Dissertationen zum Thema „Diet during pregnancy“

The SEATON cohort comprising 2000 pregnant women recruited 1997-99 was established to test if maternal nutrition during pregnancy affects the likelihood of children developing asthma. At 32 weeks gestation mothers’ diets were assessed by food frequency questionnaire. 1,924 live singleton births comprised the birth cohort with follow-up at 6 months, 1, 2, 5 and 10 years (the latter the focus of this thesis). Children’s diets were assessed at 5 and 10 years. Their asthmatic status was assessed by International Study of Asthma and Allergies in Childhood questionnaire. Children participating at 5 or 10 years were also invited for measurement of spirometry and allergy. Cross-sectionally at 10 years 934 children (48% boys) participated by return of questionnaire, 449 also took part in the in-depth assessment. Higher maternal vitamin D intakes were associated with decreased odds of ‘doctor diagnosed asthma’, ‘wheeze ever’ and ‘wheeze in the last year’ in the children. Contrary to findings at 5 years no association between maternal vitamin E intake and asthma outcomes was seen. Longitudinally over the 10 years of the study, higher maternal vitamin D and E intakes during pregnancy were both associated with a decreased likelihood of ‘doctor diagnosed asthma’, ‘active asthma’ and ‘wheeze in the last year’ in the children. In conclusion, reduced maternal vitamin D and E intakes during pregnancy are associated with an increased likelihood of childhood asthma during the first ten years of life. Vitamin E appears to be associated with early asthma and wheeze possibly reflecting a role in affecting early airway remodelling processes. Associations with vitamin D were seen consistently over different time-points, possibly having its effect in an immunomodulatory fashion. Intervention trials are required to ascertain if intervention during pregnancy actually reduces childhood asthma rates.

Introduction Des études épidémiologiques ont montré qu'une restriction nutritionnelle pendant la grossesse pouvait conduire à une réponse adaptative du fœtus conduisant à une altération durable du métabolisme. Ainsi, les enfants nés avec un petit poids de naissance sont plus à risque de développer des maladies cardiovasculaires à l'âge adulte. L'exposition à des contaminants obésogènes pourrait également jouer un rôle dans l'augmentation du risque d'obésité. L’alimentation est une des principales voies d'exposition à ces contaminants. Après une description de la qualité de l’alimentation pendant la grossesse, l’objectif était d'étudier l'association entre l'exposition prénatale aux contaminants alimentaires et la croissance des enfants.MéthodesLes données de trois cohortes de naissance ont été utilisées : deux études françaises (EDEN et ELFE), et une étude norvégienne (MoBa). Les femmes de ces cohortes, ont rempli un questionnaire de fréquence alimentaire (QFA) portant sur l’alimentation pendant la grossesse. L'évaluation des contaminants a été réalisée en combinant le QFA et des bases de données de contamination, la deuxième Etude de l’Alimentation Total (EAT2) française pour EDEN et plusieurs bases de données de contamination pour MoBa. Premièrement dans ELFE, nous avons créé un score de qualité de l'alimentation et un score spécifique à la grossesse, puis nous avons étudié les facteurs associés à une meilleure qualité alimentaire. Ensuite, nous avons examiné l’association entre la qualité de l'alimentation et la croissance prénatale. Deuxièmement, nous avons étudié la relation entre un contaminant alimentaire : l'acrylamide (AA), et la croissance prénatale, dans EDEN, et la croissance postnatale, dans MoBa. Troisièmement, nous avons étendu nos analyses à tous les contaminants alimentaires de l’EAT2, en analysant les composés pris individuellement, puis considérés en mélange.RésultatsPremièrement, nous avons montré que les recommandations générales et spécifiques étaient globalement bien suivies par les femmes enceintes. Certaines caractéristiques socioéconomiques ou démographiques étaient associées à la fois au score de qualité de l’alimentation et au score spécifique de la grossesse telles que l’âge à l’accouchement, niveau d’étude et revenu du foyer et le tabagisme. Un score élevé de qualité de l’alimentation était associé à un poids de naissance plus élevé et un risque plus faible d'avoir un enfant petit pour l’âge gestationnel (PAG).Deuxièmement, nous avons montré que plus l'exposition pendant la grossesse à l’AA est importante, plus la taille de naissance était faible et plus le risque de PAG est élevé. Dans MoBa, nous avons constaté que l'exposition prénatale à l'AA était associée à une prévalence accrue d'enfants en surpoids ou obèses et à une plus grande vitesse de croissance du poids durant l’enfance.Dans EDEN, sur les 99 composés chimiques sélectionnés, le poids de naissance était associé négativement à l’exposition à quatre contaminants alimentaires et positivement à l’exposition à quatre autres. L'IMC à 5 ans était associé négativement à un contaminant. Aucune de ces associations étaient statistiquement significative après prise en compte de la multiplicité des tests. Lorsque les composés chimiques étaient considérés en mélanges, un mélange de contaminants était positivement associé au poids de naissance et aucun mélange n’était associé à l'IMC à 5 ans.ConclusionUne qualité de l’alimentation élevée est associée à un poids de naissance plus élevé et une diminution du risque de PAG, alors que l'exposition alimentaire à l'AA est associée à une altération de la croissance fœtale. L’exposition prénatale aux contaminants alimentaires, évaluée à partir des données d’EAT, ne semble pas préoccupante vis-à-vis de la croissance prénatale et postnatale précoce car les effets retrouvés sont de faible amplitude et ne sont plus significatifs après prise en compte des tests multiples
Introduction Maternal diet is the only prenatal source of nutrients and the major source for non-nutrients and can influence foetal growth and offspring’s long-term health. Chemicals known as “obesogens” might also play a role in increasing obesity risk and one of the main route of exposure to these chemicals is through foods. After a description of diet quality during pregnancy, the aim of this thesis was to study the association between prenatal exposure to food chemicals and prenatal and postnatal growth among children.MethodsWe used the data of three birth cohort studies: two French studies (EDEN and ELFE), and a Norwegian study (MoBa). We first described the compliance to dietary guidelines of French pregnant women and the impact of a better diet quality on birth outcomes using the data of the ELFE study. Secondly, we studied the relationship of a specific food contaminant, acrylamide, on birth size in the EDEN and postnatal growth in MoBa. Finally, we extended analyses to all available food chemicals in the second French Total Diet Study (TDS).ResultsThe nutritional guidelines for pregnant women were rather well followed in ELFE. The diet quality score was associated with higher birth weight and lower risk of having a small for gestational (SGA) baby. We showed that prenatal dietary exposure to acrylamide was associated with reduced birth size in EDEN, and to increased postnatal growth in MoBA. In EDEN, on the 99 selected food chemicals, birth weight was associated with eight chemicals (four negatively and four positively). BMI at 5 years was associated with one food chemical. These results were not significant after correction for multiple testing. When using the mixture approach, one mixture of chemical was positively associated with postnatal growth.ConclusionsThe diet quality score was associated with higher birth size. Whereas dietary exposure to acrylamide was associated with impaired foetal growth, when looking at a larger number of food chemicals, we did not find concerning association on child prenatal or postnatal growth. Exposure to food chemical assessed by TDS did not appear to be of major concern for growth but other windows of susceptibility, such as early childhood, and other outcomes, such as cognitive development, should be considered in future studies

