The prevalence of overweight and obesity have risen to epidemic proportions. Overweight and obesity are prominent risk factors for the development of chronic disease including diabetes, cardiovascular disease and cancer. Especially pronounced in women of reproductive age and children, the obesity epidemic represents a major threat to global health. Maternal obesity is a key predictor of childhood obesity and diseases of metabolic origin in adulthood. Previous work has demonstrated that the exposure to early life adversity, in the context of maternal obesity, is associated with an increased risk of metabolic disease and obesity in the offspring later in life. Although the mechanisms outlining the relationship between maternal and offspring obesity remain unclear, the intestinal microbiota has come forth as a promising area of research. To understand the factors involved in the maternal intestinal microbial shifts with healthy pregnancy, the preliminary study focused on investigating whether female sex-steroid hormones mediate maternal intestinal microbial shifts in non-pregnant, regularly cycling female mice. We have identified that intestinal microbial shifts are not associated with sex-steroid hormone fluctuations. The second study examined whether maternal intestinal microbial shifts that occur during obese pregnancy were associated with altered inflammatory signaling and function of the maternal intestine and placenta at a critical period of development; embryonic (E) day 14.5. Females fed a high fat diet (HFD) were significantly heavier at mating and throughout gestation compared to CON. At E14.5, High fat (HF) dams displayed increased adiposity, hyperglycemia, hyperinsulinemia, hyperleptinemia and were insulin resistant. Pregnancy and maternal obesity resulted in shifts in the maternal intestinal microbiota, where the most significant increase in microbial relative abundance was exhibited by the mucin degrading genus, Akkermansia. At E14.5, maternal intestinal microbial shifts were associated with higher maternal intestinal NFκB activity in all sections of the maternal intestine, most notably in the maternal colon. Maternal obesity was associated with increased Muc5ac mRNA levels and a modest increase in CD3+ T cells in the maternal colon at E14.5. However, maternal intestinal permeability was unchanged between groups. In the placenta, mRNA levels of key signaling components in the pro-inflammatory toll-like receptor 4 (TLR4) pathway; TRAF6, NFκB and potent pro-inflammatory cytokine TNF-α were increased and in HF females. Maternal obesity was associated with an increase in CD3+ T cells in the junctional zone (JZ), but not in the labyrinth zone (LZ) of the placenta at E14.5. These findings were associated with increased mRNA levels of critical nutrient transporters; glucose transporter 1 (GLUT1) and sodium-coupled neutral amino acid transporter 2 (SNAT2) and a modest increase in glucose transporter 3 (GLUT3) in HF placentae compared to CON. These data identify the mechanistic signaling pathways and cell types involved in modulating the intrauterine environment, thus contributing to the current literature devoted to the investigation of the developmental origins of obesity. / Thesis / Master of Science (MSc)

Background: Pregnancy induces transient bone mass loss. Dairy foods might promote bone health, yet few interventions have been conducted to optimize maternal bone health in the perinatal period. Objectives: To conduct a Nutrition+Exercise randomized controlled trial (RCT) in pregnant women to assess the impact on maternal bone health by measures of calciotropic and bone biomarkers at the end of pregnancy and in the post-partum period. Study design: In the Be Healthy in Pregnancy (BHIP) RCT, 203/241 women consented at randomization (12-17 weeks (wk) gestation) to the bone health sub-study and received either usual care or a Nutrition+Exercise intervention that provided an individualized high protein diet (50% as dairy products) and a walking program throughout pregnancy. Maternal characteristics and fasting blood samples were obtained at 12-17 wk and 36-38 wk gestation, and at six months post-partum. Vitamin D status from the BHIP participants was compared to the FAMILY birth cohort participants (assessed at 24-36 wk gestation) to assess changes over a ten-year span. The response of the calciotropic and bone biomarkers to the RCT intervention was assessed at the end of pregnancy and in the post-partum period. Results: Adequate vitamin D