Estudos epidemiológicos e experimentais têm sugerido que fatores de risco cardiovasculares podem ser parcialmente atribuídos às influências do ambiente em que vive o indivíduo, e que a nutrição materna influencia na programação de alterações metabólicas e cardiovasculares no indivíduo adulto e que caracterizam a síndrome metabólica (SM). Em contrapartida, estudos prévios de nosso laboratório demonstram que o extrato da casca de uva Vitis labrusca (GSE) possui efeito vasodilatador, antihipertensivo e antioxidante. Desta forma, o objetivo deste estudo foi avaliar o efeito do tratamento oral com GSE (200mg/kg/dia), sobre as alterações cardiovasculares e metabólicas e estresse oxidativo observados na prole adulta (fêmea e machos) com 3 e 6 meses, cujas mães foram submetidas a uma dieta rica em gordura (hiperlipídica) durante a lactação. Quatro grupos de ratas foram alimentados com dietas experimentais: controle (7% de gordura); controle + GSE (7% de gordura + GSE), hiperlipídica (24% de gordura); hiperlipídica + GSE (24% de gordura + GSE) durante a lactação. Após o desmame, todos os filhotes passaram a ser alimentados com uma dieta controle e foram sacrificados aos 3 ou 6 meses de idade. A pressão arterial sistólica (PAS) foi medida por pletismografia de cauda e o efeito vasodilatador da acetilcolina (ACh) foi avaliado em leito arterial mesentérico (LAM) perfundido. Foram avaliados o peso corporal, adiposidade (intra-abdominal e gonadal), níveis plasmáticos de colesterol total, triglicerídeos, glicose e insulina, e a resistência à insulina (RI) foi calculada pelo índice de HOMA IR. As expressões do IRS-1, Akt e GLUT-4 foram determinadas em músculo soleus. O dano oxidativo, níveis de nitritos e a atividade das enzimas antioxidantes: superóxido dismutase, catalase e glutationa peroxidase foram dosados no plasma e homogenato de LAM. A PAS e tecido adiposo foram aumentados nas proles adultas de ambos os sexos e idades do grupo hiperlipídico e revertidos pelo tratamento com o GSE. A resposta vasodilatadora à ACh em LAM não foi diferente entre os grupos de ambos os sexos, mas foram reduzidas com o envelhecimento. Nas proles fêmeas e machos do grupo hiperlipídico também foram observados o aumento dos níveis de triglicerídeos, de glicose e RI em ambas as idades e foram reduzidos pelo GSE. No grupo hiperlipídico houve redução nas expressões de IRS-1, Akt e GLUT-4 e o GSE reverteu estas expressões. Os níveis plasmáticos de malondialdeído estavam aumentados e os níveis de nitrito diminuídos no grupo hiperlipídico, de ambos os sexos e idades e foram revertidos pelo GSE. As atividades das enzimas antioxidantes no plasma e no mesentério foram reduzidas no grupo hiperlipídico e restauradas pelo GSE. Em conclusão, O GSE parece proteger as proles fêmeas e machos, cujas mães foram expostas a uma dieta hiperlipídica durante a lactação, dos fatores de riscos cardiovasculares, proporcionando uma fonte alternativa nutricional para a prevenção da SM. / Epidemiological and experimental studies have suggested that cardiovascular risk factors can be partly attributed to the influences of the environment in which the individual lives, and that maternal nutrition influences the programming of metabolic and cardiovascular diseases in adults characterizing the metabolic syndrome. On the other hand, previous studies from our laboratory show that the skin extract of grape Vitis labrusca (GSE) has antihypertensive, antioxidant and vasodilator effects. Thus, the aim of this study was to evaluate the effect of oral treatment with GSE (200mg/kg/day) on the cardiovascular and metabolic disorders and oxidative stress observed in adult offspring (female and male) at 3 or 6 months whose mothers were fed a high fat diet (HF) during lactation. Four groups of rats were fed experimental diets: control (7% fat), control + GSE (7% fat + GSE), diet (24% fat), HF + GSE (24% fat + GSE) during lactation. After weaning, all pups have become fed a control diet and were sacrificed at 3 or 6 months of age. Systolic blood pressure (SBP) was measured by plethysmography and the vasodilator effect of acetylcholine (ACh) was studied in perfused mesenteric arterial bed (MAB). We determined the body weight, adiposity, plasma total cholesterol, triglycerides, glucose, insulin, and insulin resistance was calculated by HOMA IR. The expression of IRS-1, Akt and GLUT-4 were determined in soleus muscle. Oxidative damage, nitrite levels and antioxidant enzyme activity: superoxide dismutase, catalase and glutathione peroxidase were measured in plasma and homogenate of mesentery bed. The SBP and adipose tissue were increased in adult offspring of both sex and ages of the HF group and reversed by treatment with GSE. The vasodilator response to ACh was not different between groups of both sex, but was reduced by aging. In offspring females and males of the HF group were also observed increased levels of triglycerides, glucose and insulin resistance in both ages and those changes were reduced by GSE. HF group showed a reduction in expression of IRS-1, Akt and GLUT-4 which was reversed by GSE. The malondialdehyde levels were increased and nitrite levels were decreased in the HF group of both sex and ages and those changes were reversed by GSE. The activities of antioxidant enzymes in plasma and mesentery were lower in HF group and restored by the GSE. In conclusion, GSE appears to protect the female and male offspring whose mothers were exposed to a high fat diet during lactation, against the cardiovascular risk factors, providing an alternative source of food for the prevention of metabolic syndrome.

Un certain nombre d’études épidémiologiques ont montré au cours des cinquante dernières années une augmentation des infertilités, des malformations de l’appareil reproducteur masculin et des cancers testiculaires. Une des hypothèses est que, l’exposition durant la vie foetale ou néonatale à des composés présents dans l’environnement capables d’interférer avec le système hormonal (perturbateurs endocriniens), serait responsable de l’augmentation de l’incidence de ces pathologies. Les molécules qui sont suspectées d’avoir des effets néfastes à long terme sur le tractus génital mâle possèdent des activités de type estrogénique ou antiandrogénique. Parmi les mécanismes impliqués dans l’effet à long terme, un certain nombre d’auteurs mettent en avant l’intervention de mécanismes de type épigénétiques. Dans ce contexte, nous avons utilisé deux types de modèles expérimentaux reposant sur l’exposition développementale de rats à ces composés : un modèle d’exposition néonatale à un estrogène (estradiol benzoate) et un modèle d’exposition foetale à un antiandrogène (flutamide). Les deux modèles expérimentaux induisent chez le rongeur un phénotype d’hypospermatogenèse. Dans le cas de l’exposition néonatale à l’estradiol benzoate nous montrons que l’hypospermatogenèse observée chez les animaux à l’âge adulte est due à l’activation chronique de l’apoptose des cellules germinales testiculaires. Cette apoptose mettrait en jeu, par un mécanisme post-transcriptionnel, la diminution à long terme de l’expression de protéines clés de la machinerie épigénétique de méthylation de l’ADN, les ADN méthyltransférases (DNMT 3A, 3B et 1), et du facteur antiapoptotique, MCL-1. D’un point de vue fonctionnel, la chute d’expression des DNMTs se traduit notamment par l’augmentation d’expression des éléments transposables LINE-1 et du gène Ibtk normalement contrôlés par méthylation de l’ADN. En amont, la chute d’expression des DNMTs et de MCL-1 serait dépendante de l’augmentation d’expression d’autres