Introduction Diet is the main source of exposure to persistent organic pollutants (POPs), including dioxins and PCBs. During pregnancy the fetus is exposed to POPs which can lead to adverse health effects. The research hypothesis of this thesis is that maternal diet, as a source of prenatal exposure to POPs, may be linked to impaired fetal growth and endocrine disruptive effects. Methods This thesis included 604 mother-child pairs from the European NewGeneris project, 50,651 mother-child pairs from the Norwegian Mother and Child Cohort (MoBa) and 707 mother-child pairs from the Rhea and the Hmar studies. Dietary data were collected during pregnancy by food frequency questionnaires. Three approaches were used to derive dietary estimates of prenatal exposure, either related to levels of POPs in maternal and cord blood or in food. Birth outcome information was obtained by medical registries. Anogenital distance measurements were collected and used as a marker of endocrine disruptive effects. Main predictors of anogenital distance were assessed and a reliability study was conducted. Results In the NewGeneris project, a dioxin-diet characterized by high maternal intakes of meat and fish was positively related to dioxins and dioxin-like compounds in maternal blood. High adherence to the dioxin-diet was associated with a reduction of -115g in birth weight. In the MoBa study, an inverse dose-response association was found between dietary dioxins and PCBs intakes during pregnancy and birth size. The negative association remained even for intakes lower than the tolerable weekly intake. In the Rhea and Hmar studies, anogenital distances were related to growth, tracked through early life and were highly reliable anthropometric measurements. A high-fat diet score during pregnancy was positively related to POPs in maternal blood and was associated with 15% reduction in anogenital distance of newborn boys. Conclusions Diet during pregnancy can influence maternal and fetal body burden of POPs. Prenatal exposure to POPs, through maternal diet, may lead to impaired fetal growth and endocrine disruptive effects, even in populations with low background exposures to POPs.
Introducció La dieta és la principal font d'exposició als contaminants orgànics persistents (COP), com les dioxines i els PCBs. Durant l'embaràs el fetus està exposat als COPs, que poden donar lloc a efectes adversos per a la salut. La hipòtesi principal d'aquesta tesi és que la dieta materna, com una font d'exposició prenatal als COPs, podria estar relacionada amb alteracions en el creixement fetal i efectes endocrins perjudicials. Mètodes En aquesta tesi es van incloure 604 parelles mare-fill del projecte europeu NewGeneris, 50.651 parelles mare-fill de la cohort noruega (MOBA) i 707 parells de mares i fills dels estudis RHEA (Grècia) i Hmar (Catalunya). Les dades dietètiques es van recollir durant l'embaràs mitjançant qüestionaris de freqüència d'aliments. Tres mètodes s'han aplicat per derivar estimacions de l'exposició dietètica prenatal, ja sigui en relació als nivells de COP en la sang materna i del cordó o en els aliments. Informació sobre el naixement va ser obtinguda pels registres mèdics. Mesures de les distàncies anogenitals es van recollir i s'han utilitzat com marcadors d'efectes endocrins pertorbadors. Els determinants principals de la distància anogenital van ser avaluats i es va fer un estudi de fiabilitat de les mesures. Resultats En el projecte NewGeneris, una dieta alta en dioxines es caracteritza per una alta ingesta materna de carn i peix, i estava positivament relacionada amb dioxines i compostos similars a les dioxines a la sang materna. Alta adherència a una dieta alta en dioxines es va associar amb una reducció de 115 g de pes al néixer. En l'estudi Moba, es va trobar una relació de dosi-resposta inversa entre la ingesta de dioxines i PCBs durant l'embaràs i el pes en néixer. L'associació es va mantenir fins i tot per una ingesta inferior al límit de ingesta tolerable. En els estudis Rhea i Hmar, les distàncies anogenitals estan relacionades amb el pes al néixer, les mesures al naixement s’associaven amb aquestes dels primers anys de vida, i les mesures antropomètriques van ser altament fiables. Una dieta alta en greixos durant l'embaràs va ser positivament relacionada amb els COP en la sang materna i es va associar amb un 15% de reducció en la distància anogenital dels nounats. Conclusions La dieta durant l'embaràs pot influir en la càrrega corporal materna i fetal dels COP. L'exposició prenatal als COP, a través de la dieta materna, pot conduir a alteracions en el creixement fetal i als efectes pertorbadors endocrins, fins i tot en poblacions amb exposicions sota els límits d’ingesta estipulats.