status in pregnancy was observed in 322 participants from the FAMILY and 191 from the BHIP study, impacted by season and supplement intake. For participants in the BHIP study, serum 1,25-dihydroxyvitamin D concentrations increased throughout pregnancy and were not associated with serum 25(OH)D. Participants from the intervention group had lower serum bone resorption marker CTX compared to control group, which was reflected in cord serum. No differences were observed with other bone biomarkers at the end of pregnancy or in the post-partum period. Conclusion: Higher protein and calcium intake compared to the control group during pregnancy minimized bone resorption, thus protecting maternal bone health in the perinatal period. / Thesis / Doctor of Philosophy (Medical Science) / Background: Adaptations in maternal bone metabolism during pregnancy and the post-partum period provide the offspring with the nutrients needed to mineralize their bones. Maternal diet and hormonal changes influence these metabolic changes. Method: In 203 women recruited to the Bone-Be Healthy in Pregnancy Study randomized controlled trial, we compared changes in bone metabolism during pregnancy and at six months post-partum between women randomized to an individualized and monitored Nutrition + Exercise intervention or usual care (control) throughout pregnancy. Results: The intervention group consumed more protein and calcium, but had similar and adequate vitamin D status. At the end of pregnancy, women in the intervention group had less bone loss compared to the control group, but all measures were similar at 6 months post-partum. Clinical significance: The nutrition and exercise intervention reduced maternal bone loss during pregnancy, and could be a feasible intervention to support bone health of pregnant women.

Introdução: O modelo teórico, no qual perfis extremos de desigualdade coexistem num cenário complexo promovendo desfechos de saúde similares, denominado “similaridades nas desigualdades”, surgiu de evidências em humanos. O objetivo deste trabalho foi propor um modelo animal para refletir o fenômeno "similaridades nas desigualdades". Métodos: As ratas prenhes foram randomizadas pelo peso corporal, mantidas individualmente e no dia 10 de gestação foram divididas em três grupos: Controle (Cont), que recebeu ração padrão à vontade; Restrição Alimentar 50% (R50%), que recebeu 50% do consumo do grupo controle e Dieta Rica em Gordura (RG), que recebeu uma dieta rica em gordura à vontade. Essas dietas foram oferecidas a partir do dia 10 de gestação até o dia 21 de lactação. Em até 24 horas após o nascimento, todos os filhotes foram adotados por outras mães, formando os seguintes grupos: Cont_Cont, R50%_Cont, R50%_R50%, Cont_R50%, RG_Cont, RG_RG, Cont_RG. Peso corporal e consumo alimentar das genitoras, peso ao nascer, peso ao longo da vida e exercício físico voluntário foram comparados entre grupos por Equação de Estimação Generalizada (GEE), usando diferentes modelos estatísticos. ANOVA de duas vias foi usada para avaliar os desfechos de gordura abdominal e medidas bioquímicas. Resultados: O peso corporal das genitoras Cont e RG foi maior, comparado ao peso das genitoras R50%. Além de alguns efeitos isolados da exposição às dietas R50% ou RG durante momentos específicos perinatais (gestação e/ou lactação), o efeito das "similaridades nas desigualdades" foi observado no peso ao nascer (ambos filhotes R50% e RG foram mais leves do que os Cont) e na atividade física (os grupos extremos R50%_Cont e RG_Cont foram igualmente diferentes do grupo de referência Cont_Cont, sendo machos menos ativos e fêmeas mais ativas). O acompanhamento do peso corporal ao longo da vida mostrou que os machos pesaram mais que as fêmeas. Nenhum dos três modelos estatísticos evidenciou diferenças entre grupos no total de gordura abdominal. Conclusão: Este estudo contribui com a idéia de que as desigualdades em saúde estão relacionadas a resultados similares em saúde para ambos os extremos populacionais, e propõe um modelo animal para explorar ainda mais este efeito. / Introduction: We have previously proposed a theoretical model in which extreme unequal social backgrounds coexist in a complex scenario promoting similar health outcomes, named “Similarities in the inequalities”, and had evidence of this effect in humans. Our objective was to propose an animal model to reflect the “Similarities in the inequalities” phenomenon. Methods: Rats were time-mated and randomly allocated to: Control (Adlib), receiving