The anabolic androgenic steroids (AAS) came from testosterone, with restricted use in medicine in some specific clinical conditions, and when correctly administrated are well tolerated. However, there is a potential risk to health the use of AAS without medical prescription and above the recommended dose, becoming evident the collateral effects. The risk of adverse cardiovascular effects increasing is a main concerning. The abusive use of anabolic androgenic steroids (AAS) is associated with left ventricular hypertrophy. The decanoate of nandrolone (nandrolone) is one of the most used AAS in the world. The regression of left ventricular hypertrophy is a point of interest because of the possible reduction of bad prognostic that it causes to the individual. Beta-blockers can revert the variations associated to ventricular remodeling and can show the progressive deterioration benefits from ventricular dysfunction. In this study was evaluated the effects of metoprolol on histomorphological profile of heart induced by AAS in rats. Four groups, each with 10 rats, were studied: 1) Control Group (C): rats that received twice a week injections of olive oil during five weeks as a control group (1 ml intramuscular);2) Nandrolone Group (N): rats that received twice a week injections of nandrolone during five weeks (15 mg/kg weight, intramuscular); 3) Metoprolol Group (M): rats that received twice a week injections of olive oil (1 ml intramuscular) during five weeks and daily injections of metoprolol (4 mg/kg weight, intraperitonial) during five weeks and 4) Nandrolone-Metoprolol Group (NM): rats that received twice a week injections of nandrolone (15 mg/kg weight, intramuscular) during five weeks and daily injections of metoprolol (4 mg/kg weight, intraperitonial) during five weeks. The animals were weighed to control body weight and heart beat frequency. The heart weight/animal weight ratio was quantified. The evaluation of ventricular remodelling was obtained through histological processing and morphological analyses, measuring miocytes diameter using HL Image 97. These microphotographies allowed the transversal diameter measurement of, at least, five ventricular fibers, with a total of 125 fibers measured by animal. The diameter of each fiber, in micrometers, was obtained in the HL Image 97 program. It was verified that the animals from Nandrolone (N) group showed a significant increasing of the ventricular fiber diameter compared with control group (C). In the association of nandrolone and metoprolol (NM) the diameter was 50 % lower than the group that received only nandrolone (N). The nandrolone decanoate promotes ventricular remodeling characterized by the increasing of myocardiocytes transversal diameter and the metoprolol associated with this nandrolone causes cardioprotective and repairing effect, decreasing the induced myocardium hypertrophy / Os esteróides anabólico-androgênicos (EAA) são derivados da testosterona, de uso exclusivo na medicina para certas condições clínicas e, quando administrados corretamente, são em geral bem tolerados. Porém existe risco potencial à saúde quando o uso dos EAA ocorre sem vigilância médica, sem indicação clínica adequada e são empregadas doses acima das recomendadas, tornando-se prováveis os efeitos colaterais indesejados. Especialmente preocupante é o aumento do risco de efeitos adversos cardiovasculares. O uso abusivo de esteróides anabolizantes está associado ao aparecimento de hipertrofia ventricular esquerda (HVE). O decanoato de nandrolona (NAN) é um dos EAA mais utilizados no mundo. O tratamento visando a regressão da HVE vem se tornando, nos últimos tempos, um foco de interesse, principalmente pela possível redução do mau prognóstico que ela traz. Os bloqueadores beta-adrenérgicos podem reverter às alterações associadas a este tipo de remodelamento e evidenciam seus benefícios na inibição da deterioração progressiva da disfunção ventricular. Neste estudo, avaliamos os efeitos do metoprolol sobre as alterações histomorfológicas do coração produzidas pelo NAN. Foram estudados quatro grupos de ratos com 10 animais em cada um deles e assim identificados: 1) Grupo Controle (C): ratos que receberam injeção duas vezes por semana de óleo de oliva por cinco semanas como grupo controle (1ml, via intramuscular); 2) Grupo Nandrolona (N): ratos que receberam injeção duas vezes por semana de NAN por cinco semanas (15mg/kg de peso, intramuscular); 3) Grupo Metoprolol (M): ratos que receberam injeção, duas vezes por semana, de óleo de oliva, por cinco semanas (1ml, intramuscular) e injeção diária de metoprolol por cinco semanas (4mg/kg de peso, intra peritoneal) e 4) Grupo Nandrolona-Metoprolol (NM): ratos que receberam injeção, duas vezes por semana, de NAN, por cinco semanas (15mg/kg de peso, intramuscular) e injeção diária de metoprolol por cinco semanas (4mg/kg de peso, intra peritoneal). Os animais foram controlados quanto ao peso e à frequência cardíaca. A relação entre o peso cardíaco e o peso corporal também foram quantificados. A avaliação do remodelamento ventricular foi obtida por processamento histológico e análises morfométricas, medindo-se o diâmetro dos miócitos usando o software HL Image. Por meio da análise de imagem computacional foram mensurados o diâmetro de 125 fibras musculares ventriculares de cada animal. Verificou-se que os animais do grupo Nandrolona(N) apresentavam aumento significante do diâmetro das fibras musculares ventriculares em relação ao grupo controle (C). Na associação da nandrolona com o metoprolol (N-M) o diâmetro foi 50% menor em relação ao grupo que recebeu somente nandrolona (N). O decanoato de nandrolona causa remodelamento ventricular caracterizado por aumento do diâmetro transversal dos cardiomiócitos e o metoprolol, associado a este anabolizante, exerce efeito modulador neste processo reduzindo a HVE induzida. / Mestre em Ciências da Saúde

Os esteroides anabolizantes androgênicos (EAA) como o decanoato de nandrolona (ND) são hormônios sintéticos derivados da testosterona. Sabe-se que um dos efeitos mais marcantes da administração abusiva destes esteroides é o aumento do comportamento agressivo. Evidências indicam que altas doses de EAA alteram a morfologia e causam hiperativação de sinapses glutamatérgicas, o que se correlaciona com um fenótipo agressivo exacerbado. Fisiologicamente o glutamato é considerado o principal neurotransmissor excitatório no cérebro de mamíferos, entretanto, em níveis elevados, pode causar hiperexcitabilidade neuronal mediada pelos receptores glutamatérgicos ionotrópicos do tipo N-metil-d-aspartato (NMDAr) e, consequentemente alterações no metabolismo mitocondrial. A terminação da sinalização excitatória glutamatérgica é realizada majoritariamente por transportadores existentes em astrócitos. Neste sentido, o transportador astrocitário de glutamato GLT-1 é responsável por mais de 90% da remoção do glutamato da fenda sináptica, contribuindo significativamente, para a manutenção da homeostasis da sinalizacão glutamatérgica. A administração do antibiótico β-lactâmico ceftriaxona (CEF) aumenta a expressão de GLT-1 e diminui a hiperexcitabilidade glutamatérgica, o que poderia potencialmente contrapor mecanismos cerebrais associados ao aumento do fenótipo agressivo induzidos pelo decanoato de nandrolona (ND). Entretanto, estas possíveis interacões moleculares e comportamentais ainda não foram exploradas. Assim, o objetivo primário deste trabalho foi investigar se o aumento da expressão do transportador astrocitário GLT-1 modula mecanismos glutamatérgicos envolvidos na agressividade induzida pelo ND, e a atividade mitocondrial. Para tanto, camundongos CF-1 machos de 60 dias de idade foram divididos em 4 grupos: veículo oleoso (VEH), nandrolona (ND), ceftriaxona (CEF) e nandrolona+ceftriaxona (ND/CEF). A nandrolona foi injetada por via subcutânea (15mg/Kg) por 19 dias. A ceftriaxona (200mg/Kg) ou solução salina foram administradas intraperitonealmente por 5 dias. Após a última injeção foi avaliada a latência para o primeiro ataque e o número de ataques no teste do intruso. Os animais foram sacrificados logo após o teste, e homogeneizados de córtex foram utilizados para imunoquantificação do GLT-1 e da fosforilação da subunidade pNR2Bser1232 do NMDAr. A atividade mitocondrial foi avaliada em sinaptossoma de cérebro total. Os níveis de glutamato foram medidos no líquido cefalorraquidiano. Comparado com o veículo, o tratamento com ND diminuiu significativamente a expressão do GLT-1, aumentou os níveis de glutamato e a expressão da subnidade pNR2Bser1232 