Introduction: Prenatal exposure to polycyclic aromatic hydrocarbons (PAH) and to acrylamide has been suggested to reduce fetal growth. The role of diet, the main source of exposure to these compounds in the general population, remains uncertain. This thesis aimed to characterize women’s exposure during pregnancy to dietary acrylamide and the genotoxic PAH benzo(a)pyrene [B(a)P], and to assess the effects of prenatal exposure to these compounds on fetal growth indicators. Methods: This thesis was done within two large European population-based cohort studies conducted in Spain and Norway: the INfancia y Medio Ambiente (INMA; n=657) and The Norwegian Mother and Child Cohort (MoBa; n=50651). Dietary B(a)P and acrylamide intakes were estimated based on information from food frequency questionnaires and the concentrations of these compounds in foods. Results: (i) Smokers had higher dietary intakes of B(a)P and acrylamide compared to non-smokers; (ii) the main predictors of B(a)P intake were shellfish and processed/cured meats while the main predictors of acrylamide intake were snacks, fried potatoes, and crisp bread; (iii) higher prenatal exposure to dietary B(a)P and acrylamide may reduce birth weight and increase the risk of small for gestational age, independently of smoking-related exposure and (iv) stronger effects of dietary B(a)P on fetal growth were observed among women with low vitamin C intake. Conclusions: Dietary B(a)P and acrylamide intakes during pregnancy may impair fetal growth. Therefore, reducing the intake of these compounds from the diet should be recommended in dietary guidelines for pregnant women. Likewise, increasing intakes of fruits and vegetables rich in vitamin C should be recommended given its potential to prevent adverse effects from exposure to such contaminants.
Introducción: La exposición prenatal a los hidrocarburos aromáticos policíclicos (HAP) y a la acrilamida ha sido asociada con la reducción del crecimiento fetal. El papel de la dieta, la principal fuente de exposición a estos compuestos en la población general, sigue siendo incierto. Los objetivos de esta tesis son caracterizar la exposición a través de la dieta a la acrilamida y a los HAP, específicamente el compuesto genotóxico benzo(a)pireno [B(a)P], durante el embarazo, y evaluar los efectos de la exposición prenatal a estos compuestos sobre indicadores del crecimiento fetal. Métodos: Esta tesis se realizó dentro del marco de dos grandes estudios europeos de cohortes de base poblacional realizados en España y Noruega: INfancia y Medio Ambiente (INMA; n=657) y The Norwegian Mother and Child Cohort (MoBa; n=50651). La ingesta de B(a)P y acrilamida fue estimada a partir de información de cuestionarios de frecuencia alimentaria y las concentraciones de estos compuestos en los alimentos. Resultados: (i) Las fumadoras tuvieron mayor ingesta de B(a)P y acrilamida a través de la dieta en comparación con las no fumadoras; (ii) los principales predictores de la ingesta de B(a)P fueron los mariscos y los embutidos, mientras que los principales predictores de la ingesta de acrilamida fueron los aperitivos, las patatas fritas y el pan crujiente; (iii) la exposición prenatal al B(a)P y la acrilamida pueden reducir el peso al nacer y aumentar el riesgo de pequeño para la edad gestacional, independientemente de la exposición relacionada con el tabaco y (iv) los efectos de la ingesta de B(a)P a través de la dieta sobre el crecimiento fetal fueron más fuertes entre las mujeres con baja ingesta de vitamina C. Conclusiones: La ingesta de B(a)P y acrilamida a través de la dieta durante el embarazo, puede perjudicar el crecimiento fetal. Consecuentemente, recomendaciones para la reducción de la ingesta de estos compuestos a través de la dieta deberían ser incluidas en las guías dietéticas para mujeres embarazadas. Asimismo, debería recomendarse un aumento en la ingesta de frutas y verduras con alto contenido en vitamina C por su potencial para prevenir efectos relacionados con la exposición a estos contaminantes.

The purpose of this study was to find the difference, if any, between the weight gain patterns during pregnancy of women attending public health clinics in Northern Virginia who were enrolled in the NIC program and women not enrolled in the NIC program. Women on the NIC program during pregnancy were identified from NIC files. The control group was chosen from among women who were shown to be both nutritionally at risk and eligible for NIC based on income, but who were not receiving NIC benefits during pregnancy.

The sample consisted of M8 subjects in each group who met certain other selection criteria. With the exception of income, there was no statistically significant difference when selected maternal and infant variables were compared.

There was no significant difference (p>.O5) between total weight gain of the two groups, although the NIC mothers gained slightly more during pregnancy than the non-NIC mothers. A series of t-tests, performed between the means of the weekly weight gains, showed no significant difference in the weekly weight gain of the two samples at any week of pregnancy.

