Thèse de doctorat : Sciences de la vie et de la santé : Tours : 2008. / Titre provenant de l'écran-titre.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 91-106).

Migraine headache is one of the most common neurological disorders. While the mechanisms contributing to migraine pathophysiology have yet to be fully elucidated, the disproportionate number of post-pubescent, pre-menopausal women affected suggests a central role for female hormones, such as estrogen. The mechanism(s), however, by which estrogen contributes to migraine have yet to be deciphered. Cortical spreading depression (CSD) is associated with "Classic Migraine", now referred to as migraine with aura. Here we use a well-established animal model for migraine with aura to test the putative role of estrogen in the development of CSDs in awake and freely moving female rats. Beta estradiol administration in ovariectomized female rats resulted in a significant increase in CSD episodes over a 12-hour recording period. Additionally, beta estradiol administration in these rats promoted migraine-associated behavior, significantly reducing exploratory behavior (i.e., number of vertical rearing episodes) when compared to vehicle-treated controls. Critically, the increase in CSD episodes was completely abolished with pre-administration of ICI 182,780 a pure alpha and beta estrogen receptor antagonist. ICI 182,780administration also blocked beta estradiol-induced migraine-associated behaviors, restoring vertical rearing episodes to baseline levels. These data illustrate that an increase in estrogen levels in an animal that no longer produces estrogen (postmenopausal characteristic) can promote the development of CSDs. These data suggest that an estrogen receptor-mediated mechanism may drive episodes of migraine with aura and highlight the need for further investigation into estrogen's role in migraine.

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.

We investigated possible sex differences in PRL secretory patterns and regulation by E$ sb2$ in gonadectomized Dorset x Leicester x Suffolk sheep kept under natural photoperiod (latitude 45$ sp circ 31 sp prime$). Patterns were assessed over 14 months in groups of 10 rams and ewes, half of which received E$ sb2$ replacement (Silastic implants) at the time of gonadectomy to maintain blood E$ sb2$ at ram breeding-season values. Mean monthly PRL level (based on two 3-h periods of blood sampling) was consistently elevated by E$ sb2$ in the ram (mean 19%), and during all but a few months in the spring and summer in the ewes (mean 90%). Sex differences in the mean PRL were most apparent for the E$ sb2$-treated sheep in August (rams 280 $ pm$ 54 ng/ml vs ewes 128 $ pm$ 18 ng/ml) and for the control sheep in November (rams 19 $ pm$ 5 ng/ml vs ewes 10 $ pm$ 2 ng/ml). Episodic PRL secretion (with 5-min sampling for 4 h) was assessed in every season. In all four groups, pulse amplitude and frequency and basal level were higher in summer than winter. E$ sb2$ treatment was associated with larger PRL pulses in both sexes in every season but summer, and with decreased (from 8.2 to 4.6 per 4 h) and increased (from 2.2 to 6.6 per 4 h) frequencies of pulses in rams in the spring and summer, respectively. The PRL response to TRH (two iv injections 50 ng/kg BW given 80 min apart) was also assessed in every season. Mean 40-min increases after injection were highest in spring and summer. E$ sb2$ treatment produced in both sexes a 2-3 fold larger increment 1 in every season, and increment 2 in specific seasons. Preinjection and increment values were positively correlated within animals of each group across seasons (r = 0.89 and 0.65). The Incr 2/lncr 1 ratio (mean 0.76 $ pm$ 0.10) was not affected by seasons or E$ sb2$, and did not denote a self priming effect of TRH. Diurnal patterns indicated that PRL mean levels during light and dark phases were not different from each other within

During the nonbreeding season (July), three groups of five Dorset x Leicester x Suffolk rams were assessed over a period of 5 days. One group of rams (control) was implanted (sc) with five 5cm empty Silastic capsules (i.d. 3.4mm, o.d. 4.6mm); two other groups, designated as Low-E$ sb2$ and High-E$ sb2$, received five estradiol filled capsules of either 5cm or 10cm, respectively for 4 days. Estradiol treatment elevated serum estradiol concentration about 150% in the Low-E$ sb2$ groups (15.7 $ pm$ 1.3 pg/ml) and 300% in the High-E$ sb2$ groups (26.6 $ pm$ 2.4 pg/ml) compared with controls (6.3 $ pm$ 0.8 pg/ml). In the absence of LH pulsing, mean LH, FSH and testosterone concentrations were all decreased significantly (P $<$.05) with increasing estradiol concentration, while PRL concentration was increased (P $<$.05) by as much as 105%. In the LH-pulsed groups, LH-peak height on day 4 was comparable for all three groups of rams and peak frequency was, as expected, consistently increased to 4 peaks per 6 hours. The increase in mean testosterone concentration (P $<$.05) in all three groups was due to an increase in testosterone baseline concentration and testosterone peak frequency.

Environmental xenoestrogens (EEs) are chemicals that when they enter the body, the body responds to them as it would to endogenous estrogens. Humans are exposed to these chemicals on a daily basis via natural components, additives and contaminants in food and water, through the use of pharmaceuticals and personal care products such as sunscreens, lotions and toothpaste. Exposure to EEs is thought to result in adverse effects on humans such as decreased fertility, increased susceptibility to hormone-sensitive cancers, deformities of the male genitalia and precocious puberty in females. The critical window of exposure is thought to be early fetal development, when tissues are rapidly differentiating under the control of endogenous estrogens. However, there is limited data in the literature on human fetal exposure to EEs. The first objective of this study was to assess human fetal exposure to a suite of 35 EEs by analysis of paired samples of amniotic fluid and maternal urine were collected from 32 New Zealand women between 14 and 20 weeks gestation. The analytical chemistry methods required for this study were developed and validated. The results demonstrate that fetal exposure is highly correlated with maternal exposure. This study is the first to report maternal urine levels of two UV filters and amniotic fluid levels of parabens, UV filters and triclosan. A model based on simple additivity of effect was developed that combined the measured concentrations with literature data on relative estrogenic potency to assess the magnitude of the estrogen signal that may be attributed to the EEs. This model suggests that the fetus may experience an estrogen signal due to the measured EEs that could be as large as the endogenous estrogen signal. A second objective was to use computational docking to study the interactions of the EEs with the human estrogen receptor (hER) protein. The docking studies show that the rigid endogenous ligand, 17β-estradiol (E2) interacts with the hER to produce a single, well-defined complex with the receptor and the flexible EEs produce multiple, distinct energy-equivalent complexes. EEs are not able to interact with the binding cavity to stabilise the rigid hER-E2-like topology of the complex. As a result, the hER-EE complexes can be thought of as more pliable or ‘floppy’ and thus able to respond to the cell context in multiple ways, leading to variations in gene expression in different target tissues. These multiple pathways may explain the range of physiological responses attributed to exposure that depend on the timing of exposure and the sex of the individual exposed.

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.

Thesis (M. Phil.)--University of Hong Kong, 2008. / Includes bibliographical references (leaves 74-93) Also available in print.

Thesis (Ph. D.)--Florida State University, 2004. / Advisor: Dr. Zuoxin Wang, Florida State University, College of Arts and Sciences, Dept. of Psychology. Title and description from dissertation home page (viewed Sept. 22, 2004). Includes bibliographical references.