Les liposomes, vésicules à base de phospholipides, sont des systèmes colloïdaux utilisés en recherche et dans différents domaines industriels (pharmaceutique, cosmétique, nutrition). Néanmoins, leur développement se heurte au manque de diversité des sources de phospholipides (soja et jaune d’oeuf). Parallèlement, les méthodes industrielles d’extraction des phospholipides sont basées essentiellement sur l’utilisation de solvants organiques. Dans ce contexte, mon sujet de thèse a eu pour but d’étudier l’extraction de PL, par le CO2 supercritique, à partir de différentes sources avec comme objectif final la formulation de ces PL en liposomes. La démarche a consisté à explorer différents sous-produits de l’huilerie (tourteau d’oléagineux) et de la pêche (sous-produit de la coquille Saint Jacques), potentiellement riches en phospholipides, puis à mettre en place différentes techniques analytiques pour discriminer et quantifier les types de lipides. Parallèlement, l’influence de différents paramètres de l’extraction par CO2 supercritique sur la pureté des fractions obtenues est abordée ainsi qu’une première approche de formulation de PL en liposomes et la caractérisation de ces vésicules. / Liposomes, phospholipids vesicles, are colloidal systems used in search and different industrial fields (pharmaceutical, cosmetic, nutrition). Nevertheless their development face lack of phospholipid sources (soya and egg yolk). At the same time, industrial methods to extract phospholipids use organic solvents. In this context, the phospholipid extraction were studied using a green technology from new different sources in order to formulate liposomes. Oil mill and fishery by-products (seed cake and scallop) were studied to know phospholipid quantities. Analytical techniques were established to discriminate and quantify lipid types. Simultaneously, varying the operating conditions of CO2 supercritical extraction allowed obtaining extracts with different purities and contents in phospholipids and a first study of liposome formulation was carried out.

La mucoviscidose est une maladie génétique présentant des altérations ioniques causées par une protéine membranaire défectueuse ou inexistante la CFTR entraînant des perturbations métaboliques. Nous sommes intéressés à l’altération du métabolisme des acides gras polyinsaturés (AGPI) n-3 et n-6, caractérisé par une déficience en acides linoléique (LA) et docosahexaénoïque (DHA) et une élévation de l’acide arachidonique (AA). Ce déséquilibre peut être préjudiciable à l’état des patients du fait du rôle clé de certains AGPI à différents niveaux de la vie. Nos travaux ont portés sur la recherche des bénéfices d’un vecteur riche en un AGPI n-3 d’intérêt, le DHA, dans le contexte de la mucoviscidose à travers deux approches : une approche par supplémentation réalisée chez un modèle murin présentant la mutation la plus répandue chez les patients, et une approche sur un modèle d’entérocyte humain afin d’étudier de façon plus approfondie l’intérêt du supplément sur la fonctionnalité cellulaire (absorption des nutriments lipidiques). Nos résultats nous ont conduits à différentes conclusions : les souris delF508 nourries avec du Peptamen Junior présentent une perturbation du métabolisme des n-6 (LA, AA) dès l’âge de 3 mois ; cette altération apparaît mais plus tard sous régime standard. Par contre, quelque soit le régime alimentaire notre modèle ne développe pas de déficience en DHA jusqu’à l’âge d’1 an. L’évolution du statut en AGPI n-6 est donc dépendante du régime et de l’âge. L’apport de glycérophospholipides enrichis en DHA administré à faible dose permet de corriger les perturbations en AGPI n-6 et d’augmenter le rapport en DHA/AA dans la plupart des organes. Ce vecteur s’avère potentiellement intéressant en nutrithérapie chez le patient. Un enrichissement physiologique en DHA de l’entérocyte ne modifie pas ses capacités absorptives qui sont plutôt régulées par le type de particules véhiculant les produits de lipolyses, micelles de sels biliaires versus liposomes. / Cystic fibrosis is a genetic disease showing ionic alterations, caused by an absent or defective membrane protein CFTR leading to