effecteurs épigénétiques, les microRNAs de la famille miR-29. Dans le cas de l’exposition in utero au flutamide, notre travail indique que l’apoptose chronique des cellules germinales serait liée à la diminution à long terme de l’expression des inhibiteurs d’apoptose cIAP1 et cIAP2, et une augmentation d’expression de leur inhibiteur SMAC/DIABLO. En revanche, l’absence de mort des cellules somatiques testiculaires (Sertoli et Leydig) dans ce modèle serait due à l’augmentation d’expression spécifiquement dans ces cellules des inhibiteurs d’apoptose XIAP et SURVIVIN. Par ailleurs, le phénotype d’apoptose observé à l’âge adulte impliquerait également une altération précoce de l’expression des DNMTs. En conclusion, nous apportons une réponse mécanistique au phénotype de programmation foetale/néonatale d’apoptose des cellules germinales testiculaires adultes. En effet, l’augmentation des miR-29s provoquerait : (1) une chute d’expression des DNMTs altérant ainsi le profil de méthylation des gènes, et (2) une chute d’expression de facteurs protégeant les cellules germinales contre l’apoptose comme le facteur MCL-1. / During the five past decades, a number of epidemiological studies have indicated a higher incidence of infertility problems, male reproductive tract abnormalities and testicular cancers. Among the different hypotheses proposed, fetal or neonatal exposure to environmental compounds that can interfere with endocrine system, termed endocrine disruptors, may be at the origin of the rising incidence of these diseases. The molecules that are supposed to have long term adverse effects on the male genital tract have estrogenic or antiandrogenic properties. Some authors have suggested that the long term effects of endocrine disruptors could be mediated through epigenetic mechanisms. In this context, we have used two types of experimental models based on developmental exposure to these compounds: one model of neonatal exposure to an estrogen (estradiol benzoate) and another model of fetal exposure to an antiandrogen (flutamide). The two experimental models induce a phenotype of hypospermatogenesis in rodents. In the context of neonatal exposure to estradiol benzoate we show that the hypospermatogenesis observed in adult animals is the consequence of a chronic activation of the apoptotic process of testicular germ cells. This cell death process seem to involve the decrease of the key epigenetic effectors of DNA methylation machinery DNA methyltransferases (DNMT3A, 3B & 1), and of the antiapoptotic protein MCL-1 through post transcriptional mechanisms. In term of functional consequences the decrease of DNMTs proteins leads to increased expression of transposable element LINE-1 and Ibtk gene that are normally controlled by DNA methylation. Upstream DNMTs and MCL-1 decrease may be triggered by the increase of other epigenetic factors, the microRNAs belonging to miR-29 family. Concerning in utero exposure to flutamide, our work indicate that the chronic apoptotic process of germ cells may be linked to long term decrease of the inhibitors of apoptosis cIAP1 & 2, and an increase of proapoptotic factors SMAC/DIABLO. On the other hand, the lack of testicular somatic cell death in this model may be the result of higher expression of inhibitors of apoptosis XIAP and SURVIVIN in these cells. Besides, the apoptotic process observed at the adult age may also involve a precocious alteration of DNMTs expression. In summary, our work provides a mechanistic view to the fetal/neonatal programming of adult germ cell death. Indeed, the increased levels of miR-29s may induce: (1) a decrease in DNMTs expression levels that consequently could alter the methylation pattern of some genes, and (2) a decrease in factors that normally prevent germ cells death such as MCL-1.