an ad libitum diet of standard laboratory chow, 50% food restricted (FR), receiving 50% of the ad libitum-fed dam’s intake and high fat diet (HF), receiving a diet containing 45.0% fat. These diets were provided from day 10 of pregnancy throughout the 21-day of lactation. Within 24 hours after birth, all pups were cross-fostered to other dams, forming the following groups: Adlib_Adlib, FR_Adlib, FR_FR, Adlib_FR, HF_Adlib, HF_HF, Adlib_HF. Dam’s body weight and show consumption, pup’s birth weight, growth and physical activity in running wheels, was compared between groups through GEE, using different statistical models. Twoway ANOVA was used to evaluate abdominal fat and biochemical outcomes. Results: Body weight of Adlib and HF dams was higher compared to FR dams. Apart from some isolated effects of the exposure to the FR or HF diets during specific perinatal times (gestation and/or lactation), the “Similarities in the inequalities” effect was seen in birth weight (both FR and HF pups were smaller than Adlib pups) and physical activity (the extreme groups FR_Adlib and HF_Adlib were similarly different from the reference group Adlib_Adlib, being less active in males and more active in females). Body weight monitoring throughout life showed that males were heavier than females. None of the three statistical models showed differences between groups in total abdominal fat. Conclusion: Our study contributes to the idea that health inequalities are related to similar health outcomes for both populational extremes, and proposes an animal model to further explore this effect.

Introdução: O modelo teórico, no qual perfis extremos de desigualdade coexistem num cenário complexo promovendo desfechos de saúde similares, denominado “similaridades nas desigualdades”, surgiu de evidências em humanos. O objetivo deste trabalho foi propor um modelo animal para refletir o fenômeno "similaridades nas desigualdades". Métodos: As ratas prenhes foram randomizadas pelo peso corporal, mantidas individualmente e no dia 10 de gestação foram divididas em três grupos: Controle (Cont), que recebeu ração padrão à vontade; Restrição Alimentar 50% (R50%), que recebeu 50% do consumo do grupo controle e Dieta Rica em Gordura (RG), que recebeu uma dieta rica em gordura à vontade. Essas dietas foram oferecidas a partir do dia 10 de gestação até o dia 21 de lactação. Em até 24 horas após o nascimento, todos os filhotes foram adotados por outras mães, formando os seguintes grupos: Cont_Cont, R50%_Cont, R50%_R50%, Cont_R50%, RG_Cont, RG_RG, Cont_RG. Peso corporal e consumo alimentar das genitoras, peso ao nascer, peso ao longo da vida e exercício físico voluntário foram comparados entre grupos por Equação de Estimação Generalizada (GEE), usando diferentes modelos estatísticos. ANOVA de duas vias foi usada para avaliar os desfechos de gordura abdominal e medidas bioquímicas. Resultados: O peso corporal das genitoras Cont e RG foi maior, comparado ao peso das genitoras R50%. Além de alguns efeitos isolados da exposição às dietas R50% ou RG durante momentos específicos perinatais (gestação e/ou lactação), o efeito das "similaridades nas desigualdades" foi observado no peso ao nascer (ambos filhotes R50% e RG foram mais leves do que os Cont) e na atividade física (os grupos extremos R50%_Cont e RG_Cont foram igualmente diferentes do grupo de referência Cont_Cont, sendo machos menos ativos e fêmeas mais ativas). O acompanhamento do peso corporal ao longo da vida mostrou que os machos pesaram mais que as fêmeas. Nenhum dos três modelos estatísticos evidenciou diferenças entre grupos no total de gordura abdominal. Conclusão: Este estudo contribui com a idéia de que as desigualdades em saúde estão relacionadas a resultados similares em saúde para ambos os extremos populacionais, e propõe um modelo animal para explorar ainda mais este efeito. / Introduction: We have previously proposed a theoretical model in which extreme unequal social backgrounds coexist in a complex scenario promoting similar health outcomes, named “Similarities in the inequalities”, and had evidence of this effect in humans. Our objective was to propose an animal model to reflect the “Similarities in the inequalities” phenomenon. Methods: Rats were time-mated and randomly allocated to: Control (Adlib), receiving an ad libitum diet of standard laboratory chow, 50% food restricted (FR), receiving 50% of the ad libitum-fed dam’s intake and high fat diet (HF), receiving a diet containing 45.0% fat. These diets were provided