o que foi mecanisticamente associado ao aumento do fenótipo agressivo; diminuicão da latência e aumento do número de ataques ao intruso. Ainda, a ND diminuiu o controle respiratório mitocondrial. A administração de CEF aumentou significativamente a expressão do GLT-1 e diminuiu os níveis de glutamato em relação ao grupo ND, enquanto que os níveis de pNR2Bser1232 e a agressividade foram similar ao grupo controle. No grupo ND/CEF o immunoconteúdo de GLT-1 e de pNR2Bser1232, os níveis de glutamato e o fenótipo agressivo, foram significativamente menores que no grupo ND, e similares ao grupo controle. Ainda, a CEF foi capaz de atenuar o prejuízo no controle respiratório mitocondrial causado pela ND. Nossos resultados demonstram que a interação bidirecional entre o transportador astrocitário GLT-1 e a subunidade pNR2Bser1232 neuronal mediada pelo glutamato, exercem um impacto regulatório no fenótipo agressivo induzido pela ND, e no controle respiratório mitocondrial. Desta maneira, este modelo reforça a importância da homeostasia funcional da sinapse tripartide glutamatérgica no fenótipo agressivo. / Anabolic androgenic steroids (AAS) such as nandrolone decanoate (ND) are synthetic hormones derived from testosterone. It is known that one of the most important adverse effects of abusive administration of these steroids is the increase in aggressive behavior. Evidence indicates that high doses of AAS alter morphology and cause hyperactivation of glutamatergic synapses which correlates with an aggressive exacerbated phenotype. Physiologically, glutamate is considered the main excitatory neurotransmitter in the mammalian brain. At high glutamate levels, occurs neuronal hyperexcitability mainly trhough the ionotropic N-methyl-d-aspartate (NMDAr) type of glutamatergic receptors and, consequently, changes in mitochondrial metabolism. Existing transporters in astrocytes predominantly perform the termination of glutamatergic excitatory signaling. In this sense, the GLT-1 glutamate astrocytic transporter is responsible for more than 90% of glutamate removal from the synaptic cleft, contributing significantly to the maintenance of glutamatergic signaling homeostasis. Administration of the β-lactam antibiotic ceftriaxone (CEF) increases GLT-1 expression and decreases glutamatergic hyperexcitability, which could potentially counteract brain mechanisms associated to increased aggressive phenotype mediated by nandrolone decanoate (ND). However, a possible molecular and behavioral interaction has not yet been explored in context. Thus, the primary objective of this work was to investigate whether increased expression of the GLT-1 astrocyte transporter modulates the glutamatergic mechanisms involved in ND-induced aggressive phenotype, and mitochondrial activity. Sixty-day-old male CF-1 mice were divided into 4 groups: oil vehicle (VEH), nandrolone (ND), ceftriaxone (CEF) and nandrolone + ceftriaxone (ND / CEF). Nandrolone was injected subcutaneously (15mg / kg) for 19 days. Ceftriaxone (200mg / kg) or saline solution were administered intraperitoneally for 5 days. After the last injection, the latency for the first attack and the number of attacks on the intruder test were evaluated. The animals were sacrificed after the test, and homogeinized cortex were used for immunoquantification of GLT-1 and phosphorylation of the NMDAr pNR2Bser1232 subunit. Mitochondrial activity was evaluated in total brain sinaptossomes. Glutamate levels were measured in the cerebrospinal fluid. Compared to the vehicle group, treatment with ND significantly decreased the expression of GLT-1, increased glutamate levels and expression of the pNR2Bser1232 which was mechanistically associated with an increase in the aggressive phenotype; decrease in the latency and increase in the number of attacks. Also, ND decreased mitochondrial respiratory control. Administration of CEF significantly increased GLT-1 expression and decreased glutamate levels relative to the ND group, whereas pNR2Bser1232 levels and aggressive phenotype were similar to the control group. In the ND / CEF group the expression of GLT-1 and pNR2Bser1232, glutamate levels and aggressive phenotype were significantly lower than in the ND group, and similar to the control group. Furthermore, CEF was able to attenuate the alteration in the mitochondrial respiratory control caused by ND. Our results demonstrated that the levels of glutamate astrocytic transporter GLT-1 and pNR2Bser1232 are important mechanism behind the increased aggressive phenotype induced by ND, and decreased mitochondrial respiratory control. Also, this model reinforces the importance of glutamate levels and astrocytic molecular targets in the regulation of the aggressive phenotype.