Un certain nombre d’études épidémiologiques font état d’une augmentation de l’infertilité masculine durant ces cinquante dernières années, en particulier dans les pays industrialisés, mais aussi d’une augmentation des malformations de l’appareil reproducteur masculin telles que la cryptorchidie (absence de migration des testicules dans les bourses) ou l’hypospadias (malformation du pénis), et des cancers testiculaires. Des données expérimentales suggèrent que ces anomalies du tractus génital mâle sont liées. Ces symptômes forment le syndrome de dysgénésie testiculaire. Les causes d’apparition ce syndrome semblent être d’origine environnementale. En effet, les évolutions relativement rapides de ce syndrome suggèrent des facteurs dynamiques, en lien avec le mode de vie ou l’environnement. Une des hypothèses est que, l’exposition durant la vie fœtale ou néonatale à des composés présents dans l’environnement capables d’interférer avec le système hormonal (perturbateurs endocriniens environnementaux, PEEs), serait responsable de l’augmentation de l’incidence de ces pathologies. Au banc des principaux accusés, les molécules qui possèdent des activités de type estrogénique ou antiandrogénique. A ce jour, les mécanismes d’action à l’origine du syndrome de dysgénésie testiculaire sont encore mal connus. Certaines études suggèrent des mécanismes de type épigenétique dans les effets à long terme des PEEs. L’objectif de notre travail était d’identifier et caractériser les mécanismes d’action de type épigenétique impliqué dans l’infertilité mâle. Pour cela, nous avons utilisé un modèle expérimental (rats nouveau-nés) reposant sur une exposition développementale à un estrogène (estradiol benzoate). Ce modèle induit chez le rat adulte un phénotype d’hypospermatogenèse liée à une à apoptose chronique des cellules germinales testiculaires. Nous montrons que ce phénotype est lié à l’altération de deux voies, impliquant en amont des effecteurs épigénétiques. La première voie implique la famille des miR-29s. Ainsi, nous observons une augmentation de l’expression des miR-29a, b, c qui provoque une diminution de deux de ses cibles: la protéine antiapoptotique MCL-1 et les enzymes de méthylation de l’ADN DNMTs. La chute des DNMTs entraine une hypométhylation globale (estimée à travers le gène Line-1) et spécifique du facteur de choc thermique HSF1. Ceci provoque une réexpression de ces facteurs entrainant l’apoptose des cellules germinales adultes. La deuxième voie implique le miR-18a. L’augmentation de son expression provoque une chute de l’expression de sa cible HSF2 qui régule la protéine de choc thermique HSP70/HSPA2. Le faible taux d’HSPA2 est une autre explication de l’apoptose des cellules germinales dans notre modèle. Nous montrons aussi que ce phénotype est irréversible lorsque l’exposition à lieu chez le nouveau-né alors qu’il est réversible quand l’exposition à lieu à l’âge adulte. Ces données suggèrent que l’exposition néonatale à l’estradiol benzoate induit une programmation développementale de l’hypospermatogenèse.Enfin, les anomalies tissulaires d’expression des miRNAs se retrouvent au niveau sanguin, suggérant leur utilisation potentielle comme biomarqueurs. Nous avons validé cet aspect chez l’homme en montrant que l’expression des miR29s et du miR-18a était plus élevée chez les patients oligo- ou azoospermiques que les chez patients normospermiques.En conclusion, nos résultats indiquent que l’hypospermatogenèse due à une apoptose chronique des cellules germinales observée chez l’animal adulte après exposition néonatale à l’EB met en jeu une modification d’expression de plusieurs effecteurs épigénétiques clés: miR-29s, miR-18a et DNMTs. De plus, les miR-29s et miR-18a pourraient être de nouveaux biomarqueurs circulants non invasifs de la stérilité masculine dans le contexte d’une oligo ou azoospermie chez l'homme. / Epidemiological studies have reported an increase in male infertility over the past fifty years, especially in industrialized countries, but also an increase in malformations of the male reproductive tract such as cryptorchidism (no migration of the testes into the scrotum) and hypospadias (malformation of the penis), and testicular cancers. Experimental data suggest that these abnormalities