metabolic disturbances. We are interested in n-6 and n-3 polyunsaturated fatty acid (PUFA) metabolism alteration characterized by a linoleic (LA) and docosahexaenoic (DHA) acids deficiency and high level of arachidonic acid (AA). This imbalance can affect patient health due to the key role of some PUFAs in different levels of life. Our studies focused on finding the benefits of a vector enriched in one interesting n-3 PUFA, DHA, in context of cystic fibrosis, through two approaches: a nutritional supplementation conducted in a mouse model with the most common mutation of cystic fibrosis patients, and an approach on a model of human enterocyte to investigate more thoroughly the effect of the vector on cell functionality (absorption of lipid nutrients). Our results led us to different conclusions: del F508 mice fed with Peptamen Junior have a metabolic disorder of the n-6 PUFA (LA, AA) at the age of 3 months, but this alteration appears later under standard regime . But, whatever the diet, our model does not develop a DHA deficiency to the age of 1 year. The changing status of n-6 is dependent on diet and age. Glycerophospholipids enriched in DHA given at low doses can correct disturbances in PUFA n-6 and increase the DHA/AA ratio in most organs. This vector is potentially interesting for a patient nutritherapy. A physiological DHA enrichment of enterocyte does not alter its absorption capacity, which is rather regulated by the type of particles carrying the lipolysis products, bile salt micelles versus liposomes.

Dentro da perspectiva da utilização de compostos fenólicos como antioxidantes naturais para minimizar os efeitos in vitro e in vivo do processo oxidativo dos lípides insaturados, foi realizada a monitoração dietética de duas dietas ricas em lípides das séries ω3 e ω6 e a suplementação de um chá de uma mistura de especiarias, em ratos Wistar, com o objetivo de verificar a influência dos compostos fenólicos, presentes nas especiarias, sobre o metabolismo de ácidos graxos das séries ω3 e ω6. Extratos e frações das especiarias mostarda, canela e erva doce foram obtidos e tiveram suas atividades antioxidantes testadas em sistemas aquoso (cooxidação de substratos com o uso de ácido linoléico/β-caroteno) e lipídico (RANCIMAT) e o perfil de compostos fenólicos identificados e quantificados por CGMS. A partir de uma mistura de especiarias, foi elaborado um chá que foi fornecido aos animais de cada grupo dietético (ω3 e ω6). Após 45 dias de tratamento, os animais foram sacrificados e tiveram seus tecidos coletados para análise de TBARs e do perfil lipídico por CGMS. Todos os extratos das especiarias apresentaram atividade antioxidante equivalente ou superior ao BHT. Foram identificados por CGMS os ácidos fenólicos: catecol, salicílico e caféico. Foi obtido nos tecidos dos animais que o somatório do perfil de ácidos graxos saturados e dos insaturados apresentaram diferença entre os grupos testes e controles. Logo, no tecido cerebral, o EPA foi incorporado apenas no grupo ω3 que recebeu o extrato das especiarias. Já para o DHA, do mesmo grupo dietético, os tecidos hepático e renal também apresentaram incorporação aumentada em relação ao controle. No grupo dietético ω6, destaca-se um aumento no percentual de incorporação do ácido linoléico nos tecidos cardíaco e renal no grupo experimental. Enquanto, para o ácido araquidônico, houve diferença em todos os tecidos. Já, para os resultados da lipoperoxidação, observou-se que todos os tecidos dos animais que receberam o extrato das especiarias apresentaram baixos valores em comparação aos seus respectivos controles. Este estudo também avaliou a ação de compostos fenólicos do chá da mistura das especiarias mostarda, canela e erva doce sobre as enzimas lipoxigenase e cicloxigenase. O extrato da mistura das especiarias a 100 e 200 ppm foi adicionado no meio de reação contendo o substrato e a enzima lipoxigenase 1B da Sigma com 112.000 und/mg. A cicloxigenase foi obtida de vesículas seminais de carneiro e seguiu-se o mesmo protocolo de atividade para a lipoxigenase. Indometacina foi o inibidor utilizado como controle positivo da reação. Observou-se que a 200 ppm, como na concentração