No description available.

No description available.

No description available.

The classical model of sexual differentiation states that genes influence gonadal differentiation, and gonadal hormones then drive sexual differentiation throughout development. This model has been called into question by research, especially in songbirds, providing evidence for alternative mechanisms like direct effect of genes and local production of steroids via de novo synthesis or local metabolism of steroid precursors like DHEA, which can be metabolized to testosterone and E₂. In order to assess the role of local steroid production on sexual differentiation in songbirds, levels of DHEA and E₂ were measured in brachial and jugular plasma, as well as brain and peripheral tissues in zebra finches at critical ages during development and in adulthood. DHEA levels in brachial and jugular plasma peaked at P30 and higher DHEA levels in jugular plasma were found in males relative to females at P30. Also, at P30, higher DHEA levels were found in rostral telencephalon in females relative to males. The findings of this study indicate that DHEA may play a role in sexual differentiation of songbirds. Surprisingly, E₂ was non-detectable in many plasma and tissue samples. Higher E₂ was found in the diencephalon in females relative to males at P3/P4 and higher E₂ was found in gonads in adult females relative to males. There was little evidence to suggest that E₂ is synthesized de novo in the brain, although perhaps E₂ is being rapidly metabolized into another estrogen or E₂ synthesis is more localized in the synapse. The findings of this study support the role of alternative mechanisms like de novo steroid synthesis and local metabolism of steroid precursors and challenge the role of classical mechanisms of sexual differentiation in songbirds. Also, these findings may have important implications for sex differences, which develop independently of gonadal hormones, in other animal species.

The classical model of sexual differentiation states that genes influence gonadal differentiation, and gonadal hormones then drive sexual differentiation throughout development. This model has been called into question by research, especially in songbirds, providing evidence for alternative mechanisms like direct effect of genes and local production of steroids via de novo synthesis or local metabolism of steroid precursors like DHEA, which can be metabolized to testosterone and E₂. In order to assess the role of local steroid production on sexual differentiation in songbirds, levels of DHEA and E₂ were measured in brachial and jugular plasma, as well as brain and peripheral tissues in zebra finches at critical ages during development and in adulthood. DHEA levels in brachial and jugular plasma peaked at P30 and higher DHEA levels in jugular plasma were found in males relative to females at P30. Also, at P30, higher DHEA levels were found in rostral telencephalon in females relative to males. The findings of this study indicate that DHEA may play a role in sexual differentiation of songbirds. Surprisingly, E₂ was non-detectable in many plasma and tissue samples. Higher E₂ was found in the diencephalon in females relative to males at P3/P4 and higher E₂ was found in gonads in adult females relative to males. There was little evidence to suggest that E₂ is synthesized de novo in the brain, although perhaps E₂ is being rapidly metabolized into another estrogen or E₂ synthesis is more localized in the synapse. The findings of this study support the role of alternative mechanisms like de novo steroid synthesis and local metabolism of steroid precursors and challenge the role of classical mechanisms of sexual differentiation in songbirds. Also, these findings may have important implications for sex differences, which develop independently of gonadal hormones, in other animal species.

The classical model of sexual differentiation states that genes influence gonadal differentiation, and gonadal hormones then drive sexual differentiation throughout development. This model has been called into question by research, especially in songbirds, providing evidence for alternative mechanisms like direct effect of genes and local production of steroids via de novo synthesis or local metabolism of steroid precursors like DHEA, which can be metabolized to testosterone and E₂. In order to assess the role of local steroid production on sexual differentiation in songbirds, levels of DHEA and E₂ were measured in brachial and jugular plasma, as well as brain and peripheral tissues in zebra finches at critical ages during development and in adulthood. DHEA levels in brachial and jugular plasma peaked at P30 and higher DHEA levels in jugular plasma were found in males relative to females at P30. Also, at P30, higher DHEA levels were found in rostral telencephalon in females relative to males. The findings of this study indicate that DHEA may play a role in sexual differentiation of songbirds. Surprisingly, E₂ was non-detectable in many plasma and tissue samples. Higher E₂ was found in the diencephalon in females relative to males at P3/P4 and higher E₂ was found in gonads in adult females relative to males. There was little evidence to suggest that E₂ is synthesized de novo in the brain, although perhaps E₂ is being rapidly metabolized into another estrogen or E₂ synthesis is more localized in the synapse. The findings of this study support the role of alternative mechanisms like de novo steroid synthesis and local metabolism of steroid precursors and challenge the role of classical mechanisms of sexual differentiation in songbirds. Also, these findings may have important implications for sex differences, which develop independently of gonadal hormones, in other animal species. / Medicine, Faculty of / Graduate

No description available.