of the male genital tract are related. These symptoms form the testicular dysgenesis syndrome. The causes of the occurrence of this syndrome appear to be environmental in origin. Indeed, the relatively rapid evolution of this syndrome suggests dynamic factors related to lifestyle or environment. One hypothesis is that exposure during fetal or neonatal life to compounds present in the environment can interfere with the hormonal system (environmental endocrine disruptors), would be responsible for the increased incidence of these pathologies. Bench of the main accused, molecules that have estrogenic or anti-androgenic activity types. To date, the mechanisms of action behind the testicular dysgenesis syndrome are poorly understood. Some studies suggest that epigenetic mechanisms are at playThe objective of our work was to identify and characterize the epigenetic mechanisms of action involved in male infertility induced by neonatal exposure to xenoestrogen. For this, we used an experimental model based on a developmental exposure to estrogen (estradiol benzoate). This model induced in adult rats a hypospermatogenesis phenotype due to chronic apoptosis of germ cells.We show that this phenotype is related to an alteration of two pathways, involving upstream effectors epigenetic. The first pathway involves the family of miR- 29s. Thus, we observe an up-regulation of miR -29a, b, c, which causes a decrease in two of his targets: the anti-apoptotic protein MCL- 1 and the enzymes of DNA methylation DNMTs. Falling DNMTs leads to a global hypomethylation (estimated through the Line -1 gene) and to specific hypomethylation of the heat shock factor, HSF1. This causes a re-expression of factors that induce apoptosis in adult germ cells. The second pathway involves up-regulation of miR -18a that causes a down-regulation of its target HSF2 which regulates the heat shock protein HSP70/HSPA2. The down-regulation of HSPA2 is another explanation of germ cell apoptosis in our model. We also show that this phenotype is irreversible when the estrogen exposure takes place in the newborn whereas it is reversible when exposure takes place in adulthood, suggesting that neonatal exposure to estradiol benzoate induced a developmental programming of hypospermatogenesis.Finally, abnormal tissue expressions of miRNAs are found in the blood, suggesting their potential use as biomarkers. We validated this aspect in humans showing that the expression of miR29s and miR-18a was higher in patients with decrease or no sperm counts compared to normal sperm count. In conclusion, our results indicate that hypospermatogenesis due to chronic germ cell apoptosis observed in adult animals after neonatal exposure to EB involves a change in expression of several key epigenetic effectors: miR-29, miR-18a and DNMTs. In addition, miR-29 and miR-18a could be new non invasive circulating biomarkers of men infertility.

Estudos epidemiológicos e experimentais têm sugerido que fatores de risco cardiovasculares podem ser parcialmente atribuídos às influências do ambiente em que vive o indivíduo, e que a nutrição materna influencia na programação de alterações metabólicas e cardiovasculares no indivíduo adulto e que caracterizam a síndrome metabólica (SM). Em contrapartida, estudos prévios de nosso laboratório demonstram que o extrato da casca de uva Vitis labrusca (GSE) possui efeito vasodilatador, antihipertensivo e antioxidante. Desta forma, o objetivo deste estudo foi avaliar o efeito do tratamento oral com GSE (200mg/kg/dia), sobre as alterações cardiovasculares e metabólicas e estresse oxidativo observados na prole adulta (fêmea e machos) com 3 e 6 meses, cujas mães foram submetidas a uma dieta rica em gordura (hiperlipídica) durante a lactação. Quatro grupos de ratas foram alimentados com dietas experimentais: controle (7% de gordura); controle + GSE (7% de gordura + GSE), hiperlipídica (24% de gordura); hiperlipídica + GSE (24% de gordura + GSE) durante a lactação. Após o desmame, todos os filhotes passaram a ser alimentados com uma dieta controle e foram sacrificados aos 3 ou 6 meses de idade. A pressão arterial sistólica (PAS) foi medida por pletismografia de cauda e o efeito vasodilatador da acetilcolina (ACh) foi avaliado em leito arterial