do chá (0,02%), a lipoxigenase foi inibida em aproximadamente em 90%. Já para a cicloxigenase, o extrato a 200 ppm resultou numa média de 75% de inibição da atividade da enzima, enquanto que a indomentacina apresentou uma média de 77% de inibição. A absorção aparente do chá das especiarias indicou que os fenólicos presentes na mistura foram absorvidos em média de 75%. O estudo histopatológico dos intestinos delgados dos animais não apresentou nenhuma diferença na área de absorção entre o grupo experimental e o controle. Estes dados sugerem, portanto, um efeito antioxidante das substâncias fenólicas identificadas nas especiarias sobre os ácidos graxos das séries ω3 e ω6, podendo agir diretamente: (1) no alimento (óleo), (2) com modificação do perfil lipídico, (3) proteção quanto à oxidação de tecidos e (4) inibição das enzimas da biossíntese dos eicosanóides. / Considering the perspective for the use of phenolic compounds as natural antioxidants to minimize in vitro and in vivo effects of oxidative processes on unsaturated lipids, this work monitored Wistar rats fed with two diets rich in ω3 and ω6 polyunsaturated lipids, supplemented with tea made from a blend of spices. The objective of the work was to study the influence of phenolic compounds present in spices on the metabolism of ω3 and ω6 fatty acids. Extracts and fractions of mustard, cinnamon and anise were obtained and had their antioxidant activity tested in aqueous (co-oxidation of substrates using linoleic acid/β-carotene) and lipidic systems (RANCIMAT). Their phenolic compounds profile was determined and quantified using CGMS. The rats of each diet group (ω3 and ω6) were given tea made from a blend of spices and sacrificed after 45 days. Their tissues were then collected and analyses of TBARS and lipid profile were performed using CGMS. Ali the extracts of spices showed equal or higher antioxidant activity than BHT. The following phenolic acids were identified using CGMS: cathecol, salicilic and cafeic. It was observed that the total amount of the profile of saturated and unsaturated fatty acids in the rat tissues were different in the test group and the control group. In brain tissue, EPA was found only in the ω3 diet group which was given the tea. Concerning DHA, liver and kidney tissues of the same diet group showed higher concentrations than the control group. In the ω6 diet group, an outstanding increase of linoleic acid in cardiac and kidney tissues was found. Concerning the arachidonic acid, a difference in concentration was observed in ali tissues. Ali the tissues from rats given the tea presented a lower level of lipid peroxidation than their respective control groups. The present research also evaluated the action of phenolic compounds found in the tea made from the blend of mustard, cinnamon and anise on the enzymes lipoxygenase and cycloxygenase. The extract of the blend of spices, in the concentrations of 100 and 200 ppm, was added to the substrate and Sigma lipoxygenase 112.000 units/mg. Cycloxygenase was obtained from sheep seminal bladders and underwent the same protocol as lipoxygenase. Indomethacin was the inhibitor used as the positive control of the reaction. It was observed that in the concentration of 200 ppm (that is 0.02%, the same concentration as in the tea), lipoxygenase presented an average 90% inhibition. The extract of cycloxygenase 200 ppm presented 75% inhibition of the enzyme activity, while indomethacin presented an average 77% inhibition. It was found that around 75% of the phenolic compounds present in the tea made from the blend of spices were absorbed, thus leading to the conclusion that apparent absorption of the tea took place. Histopathologic examinations on the small intestines of the rats did not reveal any difference in the absorption area between the experimental and the control groups. Such results suggest therefore an antioxidant effect of the phenolic substances identified in the spices on the ω3 and ω6 fatty acids, this effect being possible directly (1) on the food (oil) , (2) modification of the profile fatty acids, (3) oxidation protection tissues and, (4) inhibition of enzymes of eicosanoids biosinthesys.

