Le cancer est une maladie qui touche des millions de personnes et ne discrimine pas. La forme de cancer la plus répandue chez les femmes au Canada est le cancer du sein et la deuxième cause de décès par le cancer chez cette population. Les traitements dépendent de plusieurs facteurs dont le stade du cancer, la ménopause, le statut des récepteurs hormonaux et du récepteur HER2 du cancer, etc. Les traitements qui existent sont la chirurgie suivie par la radio- et/ou chimiothérapie et l’hormonothérapie. Malgré les nombreuses études et les avancées dans les traitements pour différents cancers, plusieurs patients ont des cancers du sein qui sont réfractaires aux traitements disponibles. Une alternative naissante est l’utilisation de virus oncolytiques, c’est-à-dire des virus qui ciblent spécifiquement les cellules cancéreuses et laissent intact les cellules saines. Malheureusement, certains cancers demeurent réfractaires aux traitements avec virus oncolytiques. Ceci nous amène donc à regarder plus en détail des facteurs de l’environnement tumoral qui pourraient prédire la susceptibilité virale et engendrer des résultats positifs. C’est dans cette perspective que nous avons découvert que l'estrogène, précisément l’estradiol, rend les cellules cancéreuses qui en expriment le récepteur plus sensible au virus oncolytique VSV (virus de la stomatite vésiculaire). Cependant, nous ignorons toujours si d’autres hormones peuvent également moduler l’action de VOs. Nous émettons donc l’hypothèse que, comme l’estrogène, d’autres hormones vont affecter l’efficacité des VOs et qu’il serait possible de manipuler ces interactions pour améliorer la réponse au traitement. Notre étude nous permettra de concevoir des stratégies thérapeutiques améliorées pour les patients atteints du cancer du sein. L’importance de cette étude est que jusqu’à présent l’impact des hormones sur l’efficacité des virus oncolytiques reste un sujet inexploré. Nous allons déterminer l’effet de différents niveaux d’hormones sur la réplication et l’effet oncolytique de VSV. Ceci nous donnera ainsi la possibilité et les connaissances d’améliorer la sélection des patients pour le traitement et la conception d’une nouvelle génération de virus oncolytiques perfectionnés. / Cancer is a disease that affects millions of people across the world. The most common cancer in Canadian women is breast cancer and it also represents the second cause of death by cancer in this same group. The treatment depends on multiple factors including the stage of the cancer, menopause status, hormone receptor status, HER2 receptor status, etc. The available treatments for breast cancer are surgery followed by either radiation or chemotherapy as well as endocrine therapy. Despite numerous studies and advances in the treatment of different cancers, many patients’ cancer still remains refractory to these treatments. An exciting new alternative treatment is the use of oncolytic viruses. An oncolytic virus is a virus that can specifically target cancer cells all while leaving healthy normal cells intact. However, many cancers remain refractory to treatment with oncolytic viruses. There was thus a need to investigate different factors or the tumor microenvironment that may predict viral susceptibility and obtain positive outcomes. In this vein, it was found that estrogen (specifically estradiol), a hormone found in the body, can render cancer cells that express its receptor more sensitive to oncolytic virus infection by VSV (vesicular stomatitis virus). In spite of that, we are unaware if there are other hormones capable of modulating the actions of oncolytic viruses. Our hypothesis is that, like estrogen, other hormones will affect the efficacy of oncolytic viruses and that it will be possible to manipulate these interactions with the goal to improve treatment response. Our research will allow the conception of enhanced therapeutic strategies for patients with breast cancer. The importance of this study is that as of now the interplay between hormones and oncolytic viruses remains unexplored. We will determine the effects of hormone levels on viral replication and oncolytic ability of VSV. This knowledge will allow for a greater selection of patients for which oncolytic virus treatment will have a positive outcome. Additionally, it will allow for the development of a new generation of perfected oncolytic virus platforms.