mesentérico (LAM) perfundido. Foram avaliados o peso corporal, adiposidade (intra-abdominal e gonadal), níveis plasmáticos de colesterol total, triglicerídeos, glicose e insulina, e a resistência à insulina (RI) foi calculada pelo índice de HOMA IR. As expressões do IRS-1, Akt e GLUT-4 foram determinadas em músculo soleus. O dano oxidativo, níveis de nitritos e a atividade das enzimas antioxidantes: superóxido dismutase, catalase e glutationa peroxidase foram dosados no plasma e homogenato de LAM. A PAS e tecido adiposo foram aumentados nas proles adultas de ambos os sexos e idades do grupo hiperlipídico e revertidos pelo tratamento com o GSE. A resposta vasodilatadora à ACh em LAM não foi diferente entre os grupos de ambos os sexos, mas foram reduzidas com o envelhecimento. Nas proles fêmeas e machos do grupo hiperlipídico também foram observados o aumento dos níveis de triglicerídeos, de glicose e RI em ambas as idades e foram reduzidos pelo GSE. No grupo hiperlipídico houve redução nas expressões de IRS-1, Akt e GLUT-4 e o GSE reverteu estas expressões. Os níveis plasmáticos de malondialdeído estavam aumentados e os níveis de nitrito diminuídos no grupo hiperlipídico, de ambos os sexos e idades e foram revertidos pelo GSE. As atividades das enzimas antioxidantes no plasma e no mesentério foram reduzidas no grupo hiperlipídico e restauradas pelo GSE. Em conclusão, O GSE parece proteger as proles fêmeas e machos, cujas mães foram expostas a uma dieta hiperlipídica durante a lactação, dos fatores de riscos cardiovasculares, proporcionando uma fonte alternativa nutricional para a prevenção da SM. / Epidemiological and experimental studies have suggested that cardiovascular risk factors can be partly attributed to the influences of the environment in which the individual lives, and that maternal nutrition influences the programming of metabolic and cardiovascular diseases in adults characterizing the metabolic syndrome. On the other hand, previous studies from our laboratory show that the skin extract of grape Vitis labrusca (GSE) has antihypertensive, antioxidant and vasodilator effects. Thus, the aim of this study was to evaluate the effect of oral treatment with GSE (200mg/kg/day) on the cardiovascular and metabolic disorders and oxidative stress observed in adult offspring (female and male) at 3 or 6 months whose mothers were fed a high fat diet (HF) during lactation. Four groups of rats were fed experimental diets: control (7% fat), control + GSE (7% fat + GSE), diet (24% fat), HF + GSE (24% fat + GSE) during lactation. After weaning, all pups have become fed a control diet and were sacrificed at 3 or 6 months of age. Systolic blood pressure (SBP) was measured by plethysmography and the vasodilator effect of acetylcholine (ACh) was studied in perfused mesenteric arterial bed (MAB). We determined the body weight, adiposity, plasma total cholesterol, triglycerides, glucose, insulin, and insulin resistance was calculated by HOMA IR. The expression of IRS-1, Akt and GLUT-4 were determined in soleus muscle. Oxidative damage, nitrite levels and antioxidant enzyme activity: superoxide dismutase, catalase and glutathione peroxidase were measured in plasma and homogenate of mesentery bed. The SBP and adipose tissue were increased in adult offspring of both sex and ages of the HF group and reversed by treatment with GSE. The vasodilator response to ACh was not different between groups of both sex, but was reduced by aging. In offspring females and males of the HF group were also observed increased levels of triglycerides, glucose and insulin resistance in both ages and those changes were reduced by GSE. HF group showed a reduction in expression of IRS-1, Akt and GLUT-4 which was reversed by GSE. The malondialdehyde levels were increased and nitrite levels were decreased in the HF group of both sex and ages and those changes were reversed by GSE. The activities of antioxidant enzymes in plasma and mesentery were lower in HF group and restored by the GSE. In conclusion, GSE appears to protect the female and male offspring whose mothers were exposed to a high fat diet during lactation, against the cardiovascular risk factors, providing an alternative source of food for the prevention of metabolic syndrome.