SELECTED NUTRIENTS IN ETIOLOGY, PREVENTION AND TREATMENT OF OBESITY The 21st century pandemic of obesity is given by to the obesitogenic environment that helps to develop a positive energy balance, where the energy intake of an individual chronically exceeds his energy need, ie energy expenditure. There is an increase in body weight by increased or abnormal body fat accumulation in the body. Preventing the development of obesity is aimed at achieving energy balance, in the case of existing overweight or obesity, the treatment lies in inducing and maintaining a negative energy balance for some time, ie stimulating energy expenditure and reducing energy intake. Selected diet determines not only energy intake, but its individual nutrients can also partially affect energy expenditure and fat tissue physiology. The aim of this work is to describe and experimentally verify some nutrients that could help in weight reduction and physiological function of adipose tissue. Based on the literature data, 19 active substances or mixtures were considered. A mixture of ω-3 polyunsaturated fatty acids (ω-3 PUFA), eicosapentaenoic acid and docosahexaenoic acid, in a daily dose of 0.6 g, in the form of fish oil in a certified food supplement was chosen as the most suitable for the experiment. In a 12-week, three-arm, parallel...

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Background Iron deficiency (ID) is the world‟s most prevalent micronutrient deficiency and predominantly affects developing countries, also South Africa. In areas with low fish consumption and high n-6 PUFA vegetable oil intake, there is a risk for having inadequate n-3 PUFA status. Both iron and n-3 PUFA play important roles in the immune response, and supplementation is a strategy to alleviate deficiencies. However, little is known about potential interactive effects between concurrent iron and n-3 PUFA supplementation on the immune system. This is also important in the context that iron supplementation may be unsafe and may increase morbidity and mortality. Aim The overall aim of this thesis was to assess the effects of iron and docosahexaenoic (DHA)/eicosapentaenoic acid (EPA) supplementation, alone and in combination, on the immune system of ID children. More specifically, these effects were investigated on the occurrence and duration of illness and school-absenteeism due to illness, peripheral blood mononuclear cell (PBMC), red blood cell (RBC) and plasma total phospholipid fatty acid composition, iron status, fatty acid-derived immune modulators and targeted PBMC gene expression. Furthermore, association of PBMC, RBC and plasma total phospholipid fatty acid composition with allergic disease, were also examined. Design In a 2-by-2 factorial, randomised, double-blind, placebo-controlled trial, South African children (n = 321, aged 6–11 y) were randomly assigned to receive oral supplements of either 1) iron (50 mg as ferrous sulphate) plus placebo; 2) DHA/EPA (420/80 mg) plus placebo; 3) iron plus DHA/EPA (420/80 mg); or 4) placebo plus placebo for 8.5 mo, four times per week. Absenteeism and illness symptoms were recorded and biochemical parameters for compliance as well as parameters fundamental to immune function were assessed at baseline and endpoint. Furthermore, in a cross-sectional design, associations of allergic disease with baseline fatty acid composition of PBMC, RBC and plasma were examined. Results The combination of iron and DHA/EPA significantly attenuated respiratory illness caused by iron supplementation. DHA/EPA supplementation alone improved respiratory symptoms at school, but increased headache-related absenteeism. DHA/EPA and iron supplementation individually tended to increase and decrease anti-inflammatory DHA and EPA-derived mediators, respectively. Furthermore the anti-inflammatory DHA-derived immune mediator, 17HDHA was higher in the DHA/EPA plus placebo and iron plus DHA/EPA groups than in the iron plus placebo group. Also, the pro-inflammatory arachidonic acid (AA)-derived modulators (5- and 15-hydroxyeicosapentaenoic acid) were significantly lower in the iron plus DHA/EPA group compared to the placebo plus placebo groups. In the study population, 27.2% of the children had allergic disease and AA in PBMC phospholipids was significantly lower in the allergic children than in the non-allergic children. In RBC phospholipids dihomo-gamma-linolenic acid (DGLA) and the ratio of