportements. / Background: While exposure to lower family socioeconomic status (SES) has been proposed to induce alterations in hypothalamic-pituitary-adrenal (HPA) axis activity and its production of the hormone cortisol, existing findings are inconsistent and suggest the presence of additional factors that may modify these associations. Yet, few of the past studies have taken a developmental approach sensitive to the timing, stability, and change within family SES when investigating the association between SES and cortisol secretion. Furthermore, little empirical attention has been devoted to assessing the possibility that this association might be nonlinear or is modulated by youth’s perceived availability of social support. Lastly, the extent to which this association is affected by genetic factors as well as gene-environmental interplays has seldom been investigated, particularly in adolescence. Objectives: Rooted in a developmental psychopathology perspective, the present thesis’s main objective is to examine the gene-environment processes implicated in the associations of family SES with multiple indicators of cortisol secretion during adolescence. This thesis also investigated to what extent these associations are affected by the timing, chronicity and change in SES and buffered by perceived social support. Methods: Participants are from the Québec Newborn Twin Study, a population-based sample of twin pairs recruited at birth. Family SES was collected in early childhood (ages 0–5) and mid-adolescence (age 14). Perceived social support was reported by twins at aged 14 and 19. Diurnal cortisol (n=569) was measured at age 14 at awakening, 30 min later, in the afternoon and evening over four non-consecutive days. Hair cortisol (n=704) was measured at age 19. Results: This thesis is comprised of three articles. The results of the first two papers indicate that the genetic etiology of adolescence awakening cortisol and HCC fluctuated along the continuum of early childhood family SES. The patterns of these gene-environment interactions were, however, distinct for these indicators. Furthermore, our results pointed to unique associations between mid-adolescence family SES and most of the diurnal and hair cortisol indicators, either according to a linear or nonlinear function. We also found that the association linking mid-adolescence family SES to HCC is not explained by a common genetic etiology but appears to reflect shared environmental effects. Finally, the results of the third paper revealed that the synergistic effect of early childhood and mid-adolescence SES predicted cortisol secretion. Moreover, the concomitant association between SES and awakening cortisol was found to be modulated by mid-adolescence social support. Conclusions: Collectively, these findings underscore the necessity of espousing a developmental and genetically sensitive approach in studies investigating the impact of adversity on stress physiological systems. Such investigations may pave the way to a fuller understanding of the mechanisms underlying the early roots of socioeconomic disparities in health, learning and behaviours.

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Cannabinoid (CB) receptors have been found in most vertebrates that have been studied. The location of various CB receptors in the body and brain are known, but their physiological functions are not fully understood. The effects CBs have on the cardiovascular system have been of growing interest in recent years. Increasing reports from emergency departments and law enforcement agencies detail acute cardiovascular and psychological effects from synthetic CB intoxication, such as JWH-018. This major health concern is substantiated by governmental agencies like the CDC and NIDA. This pilot study investigates the acute toxic effects of the synthetic CB, JWH-018, on the cardiovascular and neuroendocrine systems in Ictalurus punctatus (channel catfish). Research in organisms besides the traditional mammal models can provide new insights into CB function and physiology. Ictalurus punctatus lend multiple benefits as a model organism that permits researchers to investigate in vivo effects of both cardiovascular and neuroendocrine systems without much influence from traditional sampling methods, and further more provide ample size and tissue to perform specific cardiovascular experiments. Multiple methods were used to assess cardiovascular function and sympathetic nervous system activation. Two different doses, low (500 µg/kg) and high 1,500 µg/kg, of JWH-018 were evaluated in the study. Delivery of JWH-018, via dorsal aorta cannulation, was administered to channel catfish in order to measure cardiovascular functions and sample blood. Plasma levels of the hypothalamus-pituitary-adrenal/interrenal (HPA/I) biomarkers; ACTH, cortisol, epinephrine, and norepinephrine, were measured using ELISAs. Myocardial and neural tissue was collected after the exposures for rt-PCR analysis on β2 adrenergic and glucocorticoid receptor density change. Acute exposure of JWH-018 in undisturbed channel catfish yielded several findings: (1) High dose of JWH-018 was responsible for cardio depressor effects in catfish with a tendency to produce tachycardia, (2) rt-PCR results showed a 2.7 fold increase of glucocorticoid receptor mRNA density in catfish cardiomyocytes when exposed to each dose of JWH-018, (3) Catfish plasma ACTH levels were increased with high doses of JWH-018, while plasma cortisol was increased by low doses. Channel catfish is an excellent animal model to examine the effects of synthetic cannabinoids and cardiovascular function. Acute exposures to high levels of JWH-018 appear to produce cardiovascular dysfunction providing evidence that substantiates emergency department reports, in addition yields novel information about the interaction of CBs exposure and the increase of glucocorticoid receptors levels on cardiomyocytes. The channel catfish is a new animal model that can aid in further investigations of CB exposure and multiple physiological functions for health and toxicology studies. With relatively easy adjustments from this pilot study, the effects on CBs can be monitored on Ictalurus punctatus with confident results concerning human health.