A greater understanding of critical periods of body weight regulation, including pregnancy, may aid in efforts to optimize weight management strategies for the mother and her baby. The gestational period has been implicated to play, in the child, a vital role in the developmental origins of obesity and other cardiometabolic diseases later in life. Therefore, we initially examined existing literature on the role of maternal obesity and its link to pediatric obesity and documented the known underlying physiological mechanisms responsible for this relationship while suggesting potential intervention targets that may improve maternal-fetal outcomes. In a second paper, we aimed to quantify maternal predictors of large for gestational age (LGA) neonates in the Ottawa and Kingston (OaK) birth cohort with specific hypotheses verifying the independent contribution of maternal prepregnancy body mass index (BMI) and excessive gestational weight gain (GWG) to fetal overgrowth. This paper also highlights the clinical utility of the revised 2009 Institute of Medicine GWG guidelines and discusses the potential role of physiological factors underlying the observed associations between BMI, excessive GWG and LGA neonates. As a follow-up to our population-level analysis (i.e., OAK cohort), papers three and four highlight how the insulin-like growth factor (IGF) axis, a vital regulator of growth and development, may be compromised at the molecular level in cases of maternal obesity (paper 3) and excessive GWG (paper 4). In paper 3 we show that maternal obesity is associated with attenuated expression of IGF binding protein-4 (IGFBP4) in umbilical cord blood and discuss how this may preferentially promote fetal adipogenesis. The effects of excessive GWG on IGF axis protein expression are addressed in paper four where we show that excessive weight gain during pregnancy is associated with increased expression of IGFBP3 in maternal circulation in normoglycemic term pregnancies. In this paper we discuss the potential inhibitory role of IGFBP3 on adipogenesis and how it relates to glucose intolerance during pregnancy. Recognizing that both obesity and excessive GWG can alter physiological processes in mother and her baby, appropriate evidence-based interventions are warranted to best optimize outcomes. In paper five, we discuss the results of a study which sought to assess patient information channels and knowledge of nutrition and physical activity during pregnancy with the intent that these findings be applied to best design efficacious strategies that cater to the needs of our target group of pregnant women. In our analysis we show that the majority of pregnant women studied would be willing to participate in a lifestyle intervention for their own personal health and that of their child. Of great interest was the observation that most women were not informed of the importance of pregnancy-specific energy intake, or made aware of their own healthy GWG targets. Additionally, many of the respondents reported receiving no information pertaining to appropriate physical activity recommendations; despite the fact that the vast majority of participants consider this lifestyle modality to be safe during their pregnancy. Finally in paper six, we build on the results of our previous work and evaluate the risks and benefits of physical activity during pregnancy on maternal-fetal outcomes through a review of the literature and note that engaging in non-sedentary pursuits during gestation may aid in maternal weight regulation, protect against metabolic disorders and optimize neonatal birth weight and body composition. Overall, the collective nature of the papers presented in this dissertation provides qualitative and quantitative evidence to support not only the complexity of body weight regulation in the mother and her baby, but also highlights potential avenues for intervention that may improve maternal-fetal outcomes during this critical period.

A greater understanding of critical periods of body weight regulation, including pregnancy, may aid in efforts to optimize weight management strategies for the mother and her baby. The gestational period has been implicated to play, in the child, a vital role in the developmental origins of obesity and other cardiometabolic diseases later in life. Therefore, we initially examined existing literature on the role of maternal obesity and its link to pediatric obesity and documented the known underlying physiological mechanisms responsible for this relationship while suggesting potential intervention targets that may improve maternal-fetal outcomes. In a second paper, we aimed to quantify maternal predictors of large for gestational age (LGA) neonates in the Ottawa and Kingston (OaK) birth cohort with specific hypotheses verifying the independent contribution of maternal prepregnancy body mass index (BMI) and excessive gestational weight gain (GWG) to fetal overgrowth. This paper also highlights the clinical utility of the revised 2009 Institute of Medicine GWG guidelines and discusses the potential role of physiological factors underlying the observed associations between BMI, excessive GWG and LGA neonates. As a follow-up to our population-level analysis (i.e., OAK cohort), papers three and four highlight how the insulin-like growth factor (IGF) axis, a vital regulator of growth and development, may be compromised at the molecular level in cases of maternal obesity (paper 3) and excessive GWG (paper 4). In paper 3 we show that maternal obesity is associated with attenuated expression of IGF binding protein-4 (IGFBP4) in umbilical cord blood and discuss how this may preferentially promote fetal adipogenesis. The effects of excessive GWG on IGF axis protein expression are addressed in paper four where we show that excessive weight gain during pregnancy is associated with increased expression of IGFBP3 in maternal circulation in normoglycemic term pregnancies. In this paper we discuss the potential inhibitory role of IGFBP3 on adipogenesis and how it relates to glucose intolerance during pregnancy. Recognizing that both obesity and excessive GWG can alter physiological processes in mother and her baby, appropriate evidence-based interventions are warranted to best optimize outcomes. In paper five, we discuss the results of a study which sought to assess patient information channels and knowledge of nutrition and physical activity during pregnancy with the intent that these findings be applied to best design efficacious strategies that cater to the needs of our target group of pregnant women. In our analysis we show that the majority of pregnant women studied would be willing to participate in a lifestyle intervention for their own personal health and that of their child. Of great interest was the observation that most women were not informed of the importance of pregnancy-specific energy intake, or made aware of their own healthy GWG targets. Additionally, many of the respondents reported receiving no information pertaining to appropriate physical activity recommendations; despite the fact that the vast majority of participants consider this lifestyle modality to be safe during their pregnancy. Finally in paper six, we build on the results of our previous work and evaluate the risks and benefits of physical activity during pregnancy on maternal-fetal outcomes through a review of the literature and note that engaging in non-sedentary pursuits during gestation may aid in maternal weight regulation, protect against metabolic disorders and optimize neonatal birth weight and body composition. Overall, the collective nature of the papers presented in this dissertation provides qualitative and quantitative evidence to support not only the complexity of body weight regulation in the mother and her baby, but also highlights potential avenues for intervention that may improve maternal-fetal outcomes during this critical period.