Desde a primeira síntese, isolamento e caracterização dos andrógenos, particularmente da testosterona em 1935, diversos homólogos sintéticos foram desenvolvidos com os objetivos de prolongar a atividade biológica, desenvolver administração parenteral e diminuir a atividade androgênica, classe denominada de esteróides anabólicos-andrógenos (EAA). Desde 1940, os EAA são utilizados na clínica para diversos tipos de doenças, destacando-se o hipogonadismo masculino e em terapias para promoção de crescimento. Também são amplamente utilizados para fins estéticos, principalmente para manutenção e promoção do ganho de massa magra corpórea. Devido ao grande aumento do consumo destes fármacos, tanto para fins esportivos como estéticos, há uma necessidade de investigar efeitos comportamentais relacionados ao seu uso exacerbado. Milhares de pessoas se auto-administram EAA em superdoses, o que gera um problema de saúde pública. Os Resultados do presente trabalho demonstram que o uso crônico dos EAA aumento do comportamento de agressivo, e sutil prejuízo da memória espacial e memória aversiva de curta duração, e na atividade exploratória em camundongos machos da linhagem CF1. Os Resultados metabólicos demonstraram que o tratamento crônico com decanoato de nandrolona (DN) não afeta a função hepática e renal, não altera a homeostasia da glicose e nem o peso corporal, mas diminui os níveis séricos de colesterol total, HDL e triglicerídeos. Os resultados neuroquímicos apontam para uma ruptura da homeostase glutamatérgica, através da alteração da captação de glutamato e do imunoconteúdo do transportador GLT 1. Em conclusão, o uso crônico com altas doses de DN causa o aumento do comportamento agressivo e diminuição na memória aversiva de curta duração. O desequilíbrio da função glutamatérgica evidenciado pela diminuição da captação de glutamato no córtex e hipocampo e do transportador GLT-1- pode ser um dos mecanismos neuroquímicos envolvidos nas alterações comportamentais induzidas pelo tratamento com o DN. / Since the first synthesis, isolation and characterization of androgens, particularly testosterone in 1935, several synthetic counterparts were developed with the objective of prolonging the biological activity, parenteral administration and decrease the androgen activity, called the class of anabolic-androgenic (AAS). Since 1940, AAS are used in the clinic for several types of diseases, especially in male hypogonadism and therapies to promote growth. Additionally, they are widely used for esthetic purposes, mainly for maintenance and promotion of lean body mass gain. Due to the large increase in consumption of these drugs, both for aesthetic purposes and sports, the investigation of behavioral effects related to its overuse is imperative. Thousands of people self-administer AAS in overdoses, a fact that creates a public health problem. The results of this study demonstrate that chronic administration of AAS cause an increase in aggressive behavior, and subtle impairment of spatial memory and short-term aversive memory in male mice strain CF1. The metabolic results showed that chronic treatment with Nandrolone Decanoate (DN) neither affect hepatic and kidney function, nor glucose homeostasis and body weight but decreased serum levels of total cholesterol, HDL and triglycerides. The neurochemical results suggest a disruption of glutamatergic homeostasis through changes in glutamate uptake and GLT1 immunocontent. In conclusion, the chronic use at high doses of DN causes increase of aggressive behavior impairs short-term avoidance memory. The imbalance of glutamatergic function evidenced by the decreased glutamate uptake in cortex and hippocampus as well as decreased immunocontent of GLT-1 may participate in the mechanisms underlying behavioral changes induced by chronic treatment with DN.