DGLA: linoleic acid (LA) correlated negatively and the n-6:n-3 PUFA ratio positively with total immunoglobulin E (tIgE). Furthermore, trans-C18:1n-9, tended to be higher in the allergic group. Conclusion DHA/EPA prevented respiratory illness caused by iron supplementation and although DHA/EPA on its own reduced respiratory morbidity when the children were present at school, surprisingly it increased the likelihood of being absent with headache and fever. The biochemical findings compliment the clinical results and support previous observations about DHA/EPA supplementation to reduce inflammation, but add to the current knowledge base that a relatively high oral dose of non-haem iron modulates circulating lipid-derived immune modulators and related gene expression. Furthermore, when supplementing with iron and DHA/EPA combined, in this ID population with low fish intake, the anti-inflammatory effect of DHA/EPA is maintained concurrently with attenuation of respiratory morbidity. This finding support the notion that excess iron (probably as non-transferrin bound iron) becomes available for pathogens and is probably why we found that iron increased respiratory infectious morbidity. The improved clinical outcome with combined supplementation seems to be related to increased lipid-mediator synthesis gene expression and the availability of DHA/EPA, leading to a more pro-resolving profile and enhanced immune competence. Overall these results give better insight into immune function and infectious morbidity in relation to n-3 PUFA and iron status and treatment, as well as the possible association of fatty acid status with allergic disease in young South-African school children. / PhD (Nutrition), North-West University, Potchefstroom Campus, 2015

Background Iron deficiency (ID) is the world‟s most prevalent micronutrient deficiency and predominantly affects developing countries, also South Africa. In areas with low fish consumption and high n-6 PUFA vegetable oil intake, there is a risk for having inadequate n-3 PUFA status. Both iron and n-3 PUFA play important roles in the immune response, and supplementation is a strategy to alleviate deficiencies. However, little is known about potential interactive effects between concurrent iron and n-3 PUFA supplementation on the immune system. This is also important in the context that iron supplementation may be unsafe and may increase morbidity and mortality. Aim The overall aim of this thesis was to assess the effects of iron and docosahexaenoic (DHA)/eicosapentaenoic acid (EPA) supplementation, alone and in combination, on the immune system of ID children. More specifically, these effects were investigated on the occurrence and duration of illness and school-absenteeism due to illness, peripheral blood mononuclear cell (PBMC), red blood cell (RBC) and plasma total phospholipid fatty acid composition, iron status, fatty acid-derived immune modulators and targeted PBMC gene expression. Furthermore, association of PBMC, RBC and plasma total phospholipid fatty acid composition with allergic disease, were also examined. Design In a 2-by-2 factorial, randomised, double-blind, placebo-controlled trial, South African children (n = 321, aged 6–11 y) were randomly assigned to receive oral supplements of either 1) iron (50 mg as ferrous sulphate) plus placebo; 2) DHA/EPA (420/80 mg) plus placebo; 3) iron plus DHA/EPA (420/80 mg); or 4) placebo plus placebo for 8.5 mo, four times per week. Absenteeism and illness symptoms were recorded and biochemical parameters for compliance as well as parameters fundamental to immune function were assessed at baseline and endpoint. Furthermore, in a cross-sectional design, associations of allergic disease with baseline fatty acid composition of PBMC, RBC and plasma were examined. Results The combination of iron and DHA/EPA significantly attenuated respiratory illness caused by iron supplementation. DHA/EPA supplementation alone improved respiratory symptoms at school, but increased headache-related absenteeism. DHA/EPA and iron supplementation individually tended to increase and decrease anti-inflammatory DHA and EPA-derived mediators, respectively. Furthermore the anti-inflammatory DHA-derived immune mediator, 17HDHA was higher in the DHA/EPA plus placebo and iron plus DHA/EPA groups than in the iron plus placebo group. Also, the pro-inflammatory arachidonic acid (AA)-derived modulators (5- and 