A greater understanding of critical periods of body weight regulation, including pregnancy, may aid in efforts to optimize weight management strategies for the mother and her baby. The gestational period has been implicated to play, in the child, a vital role in the developmental origins of obesity and other cardiometabolic diseases later in life. Therefore, we initially examined existing literature on the role of maternal obesity and its link to pediatric obesity and documented the known underlying physiological mechanisms responsible for this relationship while suggesting potential intervention targets that may improve maternal-fetal outcomes. In a second paper, we aimed to quantify maternal predictors of large for gestational age (LGA) neonates in the Ottawa and Kingston (OaK) birth cohort with specific hypotheses verifying the independent contribution of maternal prepregnancy body mass index (BMI) and excessive gestational weight gain (GWG) to fetal overgrowth. This paper also highlights the clinical utility of the revised 2009 Institute of Medicine GWG guidelines and discusses the potential role of physiological factors underlying the observed associations between BMI, excessive GWG and LGA neonates. As a follow-up to our population-level analysis (i.e., OAK cohort), papers three and four highlight how the insulin-like growth factor (IGF) axis, a vital regulator of growth and development, may be compromised at the molecular level in cases of maternal obesity (paper 3) and excessive GWG (paper 4). In paper 3 we show that maternal obesity is associated with attenuated expression of IGF binding protein-4 (IGFBP4) in umbilical cord blood and discuss how this may preferentially promote fetal adipogenesis. The effects of excessive GWG on IGF axis protein expression are addressed in paper four where we show that excessive weight gain during pregnancy is associated with increased expression of IGFBP3 in maternal circulation in normoglycemic term pregnancies. In this paper we discuss the potential inhibitory role of IGFBP3 on adipogenesis and how it relates to glucose intolerance during pregnancy. Recognizing that both obesity and excessive GWG can alter physiological processes in mother and her baby, appropriate evidence-based interventions are warranted to best optimize outcomes. In paper five, we discuss the results of a study which sought to assess patient information channels and knowledge of nutrition and physical activity during pregnancy with the intent that these findings be applied to best design efficacious strategies that cater to the needs of our target group of pregnant women. In our analysis we show that the majority of pregnant women studied would be willing to participate in a lifestyle intervention for their own personal health and that of their child. Of great interest was the observation that most women were not informed of the importance of pregnancy-specific energy intake, or made aware of their own healthy GWG targets. Additionally, many of the respondents reported receiving no information pertaining to appropriate physical activity recommendations; despite the fact that the vast majority of participants consider this lifestyle modality to be safe during their pregnancy. Finally in paper six, we build on the results of our previous work and evaluate the risks and benefits of physical activity during pregnancy on maternal-fetal outcomes through a review of the literature and note that engaging in non-sedentary pursuits during gestation may aid in maternal weight regulation, protect against metabolic disorders and optimize neonatal birth weight and body composition. Overall, the collective nature of the papers presented in this dissertation provides qualitative and quantitative evidence to support not only the complexity of body weight regulation in the mother and her baby, but also highlights potential avenues for intervention that may improve maternal-fetal outcomes during this critical period.