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Historically, physiologists have believed steroid hormones act exclusively within the individual producing them. However, studies in mice have shown that bioactive 17β-estradiol (E2) is excreted in male urine and absorbed by female conspecifics where it binds to estrogen receptors in reproductive other tissues. This can lead to pregnancy disruption and/or cause precocious puberty in female conspecifics. In bats the transfer of tritium-labelled estradiol (3H-E2) from male to females has been shown during the mating season. I investigated the influence of season on 3H-E2 transfer and showed that females housed with 3H-E2 injected males had significantly higher levels of radioactivity in reproductive, neural, and peripheral tissues during reproductively relevant timepoints compared to the non-reproductive season. Because urine has been hypothesized as the vector of steroid hormone transmission in mice, I examined the natural patterns of sex steroids in the urine of male and female big brown bats (Eptesicus fuscus) across the annual reproductive cycle. I found that creatinine-adjusted E2, which corrects for animal hydration and activity, was significantly higher in male than female urine, and in adult compared to yearling urine. Seasonal differences in urinary E2 levels were observed within and between sexes. Finally, I designed a protocol to investigate the attractant properties of body odour and urine between bat sexes during the mating season. Using a two-alternative Y-maze arena, I found that female bats first approach the test arm containing urine of a male conspecific before exploring the arm with female urine. Females also tended to spend more time in the test-arm containing male urine and being in the male test-arm at the conclusion of the 5 min trial. My data supports the hypothesis that E2 has the potential to act as reproductive pheromone with urine as a likely vector. Given the close proximity of individual bats within a maternity roost, steroid hormone transfer between conspecifics quite likely occurs in nature and could have profound influences on female reproductive behaviour (e.g. receptivity) and physiology (e.g. estrus cycling). My research provides new evidence for the potential pheromonal actions of E2 in bats that is consistent with how sex steroids act as pheromones in other mammals. / Dissertation / Doctor of Philosophy (PhD) / Historically, physiologists have believed steroid hormones act exclusively within the individual producing them. However, studies in mice have shown that bioactive 17β-estradiol (E2) is excreted in male urine and absorbed by female conspecifics where it binds to estrogen receptors in reproductive and other tissues. This exogenous E2 can result in changes to female reproductive physiology and behaviour. Our lab has previously observed E2 to transfer between male and female captive big brown bats during the mating season. Research from this thesis provides evidence that the transfer of E2 from male to female bats is highest during times of mating and ovulation/fertilization. I also demonstrate that E2 naturally occurs in the urine of both male and females with age, sex, and seasonal differences in concentration. Lastly, I show that female bats are attracted to the urine of males. My research provides new evidence for the potential pheromonal actions of E2 in bats that is consistent with how sex steroids act as pheromones in other mammals.

Peripubertal immune stress alters adult responsiveness to estradiol (E2) and progesterone (P). When female mice are injected with the bacterial endotoxin lipopolysaccharide (LPS) at six weeks of age, or during pubertal development, they display a decrease in response to ovarian hormones. In contrast, females ovariectomized prior to peripubertal immune stress display typical levels of sexual behavior following sequential injections of E2 and P in adulthood. Additionally, intact females exposed to peripubertal immune stress display a decrease in estrogen receptor alpha (ER-α)-immunoreactive (ir) cells in the medial preoptic area (MPOA) and ventromedial nucleus of the hypothalamus (VMH) in adulthood. However, ER-α has not been studied in mice that have been ovariectomized prior to receiving LPS. The objective of the present study is two-fold: to replicate the finding that ovariectomy prior to pubertal development prevents the deleterious effects of LPS administration, and to examine the status of ER-α in areas of the brain important to sex behavior. We predicted that mice ovariectomized after LPS injection would display fewer ER-α-ir cells and a decreased responsiveness to ovarian hormones than saline controls and those mice ovariectomized prior to LPS injection. To test this, female mice were ovariectomized or sham-operated prior to LPS treatment. Then, at six weeks of age, all mice were injected with saline or LPS. Following that, sham-operated mice were ovariectomized and ovariectomized mice were sham-operated. Mice were primed weekly with E2 and P, and sex behavior testing occurred once a week for 5 weeks. After the final behavior test, all mice were euthanized, their brains removed, and stained for ER-α via immunocytochemistry. Results revealed a large variability in hormone responsiveness. However, animals that received peripubertal LPS, but still had their ovaries, had significantly lower sexual receptivity when compared to animals that were ovariectomized prior to the pubertal period and given LPS. Further, there were no differences between groups in ER-α-ir numbers. External environmental stressors, such as animal housing and vibrations and noise from nearby construction, may have caused some of the results found here, which are inconsistent with previous findings.