15-hydroxyeicosapentaenoic acid) were significantly lower in the iron plus DHA/EPA group compared to the placebo plus placebo groups. In the study population, 27.2% of the children had allergic disease and AA in PBMC phospholipids was significantly lower in the allergic children than in the non-allergic children. In RBC phospholipids dihomo-gamma-linolenic acid (DGLA) and the ratio of DGLA: linoleic acid (LA) correlated negatively and the n-6:n-3 PUFA ratio positively with total immunoglobulin E (tIgE). Furthermore, trans-C18:1n-9, tended to be higher in the allergic group. Conclusion DHA/EPA prevented respiratory illness caused by iron supplementation and although DHA/EPA on its own reduced respiratory morbidity when the children were present at school, surprisingly it increased the likelihood of being absent with headache and fever. The biochemical findings compliment the clinical results and support previous observations about DHA/EPA supplementation to reduce inflammation, but add to the current knowledge base that a relatively high oral dose of non-haem iron modulates circulating lipid-derived immune modulators and related gene expression. Furthermore, when supplementing with iron and DHA/EPA combined, in this ID population with low fish intake, the anti-inflammatory effect of DHA/EPA is maintained concurrently with attenuation of respiratory morbidity. This finding support the notion that excess iron (probably as non-transferrin bound iron) becomes available for pathogens and is probably why we found that iron increased respiratory infectious morbidity. The improved clinical outcome with combined supplementation seems to be related to increased lipid-mediator synthesis gene expression and the availability of DHA/EPA, leading to a more pro-resolving profile and enhanced immune competence. Overall these results give better insight into immune function and infectious morbidity in relation to n-3 PUFA and iron status and treatment, as well as the possible association of fatty acid status with allergic disease in young South-African school children. / PhD (Nutrition), North-West University, Potchefstroom Campus, 2015

Objectif: Définir l’effet des lipides et du traitement de la dyslipidémie sur les cancers de la prostate et de la vessie en utilisant différents devis d’étude et en tenant compte de la présence de plusieurs biais, particulièrement le biais du temps immortel. Devis: Le premier volet utilise un devis rétrospectif de type cas témoins. Un questionnaire semi-quantitatif de fréquence de consommation alimentaire validé a été utilisé. Le génotype COX2 de neuf polymorphisme nucléotidique unique (SNP) a été mesuré avec une plateforme Taqman. Des modèles de régression logistique non conditionnelle ont été utilisés pour comparer le risque de diagnostic d’un cancer de la prostate et l’interaction. Le deuxième volet utilise un devis rétrospectif de type cohorte basée sur les données administratives de la Régie de l’assurance-maladie du Québec (RAMQ). Des modèles de régression de Cox ont été employés pour mesurer l’association entre les statines et l’évolution du cancer de la vessie. Le troisième volet, porte un regard méthodologique sur le biais du temps immortel en examinant sa présence dans la littérature oncologique. Son importance est illustrée avec les données de la cohorte du deuxième volet, et les méthodes de correction possibles son appliquées. Résultats: L’étude du premier volet démontre qu’une diète riche en acides gras oméga-3 d’origine marine était fortement associée à un risque diminué de cancer de la prostate agressif (p<0.0001 pour la tendance). Le ratio de cote pour le cancer de la prostate du quartile supérieur d’oméga-3 était de 0.37 (IC 95% = 0.25 à 0.54). L’effet diététique était modifié par le génotype COX-2 SNP rs4648310 (p=0.002 pour l’interaction). En particulier, les hommes avec faible apport en oméga-3 et la variante rs4648310 avait un risque accru de cancer de la prostate (ratio de cote = 5.49, IC 95%=1.80 à 16.7), effet renversé par un apport en oméga-3 plus grand. L’étude du deuxième volet a observé que l’utilisation de statines est associée à une diminution du risque de progression du cancer de la vessie (risque relatif = 0.44, IC 95% = 0.20 à 0.96, p=0.039). Cette association était encore plus forte pour le décès de toute cause (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). L’effet des statines semble être dose-dépendant. L’étude du troisième volet démontre que le biais du temps immortel est fréquent et important dans les études épidémiologiques oncologiques. Il comporte plusieurs aspects dont certains sont mieux prévenus au stade du choix du devis d’étude et différentes méthodes statistiques permettent un contrôle de ce biais. Conclusion: 1) Une diète riche en oméga-3 aurait un effet protecteur pour le cancer de la prostate. 