Both samples had increased weekly weight gains near the end of pregnancy - the mean of the non-WIC group was higher and occurred slightly later than did that of the WIC group. These higher means near the end of pregnancy for the non-WIC group resulted in statistically significant differences in the two groups when comparing the last part of pregnancy and suggest that the non-WIC group is gaining a larger amount of weight very late in pregnancy.

Master of Science

Abstract Proper nutrition and optimal weight status in pregnancy are important for both the mother and her child. The present study was aimed at assessment of maternal food and nutrient intake, dietary supplement use, dietary patterns, and weight during pregnancy. Additionally, associations between maternal weight, socio-demographic and perinatal factors and advanced beta cell autoimmunity in the offspring were examined. The results from a one-year cohort of mothers entering the ongoing Type 1 Diabetes Prediction and Prevention (DIPP) study in 1998–99 (n =  797) suggested that healthy food choices were positively correlated with maternal age and education. Dietary supplements were used by 85% of the women. However, the intake of vitamin D did not meet the recommendation and folic acid intake was inadequate in 44% of the pregnant women when both food and supplementation intakes were taken into account. Seven dietary patterns were identified in 3730 pregnant women who entered the DIPP study between 1997 and 2002. The ‘healthy’, the ‘low-fat foods’ and the ‘alcohol and butter’ dietary patterns were positively associated with maternal age and education. The ‘fast food’ dietary pattern was positively associated and the ‘alcohol and butter’ pattern was inversely associated with the rate of maternal weight gain during pregnancy. Altogether, 4093 children and their mothers comprised the study population in which the relationships between maternal initial body mass index, weight gain rate, and the development of beta cell autoimmunity in the offspring were examined. Maternal weight status during pregnancy was not related to the risk of advanced beta cell autoimmunity. A higher level of maternal education was significantly associated with a decreased risk of advanced beta cell autoimmunity in children. More attention should be paid to nutritional guidance among Finnish pregnant women, especially as regards young and less well educated women. Dietary patterns may be useful for risk group identification and they may offer a framework for further research concerning diet and health outcomes among mothers and their children.

ABSTRACT Gestational weight gain (GWG) is a normal and expected component of a healthy pregnancy; however, gaining too much or too little weight poses significant risks to maternal and fetal health including fetal under - or overgrowth, downstream obesity, and cardio-metabolic disease. Children born to mothers who exceed the Institute of Medicine GWG recommendations are significantly more likely to have higher birth weights, classify as large for gestational age (LGA) and develop overweight/obesity in infancy, childhood, and adulthood. Furthermore, rapid increases in infant growth weight trajectory, defined by weight-for-length (WFL), as early as six months of life are also associated with obesity in childhood. Energy expenditure and energy intake are known contributors to weight management, have been identified as predictors of excess GWG (eGWG) and are mediators of metabolic dysregulation affecting maternal-fetal health, perhaps independently of eGWG. The ACOG and the Society of Obstetricians and Gynecologists of Canada/Canadian Society for Exercise Physiology (SOGC/CSEP) currently endorse exercising for 30-minute sessions four times a week during the prenatal period. However, the guidelines are currently being reviewed to update recommendations based on more recent literature. A two-arm, parallel group randomized controlled trial (RCT; the Maternal Obesity Management (MOM) trial), was established to mediate GWG and prevent downstream child obesity. Adult pregnant women mean age 32.6 ± 4.4 years, with pre-gravid BMI > 18.5 kg/m2, between 12 and 20 weeks gestation were randomized into one of two groups: lifestyle intervention (n = 41) who received a structured physical activity (PA) and nutrition program in addition to the MOM trial healthy pregnancy handbook, or a standard clinical care control group (n = 35). The intervention took place throughout pregnancy (~ 6 mos.), with postpartum follow-up assessments on mother and child. GWG and PA were objectively measured at three-time points in pregnancy (prior to intervention, second trimester 26-28 weeks, third trimester 36-40 weeks). Offspring WFL was directly measured at 3 and 6 mos postpartum. We hypothesized that women who participated in the lifestyle intervention including regular PA with a structured prenatal exercise class in combination with a nutrition intervention would be more likely to have offspring follow a healthy growth trajectory as measured by offspring WFL z-score between 3 to 6 months of age We assessed and compared PA which was directly measured at three time points throughout the study (baseline, second trimester between 26-28 weeks, and third trimester between 36-40 weeks gestation) using accelerometers and supported by PA recall for activities not captured by the accelerometer. Compliance to exercise classes was recorded by the instructor. Total GWG was calculated in kilograms, by subtracting weight measured at the first prenatal visit from the last visit as part of the study or last prenatal visit, before birth, to capture the full extent of GWG throughout pregnancy. GWG was also evaluated categorically based on being under, meeting, or exceeding the IOM GWG guidelines. Offspring neonatal birth weight was measured in grams as an absolute value and was obtained from antenatal obstetrical records. Infant birth weight was also evaluated categorically as small for gestational age (SGA), average for gestational age (AGA) or large for gestational age (LGA). Infant body length was collected using a tape measure; two measurements were taken to the nearest 0.5 cm and the mean value was taken as true. The tape measure method has been validated against a measuring board which found no statistically significant difference between the two methods. There were no significant differences in GWG between intervention group and control group (mean difference = 0.3 kg, 95% CI, -2.5 – 3.1, p = 0.838). There were also no significant differences in moderate to vigorous physical activity (MVPA) during the second trimester (Z = -0.3408, p = 0.733) and the third trimester of pregnancy (Z = -0.0121, p = 0.9904). However, an increase in light PA from the first study visit in early pregnancy to the second study visit at the end of the second trimester was significantly associated with decreased final GWG in the intervention group, but not in the control group (p = 0.014). Furthermore, a Wilcoxon Rank-Sum Test indicated that the change in weight-for-length z-score from 3 months to 6 months was significantly lower in children born to mothers in the intervention group compared to the children in the control group Ws = 481.00, z = 2.67, p = 0.007. Although GWG did not change, an improved early growth trajectory for offspring born to women engaged in the intervention was observed supporting that early exposures to PA, even light PA, may play a role in downstream child growth and development. Future research should further evaluate optimal tools and counselling techniques that help women make the best possible nutrition and PA choices throughout pregnancy in the best interest of maternal and child health.

