Orientador: Francisco Eduardo Martinez / Resumo: Introdução: O alcoolismo é doença relacionada a fatores hereditários. Seu consumo pode prejudicar à saúde reprodutiva do consumidor. Alterações observadas na prole pelo consumo parental ascendem os mecanismos epigenéticos, contudo, ainda são limitadas as investigações da ingestão precoce e a influência na vida adulta. Nós avaliamos se os parâmetros reprodutivos de ratos predispostos ao consumo e expostos ao etanol diferem de ratos não predispostos, com resposta dose-dependente, se o consumo é proporcional entre os sexos e se consumo parental pós-púbere interfere no desenvolvimento da prole não exposta. Material e métodos: Ratos das variedades Wistar e Wistar UCh (consumidores voluntários de etanol) foram divididos em: Controle - Wistar (C), pouco bebedor - UChA (A), bebedor - UChB (B) e sem etanol - UChB não exposto (SE). Os ratos A e B foram expostos ao etanol (10%) dos 65 aos 80 dias. Os UChA ingerem entre 0,1 a 1,9 g etanol/kg/dia e os UChB mais que 2 g etanol/kg/dia. Os casais C, A, B e SE foram acasalados aos 100 dias. O estudo foi conduzido em duas fases: 1ª) análise dos efeitos da predisposição genética e da dose alcoólica na reprodução, constituída por C, A e B. O consumo de etanol, a massa corpórea, o tamanho da ninhada, a proporção sexual, os parâmetros gestacionais, os órgãos reprodutivos e a morfologia espermática foram verificados; 2ª) análise dos efeitos do consumo alcoólico parental pós-púbere na prole não exposta, sendo os ratos UChB divididos em: grupo parent... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background: Alcoholism is characterized as a disease to hereditary factors. The consumption can impairs the consumer reproductive health. Changes in offspring due to parental consumption highlights epigenetic mechanism, however, investigations of early consumption and the influence on reproductive parameters in adulthood are limited. We evaluated the reproducers parameters of rats predisposed to low and high consumption and exposed to post-puberty ethanol differs from non-predisposed rats, with the dose-dependent response, if alcohol consumption is proportional between sexes and if high consumption parental impairs the development somatic and reproductive function on unexposed offspring. Material and methods: Rats Wistar and Wistar UCh (voluntary consumers) were distributed in Control - Wistar (C), low drinker - UChA (A), drinker - UChB (B) and no exposed to ethanol- unexposed UChB (SE). The A and B were exposed to 10% ethanol from 65 to 80 days of age. The UChA drink between 0.1 and 1.9 g ethanol/kg/day and the UChB more than 2 g ethanol/kg/day. The animals C, A, B, and SE were mated on 100 days. This study was conducted in two phases: 1st: analyzed of the effects of genetic predisposition and alcoholic dose on reproduction, in C, A, and B. Ethanol consumption, body weight, litter size, sex ratio of offspring, gestational parameters, reproductive organs, and sperm morphology were observed. 2nd: analyzed the effects of parental alcohol consumption on unexposed offspring. For ... (Complete abstract click electronic access below) / Mestre

Puberty is a critical period of development characterized by rapid physiological changes and significant brain reorganizing and remodeling. These rapid changes render the developing brain particularly vulnerable to stress and immune challenge. In mice, exposure to an immune challenge (lipopolysaccharide; LPS) during puberty causes enduring effects on stress reactivity, cognitive functioning, and depression- and anxiety-like behaviors later in life. However, the mechanisms underlying these effects are unknown. The gut microbiome can profoundly influence the immune system. There is also close bidirectional communication between the gut microbiome and the central nervous system (CNS) through neural, endocrine and immune signaling pathways, which can alter brain chemistry and emotional behaviour. Thus, we hypothesized that altering microbial composition during puberty could mitigate acute immune responses and prevent enduring outcomes later in life. The current thesis examined the effect of gut manipulation with probiotics during puberty on LPS-induced immune responses and enduring anxiety- and depression-like behaviours, and stress-reactivity in adulthood, in male and female CD1 mice (Article 1). Next, we examined age and sex differences in gut microbial composition before and after exposure to an immune challenge. We also examined the effects of consuming a single strain probiotic bacterium (Lactobacillus Reuteri) during puberty on the immune response and the long-term changes in memory, anxiety-like behavior, and stress reactivity in adulthood (Article 2). Lastly, we examined how microbial colonization between pubertal and adult mice can alter acute peripheral and central inflammatory responses to LPS (Article 3). The current dissertation has addressed sex-specific vulnerabilities to an immune challenge during pubertal development and the moderating influence of the gut microbiome. These studies have demonstrated that manipulating the gut microbiome during puberty can mitigate acute immune responses and prevent enduring neurobehavioural outcomes later in life.