To gain a better understanding of the role of steroid hormones in vertebrate reproduction, we quantified steroid hormone concentrations in a free ranging population of the Northern Pacific rattlesnake, Crotalus oreganus. Plasma steroid hormone concentrations were quantified for both male and female snakes throughout the active season (Mar-Oct). We measured testosterone (T), 5α-dihydrotestosterone (DHT), and corticosterone (B) concentrations in male and female snakes. 17β-estradiol (E2) and progesterone (P) were measured in females only. We also observed breeding behaviors (e.g. consortship, courtship, and copulation) in the field and measured testis and follicle size in male and female snakes from museum collections. Our results indicate that C. oreganus in central California utilizes a bimodal pattern of breeding, with mating and agonistic behavior occurring in the spring and the late summer/fall. Each breeding season corresponds with elevated or highly variable androgen (T and DHT) levels. Several female snakes had high E2 concentrations in the spring and fall, coincident with vitellogenesis and mating. Females with high E2 concentrations also had high T and DHT concentrations. Corticosterone concentrations in males are not related to either time of year or concentrations of any other hormones quantified. This suggests that the breeding season in this population may not demand a significant increase in energy mobilization by glucocorticoids. Measurements of testis volume show that testes are regressed in the spring when the majority of breeding was observed in this population and reach peak volume in August and September during spermatogenesis. Multiple regression analyses revealed that in female snakes, P is positively correlated with T and DHT, and E2 is correlated with T. Since these results are strictly descriptive, experimental studies are needed to identify the functional significance of these results.

The effects of energy balance on hormonal patterns and recovered oocytes were evaluated in 20 lactating Holstein cows during two trial periods (fall/spring). Cows were randomly selected and assigned to one of two dietary treatments formulated so that cows consumed 3.6% BW (HE- 1.78 mcal/kg; n=6 in fall, n=5 in spring) and 3.2% BW (LE-1.52 mcal/kg; n= 5 in fall, n=4 in spring). Body weight and body condition score (BCS) were recorded prior to parturition and weekly throughout the fall trial. Ultrasound guided transvaginal follicular aspirations were conducted twice weekly between d 30 and 100 of lactation. Follicle size and number were recorded. Follicular fluid (FF) was aspirated from the largest follicle, and serum samples were collected for hormone assay (IGF-1; estradiol (E2); progesterone (P4, serum ); LH and FSH). Oocytes were collected and graded based upon cumulus density and ooplasm homogeneity, then fertilized and cultured in vitro. Milk yield averaged 41.64 ± .3 kg/d (mean ± SE) for HE and 32.8 ± .3 kg/d for LE. There was a significant cubic day postpartum by treatment interaction for milk yield. Dry matter intake and BW treatment by week interactions were significant for the cubic and linear components, respectively. Oocyte numbers increased linearly from d 30 to 100 postpartum. HE cows produced more good + oocytes (1.5 ± .2 ) than LE cows (1.4 ± .1). Follicles less than or equal to 5 mm predominated throughout the study (6.4 ± 3.0). However, greater numbers of follicles 10 to 14 mm and greater than or equal to 15 mm were found in the fall (1.98 ± .08 and .50 ± .06) than spring (1.11 ± .3 and .23 ± .07). Follicular fluid IGF-1 was higher in HE (2.3 ± .2 ng/ml) than in LE cows (1.6 ± .2 ng/ml). Mean basal serum FSH concentration was lower at 28 d postpartum (173 ± 8 pg/ml) compared to later (521 ± 25 at d 60 and 650 ± 25 pg/ml at d 110). Serum P4 peaked at 35 d postpartum, with HE cows having 1 ng/ml higher P4 than LE cows. Low dietary energy reduced milk yield, DMI, BCS, FF IGF-1 and serum P4 and had a negative impact on oocyte quality. / Master of Science

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