L’impact de l’utilisation des agropesticides sur la fonction de reproduction mâle est évalué chez des agriculteurs de Djutitsa (Ouest Cameroun). Le pesticide le plus utilisé par ces agriculteurs est testé in vivo sur la fonction de reproduction du rat mâle, ex vivo et/ou in vitro sur la stéroïdogenèse Leydigienne afin d’évaluer son implication dans les déséquilibres observés chez les agriculteurs. Ensuite, l’effet protecteur des extraits de Carpolobia alba et Basella alba contre les effets délétères dudit pesticide est évalué in vivo chez des rats mâles, ainsi que leur influence sur la production de la protéine de transport des stéroïdes (SHBG) par les cellules HepG2. Les résultats montrent que les agriculteurs utilisent 25 agropesticides et présentent des symptômes liés à une protection inadéquate. De plus, ils présentent une diminution de la testostérone avec une élévation de l’androstènedione sériques comparé au groupe témoin non exposé (P < 0,05) et ces déséquilibres androgéniques sont accompagnés de difficultés de reproduction. Le manèbe est l’agropesticide le plus utilisé et perturbe chez le rat mâle la stéroïdogenèse Leydigienne (à travers l’inhibition de la CYP11A1) et la fertilité. Cette fertilité est améliorée/rétablie lorsque le pesticide est concomitamment administré avec l’un des extraits, suggérant ainsi l’effet protecteur desdits extraits qui est imputable à leur activité androgénique également démontré chez les rats. Toutefois, ces extraits et le manèbe n’affectent pas la production de la SHBG in vitro. Ces résultats soulignent l’altération de la fonction de reproduction mâle par les agropesticides et l’effet bénéfique des plantes médicinales / The effect of agropesticides use on male reproductive function was evaluated in male farmers in Djutitsa (West Cameroon). The most frequently used agropesticide by farmers was selected and tested in vivo on the reproductive function of male rats, ex vivo and/or in vitro on Leydig cells steroidogenesis, in order to evaluate its implication in disorders observed in farmers. The ability of 2 Cameroonian medicinal plants (Carpolobia alba and Basella alba) to prevent pesticide-induced toxicity was also investigated in vivo in male rats. Furthermore, both extracts and selected pesticide were tested on the release of a steroid transporter protein (SHBG) by HepG2 cells. The results showed that farmers used 25 agropesticides and presented symptoms related to inadequate protection. Moreover, they had lower serum testosterone and higher androstenedione levels compared to a control group with no history of agropesticide exposure (P < 0.05), and these androgenic imbalances were accompanied by difficulties of reproduction. Maneb was the most common ingredient, and its administration to male rats resulted in decrease/alteration of Leydig cells steroidogenesis (through inhibition of CYP11A1) as well as fertility. The latter fertility was improved/restored when maneb was coadministrated to rats with any of the plant extracts, suggesting their protective effect that may be attributed to their proven androgenic activity. However maneb and the plant extracts did not affect SHBG release by HepG2 cells. These results highlight agropesticides deleterious effect on male reproductive function, which may be prevented by the investigated plant extracts

This thesis deals with the black market of enhancing drugs with a particular focus on androgenic anabolic steroids (AAS). Medical studies agree that these substances in the form and quantity abused by athletes to improve performance are damaging the body and therefore author is looking for recommendations for economic policy on how to reduce rate of this abuse. The study of economic literature (especially the Becker's "Theory of rational addiction") shows that users of AAS are rational, often even more rational than users of other harmful substances, because they abuse these substances with long-term plan. The reason of this purposeful approach is that the desired "delight" is derived from hard-earned success unlike other drugs and therefore abuse of AAS is associated with discipline, calculation and hence a (limited ) rationality. Economists building on Becker 's theory point out to cases where this limitation is so significant that it