More than 85% of American adults do not consume recommended amounts of fruits or vegetables. Preterm birth and hypertensive disorders of pregnancy are common adverse conditions affecting pregnancy and are leading causes of maternal and fetal morbidity and mortality. Preterm birth affects nearly 10% of all births in the United States and is on the rise, as are hypertensive disorders, which have increased by 25% over the last two decades. Pregnancy is a state of controlled inflammation, and dysregulation has been linked to preterm birth and other adverse gestational outcomes. A healthy diet is recommended in pregnancy, but little is known about the effect fruit and vegetable intake on perinatal outcomes. Omega-3 (n-3) fatty acids are essential dietary components and are known to affect inflammatory state, but little is known about how they affect inflammation in pregnancy. As current evidence is lacking, further research is needed to investigate the relationships between maternal nutrition in pregnancy, inflammation and birth outcomes. The purposes of this dissertation were to: 1) to review and evaluate the current evidence on the relationship between n-3 fatty acids and inflammation in pregnancy; 2) to evaluate the current state of the science on the impact of maternal dietary consumption of fruits and vegetables on preterm birth, gestational diabetes, preeclampsia, small for gestational age, gestational weight gain and measures of inflammation or oxidative stress in pregnancy; and 3) to examine relationships between maternal dietary intake of fruits and vegetables, cytokine expression in early and mid-pregnancy, preterm birth and gestational hypertension. A critical review of literature examining the relationship between inflammation and n-3 intake during pregnancy found that multiple inflammatory cytokines in maternal and fetal tissues were lower in women who received n-3 supplements. A second review of literature review supported an inverse relationship between fruit and vegetables and risk of preeclampsia and suboptimal fetal growth. The available evidence was insufficient to establish relationships between fruit and vegetable intake and gestational diabetes, preterm birth or inflammation. A study evaluating the relationships between maternal fruit and vegetable intake, inflammation and birth outcomes was conducted. This study provided evidence supporting a relationship between first and second trimester cytokine expression and maternal dietary intake of fruits and vegetables. Those who met recommended vegetable intake in the first trimester had higher first trimester serum CRP, IL1-α, IL-6 and TNF-α and lower first trimester cervicovaginal IL-6 levels. Those who met recommendations for first trimester fruit intake had 56% lower risk for preterm birth. Those who met second trimester vegetable intake recommendations had more than twice the risk of developing gestational hypertension. The results of this dissertation provide support for the beneficial effects of omega-3 fatty acids and fruit and vegetable intake in pregnancy. Maternal intake of these dietary components may promote optimal immune status during pregnancy. Supplementation of maternal omega-3 fatty acids may help regulate inflammation via the anti-inflammatory effects their bioactive eicosanoids exert. Fruit and vegetables have antioxidant and anti-inflammatory effects that may also help balance the inflammatory state during pregnancy. These dietary components may help promote favorable immune status during pregnancy and reduce risk of adverse perinatal outcomes such as poor fetal growth, hypertensive disorders of pregnancy and preterm birth.

Maternal high fat (HF) intake before and/or during pregnancy increases female offsprings’ mammary cancer risk in several preclinical models. Here I studied if maternal HF intake during pregnancy cause transgenerational increase in mammary cancer risk, and if the increase is reversible by treating adult offspring with inhibitors of histone deacetylases (HDAC) or DNA methyltransferases (DNMT).

Pregnant C57BL/6NTac mice were fed either a diet high in n-6 polyunsaturated fatty acids (HF) or control diet (CON). HF diet was given from gestational day (GD) 10 – 20 to target fetal primordial germ cell formation and differentiation to germ cells. Offspring in subsequent F1-F3 generations were only fed CON diet. Mammary tumor incidence, induced by 7,12-dimethylbenz[a]anthracene (DMBA), was significantly higher in F1 and F3 HF offspring, than in the controls. Tumor latency was shorter and burden higher in F1 HF, with similar trends, though not statistically significant, in F3 HF.

RNA-sequencing of normal mammary glands revealed 1587 and 4423 differentially expressed genes between HF and CON offspring in F1 and F3, respectively, of which 48 genes were similarly altered in both generations. Ingenuity Pathway Analysis identified genes associated with Notch signaling as key alterations in HF mammary glands. Knowledge-fused Differential Dependency Network analysis identified 10 node genes in HF offspring uniquely connected to genes linked to increased cancer risk, therapy resistance, poor prognosis, and impaired anti-cancer immunity.

Next, I studied whether HDAC and DNMT inhibitor treatment in adulthood of the offspring, prior to tumor formation, could reverse the increased mammary cancer risk caused by in utero HF exposure. CON and HF offspring were given valproic acid and hydralazine in drinking water (epi-treatment), starting one week after tumor initiation by DMBA. Epi-treatment significantly decreased tumor burden in HF offspring, potentially through reactivation of silenced tumor suppressors CLCA1 and CDKN2A, but adversely affected CON offspring. These adverse effects were linked to upregulation of PERK, p62 and HIF-1α in CON.