from day 10 of pregnancy throughout the 21-day of lactation. Within 24 hours after birth, all pups were cross-fostered to other dams, forming the following groups: Adlib_Adlib, FR_Adlib, FR_FR, Adlib_FR, HF_Adlib, HF_HF, Adlib_HF. Dam’s body weight and show consumption, pup’s birth weight, growth and physical activity in running wheels, was compared between groups through GEE, using different statistical models. Twoway ANOVA was used to evaluate abdominal fat and biochemical outcomes. Results: Body weight of Adlib and HF dams was higher compared to FR dams. Apart from some isolated effects of the exposure to the FR or HF diets during specific perinatal times (gestation and/or lactation), the “Similarities in the inequalities” effect was seen in birth weight (both FR and HF pups were smaller than Adlib pups) and physical activity (the extreme groups FR_Adlib and HF_Adlib were similarly different from the reference group Adlib_Adlib, being less active in males and more active in females). Body weight monitoring throughout life showed that males were heavier than females. None of the three statistical models showed differences between groups in total abdominal fat. Conclusion: Our study contributes to the idea that health inequalities are related to similar health outcomes for both populational extremes, and proposes an animal model to further explore this effect.

Introdução: O modelo teórico, no qual perfis extremos de desigualdade coexistem num cenário complexo promovendo desfechos de saúde similares, denominado “similaridades nas desigualdades”, surgiu de evidências em humanos. O objetivo deste trabalho foi propor um modelo animal para refletir o fenômeno "similaridades nas desigualdades". Métodos: As ratas prenhes foram randomizadas pelo peso corporal, mantidas individualmente e no dia 10 de gestação foram divididas em três grupos: Controle (Cont), que recebeu ração padrão à vontade; Restrição Alimentar 50% (R50%), que recebeu 50% do consumo do grupo controle e Dieta Rica em Gordura (RG), que recebeu uma dieta rica em gordura à vontade. Essas dietas foram oferecidas a partir do dia 10 de gestação até o dia 21 de lactação. Em até 24 horas após o nascimento, todos os filhotes foram adotados por outras mães, formando os seguintes grupos: Cont_Cont, R50%_Cont, R50%_R50%, Cont_R50%, RG_Cont, RG_RG, Cont_RG. Peso corporal e consumo alimentar das genitoras, peso ao nascer, peso ao longo da vida e exercício físico voluntário foram comparados entre grupos por Equação de Estimação Generalizada (GEE), usando diferentes modelos estatísticos. ANOVA de duas vias foi usada para avaliar os desfechos de gordura abdominal e medidas bioquímicas. Resultados: O peso corporal das genitoras Cont e RG foi maior, comparado ao peso das genitoras R50%. Além de alguns efeitos isolados da exposição às dietas R50% ou RG durante momentos específicos perinatais (gestação e/ou lactação), o efeito das "similaridades nas desigualdades" foi observado no peso ao nascer (ambos filhotes R50% e RG foram mais leves do que os Cont) e na atividade física (os grupos extremos R50%_Cont e RG_Cont foram igualmente diferentes do grupo de referência Cont_Cont, sendo machos menos ativos e fêmeas mais ativas). O acompanhamento do peso corporal ao longo da vida mostrou que os machos pesaram mais que as fêmeas. Nenhum dos três modelos estatísticos evidenciou diferenças entre grupos no total de gordura abdominal. Conclusão: Este estudo contribui com a idéia de que as desigualdades em saúde estão relacionadas a resultados similares em saúde para ambos os extremos populacionais, e propõe um modelo animal para explorar ainda mais este efeito. / Introduction: We have previously proposed a theoretical model in which extreme unequal social backgrounds coexist in a complex scenario promoting similar health outcomes, named “Similarities in the inequalities”, and had evidence of this effect in humans. Our objective was to propose an animal model to reflect the “Similarities in the inequalities” phenomenon. Methods: Rats were time-mated and randomly allocated to: Control (Adlib), receiving an ad libitum diet of standard laboratory chow, 50% food restricted (FR), receiving 50% of the ad libitum-fed dam’s intake and high fat diet (HF), receiving a diet containing 45.0% fat. These diets were provided from day 10 of pregnancy throughout the 21-day of lactation. Within 24 hours after birth, all pups were cross-fostered to other dams, forming the following groups: Adlib_Adlib, FR_Adlib, FR_FR, Adlib_FR, HF_Adlib, HF_HF, Adlib_HF. Dam’s