justifies regulation. This thesis is based on the assumption (supported by studies) that prohibition or penalizing the users themselves are ineffective instruments and therefore is the author looking for alternative solution. The author believes that the main stimulators of demand for AAS are misleading media; benevolent government's approach towards bodybuilding competitions; and finally the prohibition leading to the formation of the black market which makes it impossible for (potential ) users to become optimally informed about health risks etc. This hypothesis is being tested in questionnaire survey distributed mainly through social networks. Finally, the author sets out recommendations for economic policy: that restrictive hand of the state should focus attention in the opposite direction than before i.e., the demand side and thereby subtly demotivate users themselves.

Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and their presence in water bodies is documented. They discharge into surface water (SW) unmonitored, posing a threat to both aquatic and terrestrial lives. This is a challenge as not all populations have access to treated drinking water (TDW). The EDC contaminated serves as a route of exposure, together with ineffective treatment plants. Given the complexity of the endocrine system, EDCs may mimic or antagonise natural hormones or disrupt their synthesis, metabolism and excretion. The associated health effects include testicular dysgenesis syndrome, metabolic disorders and cancers. Policy and internationally standardised test methods are however sti ll limited. This study therefore aimed to assess the suitability of two assays used for screening estrogenic activity and one for androgenic activity in different water sources. The study consisted of two phases. In phase 1, water sample (tap, surface and treated wastewater) were collected from a catchment area in Pretoria. The samples and a spiked MilliQ laboratory water sample were extracted with solid phase extraction (SPE) and sent to Germany for distribution to participating laboratories. Samples (n=24) from six different countries were received to test for androgenic activity in the MDA-kb2 reporter gene assay. In phase 2, SW and TDW samples were collected from April 2015 until March 2016. The samples were filtered, extracted using SPE and assayed with the YES assay, T47D-KBluc reporter gene assay for estrogenic activity and MDA-kb2 reporter gene assay for androgenic activity. In phase 1, androgenic activity was detected in 4 out of 24 (21%) samples and ranged from 0.23 ± 0.040 ng/L to 0.008 ± 0.001 ng/L DHTEqs. In phase 2, estrogenic activity was detected in 16 out of 24 (67%) SW samples in the T47DKBluc reporter gene assay and ranged from 0.31 ± 0.05 pg/L to 10.51 ± 5.74 pg/L EEqs. It was below the detection limit (dl) in the YES assay. Androgenic activity was detected in 4 out of 24 (17%) SW samples, ranging from 0.0033 ± 0.0050 ng/L to 0.090 ± 0.040 ng/L DHTEqs. Androgenic and estrogenic activity was higher i n pretreatment samples compared to post-treatment in both treatment plants. In phase 1, the MDA-kb2 reporter gene assay was successfully applied to water samples from different sources. Androgenic activity was highest in treated wastewater. In phase 2, treatment plants proved to be effective in removing estrogens detected in the SW samples, as the TDW samples were below the dl. Estrogenic activity is within the ranges reported in other studies. Positive samples were below the 0.7 ng/L proposed trigger value for health risk assessments. Detected androgenic activity was lower in TDW samples compared to the SW samples supplying the two treatment plants indicating that they were both effective in removing the androgenic activity detected. Few studies have reported androgenic activity in tap water. This study strengthens the argument for using a battery of assays when monitoring endocrine activity as EDCs occur at low concentrations in mixtures. / Dissertation (MSc)--University of Pretoria, 2017. / School of Health Systems and Public Health (SHSPH) / MSc / Unrestricted