In summary, maternal HF intake during pregnancy induced transgenerational increase in offsprings’ mammary cancer risk, causes persistent changes in the expression of genes linked to increased breast cancer risk, and epi-treatment in adulthood may reduce this risk.

Maternal overweight and obesity is associated with adverse pregnancy outcomes. Both women and healthcare professionals have expressed a desire for resources to adequately support pregnant women in successful weight management. The primary aim of this research was to identify any motivational deficits for healthy diet and physical activity behaviours in first-time mothers receiving routine antenatal education and in response develop an intervention that solved these deficits, therefore improving optimal weight gain during pregnancy. Application of the ARCS Model of Motivational Instructional Design (Keller, 1987) was undertaken using a mixed method approach with six interrelated phases: Phase one: Goal setting interventions for improving weight management during pregnancy were identified through a systematic literature review. Phase two: A motivational analysis of current antenatal instruction through non-participant observation. Phase three: Maternal motivation to eat a healthy diet and exercise was explored through one-to-one telephone interviews (n=9) and a theoretical measurement tool was developed and validated in a convenience sample (n= 196) of first-time mothers Phase four: Evidence generated in phases 1-3 was collated to create an overall audience motivational profile where lack of confidence-building instruction was identified as the key motivational problem. Phase five: Motivational objectives were established and appropriate ARCS model strategies selected to solve motivational deficits. Phase six: A new resource: "Yummy Tummies" was created and evaluated positively by maternity staff and women (n=11).

Plant-based diets have recently been gaining popularity due to emerging research that highlights their positive impact on long-term health outcomes. These studies have recently become a topic of interest among the medical community, as plant-based diets have shown to decrease the risk of obesity, stroke, cardiovascular disease, hypertension, and type II diabetes in adults. However, research on plant-based diets is more limited in pregnancy and pediatrics. There are several studies that link predominantly plant-based maternal diets during pregnancy to decreased incidence of various pediatric diseases, including asthma and cancer. While the mechanism is not entirely understood, the theory is that these effects are a result of epigenetic mechanisms known as “metabolic programming”. However, more research is needed to determine whether or not plant-based diets in pregnant women would have the same beneficial epigenetic effects on cardiovascular risk factors in the offspring, given the positive cardiovascular effects they have in adults. The proposed study is a longitudinal study in which researchers will follow female patients through the course of their pregnancy and then through the development of the offspring, in order to define the link between maternal diet during pregnancy and the incidence of childhood obesity and diabetes in the offspring. With the high incidence of obesity in children in the United States, it would be worthwhile to determine whether or not prenatal factors, such as the maternal diet, are contributing to this public health problem.

碩士
中國醫藥大學
營養學系碩士班
99
More recently, epidemiological and experimental evidences suggest that the nutrient state in embryonic period is closely associated with adulthood obesity and metabolic syndrome, giving rise to the concept of “metabolic programming”. Since it has been reported that the oxidized frying oil (OFO) consumption in animals results in growth retardation and nutrients depletion, we hypothesized that OFO consumption of female mice during pregnancy might compromise the fetus development in uterus and increase the suceptibility of their offspring to high fat diet-induced obesity (DIO) and metabolic diseases in laterlife. C57BL/6J female mice were given SO and OFO diets (10% fresh soybean oil and OFO, respectively) throughout the whole gestational period. In model 1, no additional vitE was supplemented in the OFO diet. In model 2, the OFO diet was supplemented with a-tocopherol (250mg / kg diet) and mice in OFO diet were shift to normal diet at E17. At the initiation of model 1, we noticed that the OFO dams had a higher incidence of difficulty in delivery and behavior of eating pups. We suspected these problems might associated with vitE deficiency which frequently occurred in OFO-treated animals. However, in model 2, there was no improvement in these problems after correcting vit E status. Besides, the ratio of pups with congenital malformations was increased in OFO group (15.8 % vs 0%, OFO vs. SO group), implying OFO ingestion during pregnancy might deplete vitA nutrition of dams and pups and the vitA deficiency-mediated teratogenesis was presumed to be the cause of pup-eating behavior. Measurement of hormone levels in serum shows that estradiol in OFO dams was significantly higher than that of control at the late pregnency. Corticosterone levels at E18 was also significantly higher in OFO– than in SO-dams. The pleotropic effects of PPARa activation including hepatomegaly, lowered serum TG, and reduced adiposity were seen in OFO-dams at E18. In fetus at E18, there is no significant difference between two groups in litter size and fetus weight. To further identify the susceptibility to DIO and metabolic diseases in laterlife of offspring, the survival pups were devided into OFO-male, OFO-female, SO-male and SO-female according to the maternal diet during pregnancy and their respective gender. All of them were lactated by dams receiving SO diet. After weaning, they were fed with chow diet until 7 wk of age, subsequently challenged with a high fat diet for 5 weeks. Results of model 1 showed the male offspring came from OFO dams were resistance to DIO, along with a lowered TG level was found in serum and tissues. The mRNA levels of PPARa target genes (including ACO, PGC-1a and UCP1) in the adipose tissue were significantly increased in OFO-male (vs. SO-male), which explained why they resist to obesity. In contrast, the female offspring came from OFO dams were predisposed to DIO. The TG tended to be accumulated in white adipose tissue, rather than flow to muscle. The mRNA levels of CPT-1 and UCP2 were suppressed in adipose tissue of OFO-female (vs. SO-female), which explained their predisposition to obesity. In model 2, the characteristic of resistance to DIO was disappeared in OFO-male after their mother receiving a vitE supplemented OFO diet. However, the predisposition to DIO in OFO-female was sustained-accompanied with obesity, hyperphagia, hyperlipidemia, and fatty liver were seen. We concluded that mothers receiving OFO diet during pregnancy can program the lipid metabolic capacity of offspring, thus determine their suceptibility to DIO in later lifer.