body weight and show consumption, pup’s birth weight, growth and physical activity in running wheels, was compared between groups through GEE, using different statistical models. Twoway ANOVA was used to evaluate abdominal fat and biochemical outcomes. Results: Body weight of Adlib and HF dams was higher compared to FR dams. Apart from some isolated effects of the exposure to the FR or HF diets during specific perinatal times (gestation and/or lactation), the “Similarities in the inequalities” effect was seen in birth weight (both FR and HF pups were smaller than Adlib pups) and physical activity (the extreme groups FR_Adlib and HF_Adlib were similarly different from the reference group Adlib_Adlib, being less active in males and more active in females). Body weight monitoring throughout life showed that males were heavier than females. None of the three statistical models showed differences between groups in total abdominal fat. Conclusion: Our study contributes to the idea that health inequalities are related to similar health outcomes for both populational extremes, and proposes an animal model to further explore this effect.

Although the association between social inequality and poor adult health is well established, the mechanisms by which inequality is translated into poor adult health are less clear. Increasingly, evidence suggests that many adult health problems and health disparities have their origins in early life; the developmental origins of health and disease (DOHaD) hypothesis provides an explanatory mechanism linking adverse early life conditions with permanent structural or functional changes that increase the risk for disease. This hypothesis is consistent with bioarchaeological research noting reduced lifespan among individuals exhibiting signs of childhood stress. The principal aim of this dissertation is to contribute a bioarchaeological perspective to health disparities research by investigating how health disparities can be measured and understood in the past. This study focuses on early life conditions as a source of adult health disparity by examining a skeletal sample for the association between childhood stress and adult longevity; the relationship between childhood stress and the presence of adult health conditions; and sex, ancestry, and regional differences in these relationships. The study sampled 830 age-documented, U.S. born African American males and females and Euro-American males from the Terry and the Hamann-Todd anatomical collections, representing socially-marginalized individuals from the late 19th- to early 20th centuries. Enamel hypoplasia, femoral length, and vertebral neural canal diameters represented childhood stress; skeletal fractures, tibial periostosis, and the diseased, missing, and filled tooth index represented adult health. Longevity was modeled with Kaplan-Meier survival curves and adult health relationships were modeled with logistic regression. Additionally, cause of death data from historic health department publications and the study sample morgue records were examined for disparity in the epidemiological transition from infectious to degenerative cause of death. The study found mixed results for all analyses. There was no reduction in longevity for the presence of enamel hypoplasia, short femoral length, or reduced thoracic neural canal diameter. African American males had statistically significant reduced longevity for small lumbar vertebral neural canal diameters. African American males from the Hamann-Todd Collection and Euro-American males from both collections had significant relationships between vertebral neural canal diameters and adult conditions; these relationships varied among the groups but in most cases demonstrated reduced odds for having the adult condition for individuals with smaller canal diameters. African American females had no differential survival or relationships between variables over the lifecourse. All groups except for the Terry Collection Euro-American males continued to have more infectious disease deaths than degenerative disease deaths. The study results contribute to disparities research by demonstrating that the consequences of childhood stress varied by sex and ancestry and by demonstrating within-population variation in timing of the epidemiological transition. Additionally, the study results support the contention of greater male sensitivity to environmental conditions and contributes evidence supporting the DOHaD hypothesis.