Contemporary civilization of the western world represents a combination of material development and moral degeneration, Value is measured in 'space' not in 'spirit'. Antecedent to the complications of life with its sufferings) 'fiddlers fees' and disillusionments, how very few realize that true pleasure is not in having, but in being? Fewer still are those whose feelings, thoughts and actions are conscious, aware, self-chosen and self-directed. More often than not, introspection reveals that most are not masters, but the mastered, victims of moods and conflicts... However, deep dissatisfaction with life as it appears to be and with the individual's adaption to everyday experience are universal among mankind and are not the symptom of any age or race or stage of civilization. In every age there have been those who were acutely aware of this dissatisfaction and whose lives were spent in a prolonged endeavor to find a remedy for it, and to help their fellow men benefit from this remedy. In pursuit of this objective, Indian sages impressed the wisdom of brahmacarya centuries ago. Brahmacarya is an embracive principle of life and spiritual pursuits governing each of the four stages of life. Its objective being the mastery over sensuous desires.

La différenciation sexuelle des Isopodes dépend d'une hormone sexuelle protéique, l'hormone androgène (HA), caractéristique des Malacostracés. Cet Insulin-Like Peptide suffit à induire par sa présence la différenciation mâle de ces Crustacés. Nous avons identifié in silico le transporteur circulant de l'HA, l'IGFBP-rP1, chez de nombreuses espèces d'Isopodes ainsi qu'à l'échelle des Crustacés. De la même façon, nous avons identifié deux récepteurs transmembranaires, l'IR1 et l'IR2, issus d'une duplication de gène spécifique des Malacostracés. Les patrons d'expression de ces gènes ont été étudiés sur notre espèce modèle, Armadillidium vulgare. Av-IGFBP-rP1 et Av-IR1 sont exprimés de manière ubiquiste et tout au long du développement. Av-IR2 est aussi exprimé à chaque stade de la différenciation mais ce transcrit est quasi-spécifique des glandes androgènes et ovaires. Une approche par ARNi a confirmé l'implication de ces trois protéines dans la voie de signalisation de l'HA. En effet, l'inhibition de l'HA, Av-IGFBP-rP1 et Av-IR1 provoquent l'hypertrophie des glandes androgènes, suggérant leur implication dans une boucle de rétro-contrôle de l'HA. L'inhibition de Av-IR2 semble seulement provoquer la différenciation d'ouvertures génitales femelles. Ces phénotypes sont comparables à ceux des intersexués mâles induits par la bactérie féminisante endogène Wolbachia. Nous montrons cependant que la bactérie altère seulement l'expression de l'HA et pas celle des récepteurs. Enfin, nous avons testé l'effet du bisphénol A mais nous n'observons pas d'altération de la différenciation sexuelle des larves lors d'expositions à ce perturbateur endocrinien exogène. / Sexual differentiation in Isopods relies on a proteinaceous sex hormone called androgenic hormone (AH), specific to Malacostracans. This Insulin-Like Peptide induces male differentiation by its mere presence in these Crustaceans. We identified in silico the circulating carrier of the AH, called IGFBP-rP1, in many Isopod species, but also on the crustacean scale. Similarly, we identified two transmembrane receptors, IR1 and IR2, coming from a gene duplication specific to Malacostracans. The expression patterns of these genes were investigated in our model species, Armadillidium vulgare. Av-IGFBP-rP1 and Av-IR1 are broadly expressed in the animal and throughout development. Av-IR2 is also expressed at each developmental stage but this transcript is almost specific to androgenic glands and ovaries. An RNAi approach has confirmed the implication of these three proteins in the AH signalling pathway. Indeed, the inhibition of AH, Av-IGFBP-rP1 and Av-IR1 induces androgenic gland hypertrophy, suggesting their implication in an AH feedback loop. Av-IR2 inhibition seems to provoke the differentiation of female genital apertures only. These phenotypes are similar to those of male intersexes induced by the endogenous feminizing bacterium Wolbachia. Yet, we show that the bacterium alters the expression of the AH only and not the one of its receptors. Finally, we have tested the effect of bisphenol A but we observe no alteration of the sexual differentiation in larvae upon exposition to this exogenous endocrine disruptor.