2) L’utilisation de statines aurait un effet protecteur sur la progression du cancer non invasif de la vessie. Les lipides semblent avoir un effet sur les cancers urologiques. / Purpose: To define the effects of dietary lipids and of treatment of dyslipidemia with statins on prostate and bladder cancers, using different epidemiologic study designs and accounting for biases, particularly immortal time bias. Study Design: The first part used a retrospective a case-control study design. Diet was assessed with a semi-quantitative food frequency questionnaire, and nine COX-2 tag single nucleotide polymorphisms (SNPs) were genotyped. We used logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and p-values for association and interaction. The second part used a retrospective cohort study design based on administrative databases of Québec, Canada. Cox regression models were used to measure association between statin use and bladder cancer evolution. The third part focuses on the immortal time bias by describing its presence in the oncologic literature. The importance of this bias is illustrated with data from the cohort used in the second part and statistical correction methods are applied. Results: The first part showed that an increasing intake of omega-3 fatty acids of marine origin was strongly associated with a decreased risk of aggressive prostate cancer (trend p<=0.0001). The OR (95% CI) for prostate cancer comparing the highest to the lowest quartile of omega-3 intake was of 0.37 (0.25 – 0.54). The dietary effect was modified by the rs4648310 COX-2 SNP (interaction p=0.02). This reflected the observation that men with low marine omega-3 intake and the variant rs4648310 SNP had an increased risk of disease (OR = 5.49; 95% CI: 1.80-16.7), which was reversed by increasing intake of marine omega-3. The second part showed that statin use was associated with a decreased risk of bladder cancer progression (HR = 0.44, 95% CI = 0.20 to 0.96, p=0.0388). The inverse association was even stronger for risk of mortality from all causes (HR = 0.57, 95% CI = 0.43 to 0.76, p=0.0001). The statin use effect appears dose-dependent. The third part showed that the immortal time bias is frequent and important in many epidemiological studies in oncology. It has many aspects and some of these are better prevented at time of study design selection. Various statistical methods also allowed control of this bias. Conclusion. 1) Dietary omega-3 appears to decrease prostate cancer risk. 2) Statin use appears to decrease risk of bladder cancer progression. Lipids seem to have an effect on urological cancers.

Contexte : De la conception à l’âge adulte, de nombreux déterminants environnementaux influencent le neurodéveloppement. Des études montrent que durant la fin de la grossesse et les premiers mois de vie, une grande quantité d’acides gras polyinsaturés (AGPI), notamment à longue chaîne (AGPI-LC), se fixe dans le tissu cérébral. Un apport optimal durant ces périodes critiques pourrait soutenir précocement le bon développement du cerveau et de ses fonctions.Objectifs : Étudier les relations entre les expositions pré- et postnatales précoces aux AGPI, et le neurodéveloppement d’enfants de 2 et 3 ans.Population : Les données utilisées étaient celles de l’étude EDEN, une cohorte mère enfant ayant recruté 2002 femmes enceintes dans les maternités de Nancy et Poitiers entre 2003 et 2006. L’alimentation maternelle pendant la grossesse a été évaluée par un questionnaire de fréquence alimentaire et une table de composition nutritionnelle. Quatre questionnaires postnatals ont permis d’évaluer la durée d’allaitement maternel, et la composition lipidique du colostrum des mères allaitantes a été analysée par chromatographie en phase gazeuse. Des questionnaires parentaux (2 et 3 ans) et un examen neuropsychologique (3 ans) ont permis d’évaluer plusieurs aspects du neurodéveloppement. Les analyses statistiques ont été réalisées par régressions linéaires multivariées, après ajustement sur de nombreux facteurs de