碩士
中國醫藥大學
營養學系碩士班
100
Maternal nutrition during pregnancy affects embryonic development and also permanently alter metabolic functions of offspring in adulthood. It has been reported that consumption of oxidized frying oil (OFO) can modulate lipid metabolism through acativation of peroxisome proliferator-activated receptor alpha (PPARα). By increasing the expression of PPARα target genes, including acyl-Co A oxidase (ACO) and cytochrome P450 family 4A10 (CYP4A10), the OFO diet up-regulates fatty acid β-oxidation. In our previous study, a higher incidence of dystocia and pups-eaten were observed in dams receiving OFO diet during pregnancy. We speculated that the malformation of embryo might be involved in these issues. Moreover, the survival offspring from OFO-dams are resisted and susceptible to obesity in male and female, respectively, after challenging with high fat diet during adulthood. The aims of this study were to investigate: 1) the teratogenic effects of dietary OFO, and 2) the underlying mechanism associated with gestational OFO diet and the suceptibility of offspring to obesity. C57BL/6J mice were given control (SO; 10% fresh soybean oil) or OFO (10 % OFO) diet throughout the whole gestational period. Portion of mice were killed on pregnancy day 18 (d18) for toxicological study. Others were raised to delivery and their pup were used for testing propensity to obesity. For this experiment, all pups was lactated by mothers receiving SO diet until weaning, fed with standard chow diet for 4 weeks, and followed by a high fat diet challenge for 5 weeks. Therefore, four groups of offspring were obtained, i.e. SO male, OFO male, SO female and OFO female according to the maternal diet during pregnancy and their respective gender. Results of Part I: Compared with SO dams, OFO dams had significantly higher number of dead fetus, incidence of dystocia and fetus with externally congenital anormalies (especially visceral anomalies and edema) and reduced birth weight. There was no difference in retinol content in liver between SO and OFO dams, but a significantly lower level in OFO fetus were observed compared to SO fetus. The mRNA levels of gene associated with retinoids metabolism were measured by qRT-PCR. No difference between the two groups were noticed except for retinaldehyde dehydrogenase 1a1 (RALDH1a1), which was significantly greater in liver of OFO dams compared with that in SO dams. We concluded that OFO-mediated interference in retinoid metabolism, by exposing the embryos to inappropriate retinoic acid concentration, partly contributes to the teratogenic effects on OFO fetus. Result of Part II: The male offspring came from OFO dams (i.e. OFO male) were resistance to DIO, along with a lowered TG level in serum and tissues, compare with the SO male. In contrast, the female offspring came from OFO dams (i.e. OFO female) were predisposed to DIO compared to SO female. In OFO female, the TG tended to be accumulated in white adipose tissue, rather than in muscle. The OFO-mediated PPARα activation was observed in livers of dams and fetus at pregnancy d18. The hepatic mRNA levels of PPARa was significantly greater in fetus, while lowered in adult offspring of OFO dams compared to their counterpart respectively. The mRNA levels of PPARa target genes (including PPARα, ACO, PGC-1a and UCP1) in the adipose tissue were significantly increased in OFO-male compared to the SO-male, while no difference was observed between OFO female and SO female, except for UCP-1. Accordingly, the resistance to DIO in OFO male is attributable to a greater PPARα activation and a thermogenic response in white adipose tissue. For Part II, we concluded that OFO diet during pregnancy might program PPARα activation in offspring, affecting the susceptibility to obesity in offspring with sexual dimorphism.

碩士
國立臺灣大學
生理學研究所
101
Breast cancer is associated with high-fat intake. About two thirds of breast cancer in women are estrogen-dependent that contain estrogen receptor . It has been found that not only estrogen, the estrogen metabolites can also bind with estrogen receptor for the regulation of breast cancer development. We aimed to examine the effect of high fat diet on estrogen metabolism during reproductive age and pregnancy in rats. The urine was collected during 5-day estrus cycle in adult rats fed chow or high n-6 sunflower oil diets for 80 days, or collected at gestation day 10 or day 18 in pregnant rats fed the chow diet, high n-9 safflower oil, high n-6 sunflower oil without or with fish oil supplementation, low fat or high fat diets without or with fish oil supplementation. The 12 estrogen metabolites in urine was measured by HPLC with 8-channel electrochemical detector. We found that total estrogen metabolites, 16 -hydroxyestrone, 2-hydroxyestrone and estriol were increased in rat urine fed the high n-6 sunflower oil diet during reproductive age and in pregnancy compared with that fed chow or low fat diets. The methylation of 4-hydroxyestrogen and 2-hydroxyestrogen was decreased in rat urine fed the high n-6 sunflower oil or high n-9 safflower oil diets during reproductive age and in pregnancy compared with that fed chow or low fat diets. And this decreased effect of methylation of 2-hydroxyestrogen by high n-6 fat diet was increased back by fish oil supplementation during pregnancy. We proposed that carcinogen 16 -hydroxyestrone is increased and the anti-carcinogen 2-methoxyestrone is decreased in female rats fed high fat diet.