<p>Anabolic-androgenic steroids (AAS) have been used in clinics for decades. The misuse of AAS has previously been attributed merely to sport athletes, taking AAS with intentions to increase muscle mass, enhance physical performance and to improve results in competitions. Today, the misuse of AAS has spread to adolescents and young adults not connected to sports. Alarmingly, many reports are pointing at severe psychiatric adverse effects among AAS abusers, which include mood swings, mania, anxiety, depression and aggression. Numerous examples of severe and often unprovoked violence and brutal crimes have been connected to AAS abuse and there is a strong need for a better understanding of the underlying biochemical events that might account for the adverse behaviors induced by AAS. The general aim of this thesis was to study the effect of chronic AAS administration on neuropeptide circuits in the rat brain associated with the regulation of rewarding effects, memory, anxiety, depression and aggression, using nandrolone decanoate as a prototype AAS.</p><p>Results demonstrated that daily administration of AAS to rats in doses comparable to those taken by AAS abusers, in certain brain structures significantly affected, <i>a</i>) the levels of the opioid peptides dynorphin B and Met-enkephalin-Arg⁶Phe⁷, <i>b</i>) the levels of the tachykinin substance P (SP), <i>c</i>) the density of the SP neurokinin 1 (NK1) receptor, <i>d</i>) the level of the SP metabolite SP_1-7that frequently exerts opposite effects to SP, <i>e</i>) the SP_1-7generating enzyme substance P endopeptidase (SPE) and finally, <i>f</i>) the levels of the neuropeptide calcitonin gene-related peptide (CGRP) often co-localized with SP. The alterations seen in the levels and activities of these neurochemical components are in many aspects compatible with behaviors typified among AAS abusers.</p>

Anabolic-androgenic steroids (AAS) have been used in clinics for decades. The misuse of AAS has previously been attributed merely to sport athletes, taking AAS with intentions to increase muscle mass, enhance physical performance and to improve results in competitions. Today, the misuse of AAS has spread to adolescents and young adults not connected to sports. Alarmingly, many reports are pointing at severe psychiatric adverse effects among AAS abusers, which include mood swings, mania, anxiety, depression and aggression. Numerous examples of severe and often unprovoked violence and brutal crimes have been connected to AAS abuse and there is a strong need for a better understanding of the underlying biochemical events that might account for the adverse behaviors induced by AAS. The general aim of this thesis was to study the effect of chronic AAS administration on neuropeptide circuits in the rat brain associated with the regulation of rewarding effects, memory, anxiety, depression and aggression, using nandrolone decanoate as a prototype AAS. Results demonstrated that daily administration of AAS to rats in doses comparable to those taken by AAS abusers, in certain brain structures significantly affected, a) the levels of the opioid peptides dynorphin B and Met-enkephalin-Arg6Phe7, b) the levels of the tachykinin substance P (SP), c) the density of the SP neurokinin 1 (NK1) receptor, d) the level of the SP metabolite SP1-7 that frequently exerts opposite effects to SP, e) the SP1-7 generating enzyme substance P endopeptidase (SPE) and finally, f) the levels of the neuropeptide calcitonin gene-related peptide (CGRP) often co-localized with SP. The alterations seen in the levels and activities of these neurochemical components are in many aspects compatible with behaviors typified among AAS abusers.