Die vorliegende Arbeit liefert Auswertungen aktueller Pubertätsdaten und neue Erkenntnisse zum Einfluss des SES auf die Pubertät. Wir konnten zeigen, dass ein niedriger SES vor allem bei übergewichtigen/adipösen Mädchen mit einer früheren und länger andauernden Pubertät assoziiert ist. Im Diskurs über soziale Ungleichheiten und den damit einhergehenden Gesundheitsrisiken betont die vorliegende Arbeit die Wichtigkeit, die Chancengleichheit von Kindern und Jugendlichen zu verbessern.:I Abkürzungsverzeichnis 4 1 Einleitung 5 1.1 Hintergrund 5 1.2 Die Pubertät: Weg zur reproduktiven Reife 6 1.2.1 Physiologie der Pubertätsentwicklung 6 1.2.2 Methodik zur Erfassung der Pubertätsparameter 8 1.3 Früher Pubertätsbeginn: Trends, Risiken und Einflussfaktoren 8 1.3.1 Einfluss des BMI auf den Pubertätsbeginn 9 1.3.2 Sozialer Status und Pubertätsentwicklung 10 1.3.2.1 Sozialstatus und Gesundheit 10 1.3.2.2 Sozialstatus und frühe Pubertät 11 1.3.2.3 Methodik zur Erfassung des sozialen Status 14 1.4 Rückschlüsse zur Vorgehensweise 14 1.4.1 Fragestellungen/Ziele 14 1.4.2 Studiendesign 15 2 Publikationsmanuskript 16 3 Zusammenfassung der Arbeit 26 4 References 29 II Anhang 41 III Darstellung des eigenen Beitrags 42 IV Erklärung über die eigenständige Abfassung der Arbeit 43 VI Publikation 44 VII Danksagung 45

An extensive literature has linked off-time pubertal maturation to adverse health outcomes among adults. Childhood adversities are also linked to both pubertal development and cardiometabolic disease. Despite the racial and ethnic disparities in pubertal timing and cardiometabolic health in midlife, few studies have investigated if off-time pubertal maturation is associated with Latino individuals' metabolic syndrome. Furthermore, there exists limited data assessing early life risk factors affecting the association between timing of pubertal maturation and metabolic syndrome by sex and in young adults. This dissertation used a life course perspective to test developmental hypotheses of stress on reproductive strategies and cardiometabolic health to address these limitations. The three primary aims of this dissertation research were to 1) estimate the association between family dysfunction and timing of pubertal maturation in Latino boys and girls, 2) systematically review the impact of the timing of pubertal maturation on metabolic syndrome in young adults age 18-40 years, and 3) estimate the association between timing of pubertal maturation and metabolic syndrome in young adult Latino men and women. The analytic aims were explored using data from two population-based cohorts that include different age groups: the Hispanic Community Health Study/Study of Latinos (HCSH/SOL) Youth Ancillary Study (cross-sectional design) (8-16 years), and the Boricua Youth Study Health Assessment Ancillary Study (prospective design) (5-10 years and 18-23 years). The first empirical study, using HCHS/SOL Youth data, found that the presence of family dysfunction may be associated with delayed pubertal maturation in Latino children and adolescents. The systematic review highlighted the lack of diversity by sex, measurements, and racial/ethnic representation in this area of research, but also suggested that childhood BMI may account for much of the association between pubertal timing and metabolic syndrome. The second empirical study, based on the BYS HA study, did not find meaningful associations between timing of pubertal maturation and metabolic syndrome and cardiometabolic traits in young adults. These results do not support the prevailing hypotheses nor quantitative evidence linking off-time pubertal maturation to poorer cardiometabolic health. Overall, this dissertation utilized a life course perspective to advance understanding and support of the origins of adulthood cardiovascular risk that may begin in childhood. Future investigations should be designed to be longitudinal and include measures characterizing childhood body size, health behaviors, and environmental exposures. Future studies should also explore the specific mechanisms explaining the observed associations, particularly the complex interaction between hormonal and metabolic factors that appear to affect adult health among individuals with off-time pubertal maturation adversely.

Exposure to certain stressors during a sensitive period around puberty can lead to enduring effects on an animal’s response to estradiol. In estradiol-influenced behaviors, such as sexual receptivity, hippocampal-dependent learning and memory, depression-like behavior, and anxiety-like behaviors, exposure to a peripubertal stressor such as shipping stress or an injection of lipopolysaccharide (LPS) can eliminate or even reverse the normal response to estradiol. In addition to regulating these behaviors, estradiol play a role in the regulation of body weight. While some of the previous studies touched on short-term effects on body weight, no systemic long-term study of the effects of a peripubertal stressor on body weight, particularly without interruption by ovariectomy, have been undertaken. This paper introduces a hypothesis that proposes that increased adiposity following exposure to a peripubertal stressor leads to the changes to estrogen-dependent behaviors through altered levels of estrogens and changes to estrogen receptors. The first chapter examines body weight data collected during studies with other aims, and then proposes an experiment to test whether either of two peripubertal stressors results in increased weight gain and body weight. The following chapter proposes further experiments designed to determine the proximate mechanisms leading to weight gain following peripubertal stressors and the role of diet on weight gain. The final chapter proposes experiments to test the effects of adiposity on peripheral levels of testosterone, aromatase, estradiol, and estrone; central levels of estradiol and estrone; and estrogen receptors in the brain.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20613号 / 医博第4262号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 修, 教授 篠原 隆司, 教授 近藤 玄 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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.

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