confusion potentiels.Résultats : Les scores de neurodéveloppement à 2 et 3 ans des enfants allaités étaient plus élevés que ceux des enfants non allaités. Chez les enfants allaités, la durée d’allaitement maternel était associée positivement au neurodéveloppement. Le rapport n 6/n 3 dans l’alimentation maternelle en acides gras en fin de grossesse était négativement associé à plusieurs mesures du neurodéveloppement, et cette association était renforcée chez les enfants non allaités. La composition du colostrum en AGPI et en AGPI-LC reflétait amplement les apports nutritionnels en AGPI et en AGPI-LC en fin de grossesse. L’utilisation de matières grasses alimentaires était aussi associée à la composition du colostrum. Les différences de neurodéveloppement des enfants allaités ne semblait pas être expliquées par la composition du colostrum en AGPI ni en AGPI-LC, à l’exception de la teneur en acide linoléique qui était négativement associée à certaines mesures du neurodéveloppement. Dans l’ensemble, les associations avec le neurodéveloppement étaient plus fréquemment retrouvées avec les questionnaires parentaux, mais certaines évaluations par les psychologues venaient parfois conforter ces résultats.Conclusion : Associés à ceux de la littérature, ces résultats soulignent le rôle notable des AGPI durant les périodes pré- et postnatale précoce pour le neurodéveloppement de l’enfant. Le suivi des enfants de l’étude EDEN jusqu’à leur 5 ans permettra d’étudier la persistance de ces résultats. Dans une perspective de santé publique, ces travaux rappellent la nécessité de promouvoir l’allaitement maternel dans la durée et de surveiller l’équilibre des apports nutritionnels en AGPI pendant la grossesse et la période de lactation. / Context: From conception to adulthood, many environmental determinants influence neurodevelopment. Studies showed that in late pregnancy and the first months of life, a large amount of polyunsaturated fatty acids (PUFA), especially long-chain-PUFA (LCPUFA), accretes in the brain. Optimal intake during these critical periods could support the brain development and its cognitive functions.Aims: To investigate the relationships between pre- and early postnatal exposures to PUFA, and neurodevelopment of 2 and 3 years old children.Population: Data were those from the EDEN mother-child cohort study, in which 2002 pregnant women were recruited between 2003 and 2006 in the maternities of Nancy and Poitiers. Maternal food intake during pregnancy was evaluated by food frequency questionnaire combined with a food composition table. Duration of breastfeeding was assessed by 4 postnatal questionnaires. Lipids in colostrum of breastfeeding mothers were analyzed by gas chromatography. Several aspects of the cognitive and motor development were assessed by both parental questionnaires (2 and 3 y) and neuropsychological examination (3 y). Statistical analyzes were performed by multiple linear regressions, after adjusting for many potential confounders.Results: At 2 and 3 years, scores of neurodevelopment were higher among breastfed children than among never breastfed children. Among breastfed children, breastfeeding duration was positively associated with neurodevelopment. Maternal dietary n 6/n 3 ratio during late pregnancy was negatively associated with measures of neurodevelopment, and this association was reinforced among never breastfed children. Colostrum composition in PUFA and LCPUFA greatly reflected maternal intake during pregnancy. Use of oils/fats for cooking and seasoning was associated with colostrum composition. The differences of neurodevelopment of breastfed children did not seem to be explained by PUFA nor LCPUFA in colostrum, except for total linoleic acid that was negatively associated with some measures of neurodevelopment. In general, associations with neurodevelopment were more frequently found with assessments by parental questionnaires, but measures by psychologists sometimes confirmed the results.Conclusion: Combined with the literature, these results underline the importance of PUFA exposures during pre- and postnatal periods for the child neurodevelopment. Follow-up of children up to 5 years will allow to investigate whether those results persist later in childhood. From a public health perspectives, this work reiterates the need to promote breastfeeding duration and to monitor the balance of PUFA intake during pregnancy and lactation periods.