Epidemiological studies have shown that human adults have a higher chance of developing various metabolic disorders, such as type II diabetes and hypertension, due to maternal under nutrition. The concept that conditions encountered in early development can have far reaching implications for an individual’s adult life is known as the Developmental Origins of Health and Disease (DOHaD) hypothesis. In vitro studies have shown that if the amino acid leucine is not available at a high enough concentration the embryo will not exhibit normal trophectoderm protrusive activity which precedes implantation. The amino acid transport system System B0,+ is the main gateway into these cells for leucine but its expression at the transcription level has never been shown in preimplantation blastocysts. We investigated System B0,+ expression in preimplantation blastocysts from dams fed a control versus a low-protein isocaloric diet (18% and 9% casein, respectively). Using RT-PCR to detect the System B0,+ transcript, ATB0,+, we found that indeed there is expression of this amino acid transporter in the pre-implantation rat blastocyst. Due to the gender-specific nature of many DOHaD phenomena, the blastocysts were sexed using gender specific primers and a nested PCR approach. Quantitative real time PCR (qRT-PCR) results show no significant difference in ATB0,+ expression in blastocysts taken from dams fed either diet (9% n= 56, 18% n = 52; 7 dams from each diet group). Furthermore, separating the data by gender reveals no significant difference in expression. However, while not significant, there does appear to be a trend in the protein restricted blastocysts towards increased transcription of ATB0,+, suggesting System B0,+ may be responding at the transcription level to the diet. This could be part of the predictive adaptive response leading to a reprogrammed phenotype as described by the DOHaD hypothesis. Further work is needed to elucidate System B0,+’s role in developmental programming.

碩士
中國醫藥大學
營養學系碩士班
102
There are two types of adipose tissue in mammals, white and brown. White adipose tissue stores excess energy in the form of triglycerides. Conversely, brown adipose tissue dissipates chemical energy in the form of heat through the action of mitochondrial uncoupling protein 1 (UCP-1). Recent study showed, there’s one kind of adipocyte emerge within white adipose tissue, which is called brown-fat like adipocyte (brite adipocyte) or beige adipocyte. Brite adipocytes display multilocular morphology and express brown-adipocyte-specific UCP-1. The development of these brite cells in WAT is dramatically enhanced during adaptation to cold or in response to treatment with β3-selective adrenergic agonists. According to Badman’s study, FGF21 is a target gene of Peroxisome proliferator-activated receptor alpha (PPAR-α) and FGF21 might play an important role for thermogenesis in adipocytes. Our previous study found that when oxidized frying oil (OFO), a dietary PPARα agonist, was fed to pregnant mothers, their male offsprings were resistance to diet-induced obesity (DIO), accompanied with an increased expression of thermogenic genes in adipose tissue. Therefore, we proposed a hypothesis: PPARα activation during pregnancy, through upregulated FGF21, might increase thermogenic activity of adipose tissue of offsprings and reduce their propensity to DIO. In our experiment, dams were divided into two groups to receive a control diet (Ctrl group) or 0.5% clofibrate diet (CF group) during the whole gestational period. The aims of this study were to investigate whether: 1) dams receiving CF diet during gestational period could activate PPARα, thus increasing FGF21 expression in fetus liver. 2) Impact of upregulated FGF21 expression in fetus liver on the development of newly form adipose tissue. 3) Impact of upregulated FGF21 expression in fetus liver on thermogenic ability of adipose tissue and the propensity of DIO at adulthood. Our results showed that the mRNA levels of PPARα target genes were significantly increased in livers of dams and their fetus of the CF group. Clofibrate administration successfully increased mRNA levels of FGF21 in liver of fetus and its blood levels in dams at pregnancy d18. However, the hepatic mRNA levels and blood levels of FGF21 recovered at postnatal d7 neonates. After challenging with a high-fat diet at adulthood, the fat mass showed the male offsprings from the CF group resisted to DIO, while the females offsprings from the CF group were prone to be obese. Compared with their Ctrl littermates, the CF male offsprings had significantly higher mRNA and protein levels of uncoupling protein-1 (UCP-1) and mRNA levels of brite cell markers (CD137、Tmem26 and Tbx1) in inguinal WAT. In contrast, the female offsprings of CF group showed the expression levels of brite cell markers were significantly lowered. We conclude that uteral PPARα activation caused by maternal clofibrate administration leads to a greater expression level of FGF21 in fetus liver, which might determine the browning capacity of WAT during adulthood, an effect with gender difference.

Diploma thesis is divided into a theoretical and practical part. I dedicated the theoretical part not only to prenatal and perinatal obesity risk factors, but also to diagnosis, management, health complications and prevention. In the practical part, I described the outcomes of the questionnaire survey dedicated to the mothers of children aged 1-7 years. The aim of this thesis was to find out the occurrence of selected risk factors for childhood obesity. I found out that in my study group, there were some risk factors represented in relatively small quantity (for example smoking during pregnancy, smoking during breastfeeding, gestational diabetes mellitus). Other risk factors, such as mother's or father's obesity were frequent. Some risk factors for childhood obesity are obvious, while others have not yet been proved to be directly related to obesity. However, we can certainly suggest, that the healthy parents' weight, alcohol and nicotine abstinence and exclusive breastfeeding at least until the end of fourth month of life are the factors beneficial not only for the health of the child. Key words: childhood obesity; diet during pregnancy; nutritional programming; obesity prevention; obesity risk factors