L’alpha-foetoprotéine (AFP) est la protéine majoritaire du sérum fœtal de mammifère. C’est une glycoprotéine produite et sécrétée par l’endoderme viscéral du sac vitellin, les hépatocytes fœtaux et dans une moindre mesure, par l’intestin fœtal. Son profil d’expression est onco-fœtal : la synthèse de cette protéine chute fortement après la naissance mais peut reprendre en cas de régénération hépatique ou en cas de tumeurs diverses. Cette protéine est capable de fixer les oestrogènes et jouerait un rôle dans la différenciation sexuelle du cerveau femelle. Deux invalidations du gène de l’AFP ont été réalisées au Laboratoire de Biologie du Développement afin de comprendre la fonction de cette protéine. Dans les deux cas, des souris homozygotes pour l’allèle invalidé (souris AFP KO) ont été obtenues. Elles sont viables et apparemment phénotypiquement normales, mais les femelles sont stériles, suite à une anovulation. Il a été démontré que l’absence d’ovulation provient d’un mauvais fonctionnement de l’axe hypothalamo-hypopysaire. Nous avons démontré au cours de cette thèse que l’ARN messager d’une série de gènes était sous-représenté au sein de l’hypophyse des souris femelles invalidées pour le gène Afp. Nous trouvons parmi ces gènes, ceux d’une cascade particulièrement importante pour l’ovulation, la cascade du récepteur de la GnRH. La fertilité des souris femelles AFP KO, ainsi que le taux d’expression des gènes testés dans l’hypophyse, sont restaurés si ces souris se développent dans un environnement appauvri en oestrogènes. Nous avons donc pu corriger le phénotype des souris femelles invalidées pour le gène de l’AFP. Nous avons en ce faisant démontré que l’AFP, par sa capacité de fixer les oestrogènes, protégeait le cerveau femelle en développement des effets masculinisants de ces hormones

Importance d'une certaine activité oestrogénique lors du développement et à l'âge adulte pour permettre la différenciation sexuelle du cerveau et du comportement chez le mammifère par l'étude du souche de souris portant une mutation du gène codant pour l'enzyme aromatase.

Endocrine disrupting chemicals (EDCs) are a class of environmental toxicants, of both natural and synthetic origin, that interfere with normal endocrine function. Exposure to EDCs during susceptible periods of development, particularly embryogenesis, can result in profound neurological and reproductive deficits. While the impact of developmental exposure to EDCs on reproductive function and behavior has been much studied, the underlying mechanisms responsible for these observed effects are not well understood. The goal of the research detailed in this dissertation is to elucidate the cellular and molecular targets by which a representative class of EDCs, polychlorinated biphenyls (PCBs), disrupts normal reproductive neuroendocrine function. My specific hypothesis is that PCBs cause changes in sexually dimorphic brain regions underlying sex-specific reproductive physiology and behavior through the perturbation of normal developmental apoptosis, with long-term consequences for reproductive success. The studies detailed herein focus on three areas which contribute to an understanding of the effects of PCBs on neuroendocrine reproductive function: (1) the in vitro effects of PCBs on a neuroendocrine cell line, (2) developmental effects of PCBs on the gestationally exposed F1 generation, and (3) the physiological consequences of these developmental alterations for adult reproductive function. In the first section of this dissertation, the neurotoxic and endocrine disrupting effects of PCBs on a representative developing neuroendocrine cell model, the GT1-7 GnRH cell line, are investigated in time- and dose-response experiments. Treatment and dose-dependent effects are observed for GnRH peptide concentrations, cell viability, apoptotic and necrotic cell death, and caspase activation. In general, GnRH peptide levels are suppressed by high doses and longer durations of PCBs, and elevated at low doses and shorter time points. The suppression of GnRH peptide levels was partially reversed in cultures co-treated with the estrogen receptor antagonist ICI 182,780. All PCBs tested reduced viability and increased both apoptotic and necrotic cell death. The second section of this dissertation examines whether prenatal PCB exposure alters normal neuroendocrine development in the F1 generation, including sexual differentiation of the brain. Disruption of hypothalamic development is detectable as early as the day after birth (postnatal day (P) 1), as indicated by abnormal programmed cell death, and alterations in neuroendocrine gene and protein expression. The third section discusses the physiological impact of developmental PCB exposure on reproductive maturation and adult neuroendocrine function. Pubertal onset is advanced and estrous cyclicity irregular in PCB endocrine-disrupted females. Furthermore, sexual differentiation of female neuroendocrine systems is masculinized/defeminized. Collectively, these results suggest that the disrupted sexual differentiation of the POA can be detected as early as the day after birth, effects that may underlie the adult reproductive phenotype. / text