Objectives: To investigate the preventive potential of the Developmental Origins of Health and Disease (DOHaD) hypothesis as it pertains to emotion dysregulation and psychopathology by: i) elucidating the impact of modifiable perinatal risk factors, and ii) examining whether a postnatal intervention can improve infant emotion regulation. Methods: Studies 1 and 2 used data from the Canadian Healthy Infant Longitudinal Development (CHILD) cohort and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort to examine if modifiable perinatal risk factors (including prenatal diet quality) confounded the link between prenatal metabolic complications and offspring psychopathology. Study 3 used MIREC data to examine if prenatal diet quality was linked to a biomarker of emotion regulation in infants (autonomic nervous system (ANS) function). Studies 4 and 5 used data from 40 infants of mothers diagnosed with postpartum depression (PPD) and 40 healthy control infants matched on infant age sex and socioeconomic status. These studies examined if infant emotion regulation (Study 4) and mother-infant physiological synchrony (a marker of dyadic emotion regulation-Study 5) improved following maternal cognitive behavioral therapy (CBT) for PPD. Results: In Studies 1 and 2, prenatal diet quality accounted for significant variance in the links between prenatal metabolic complications and offspring psychopathology. In Study 3, poor prenatal diet quality was associated with adverse ANS development in offspring. In Studies 4 and 5, infants exhibited more adaptive emotion regulation and mother-infant synchrony improved following maternal receipt of CBT for PPD. v Conclusions: Elucidating the impact of modifiable perinatal risk factors on offspring psychopathology provides meaningful targets for intervention, and postnatal interventions may improve offspring emotion regulation and could reduce the risk of psychopathology. This work highlights the importance of the perinatal period as a time during which modifiable risk factors can be identified and intervened upon to reduce mental disorder risk across the lifespan. / Dissertation / Doctor of Philosophy (PhD) / Healthy brain development is important for health and success in life. However, risk factors such as the mother’s poor physical and mental health during pregnancy and in the first postnatal year can increase the risk of emotion and behaviour problems in offspring. Therefore, the objectives of this thesis were to i) identify links between modifiable pre and postnatal risk factors and poorer offspring brain development and ii) determine if intervening on one of these risk factors might improve offspring brain development. Results from this thesis show that an unhealthy maternal diet in pregnancy was linked to more offspring emotion, behaviour, and brain development problems and that treating postpartum depression in mothers may improve offspring brain development. This work suggests that identifying and intervening on modifiable risk factors is important to improve early brain development and may prevent the development of mental disorders later in life.

This study investigates frailty, defined as the accumulation of deficits in physiological functioning, by applying the Skeletal Frailty Index (SFI) to a skeletal sample (N=67) recovered from the Mississippi State Asylum (MSA), and in a comparative sample, the Terry Collection. The SFI was statistically modified to increase its utility here. Variables that influence frailty, including age, sex, stress in early-life, and resilience, were assessed relative to four SFIs: Overall, Nutritional, Activity, and Infection. This study finds that the predicted relationships between the SFIs and the aforementioned variables are largely absent in the MSA sample. When compared to individuals in the Terry, MSA individuals generally manifest a lower prevalence of biomarkers but have reduced longevity, which suggests that MSA patients experienced higher frailty and lower resilience. This may be attributable to negative biosocial experiences over the life course prior to institutionalization, but primarily to often-negative environmental conditions during institutionalization.

While the impacts of maternal obesity on placental development have been extensively studied, the role of the father’s health in regulating placentation is less understood. Paternal obesity is associated with offspring metabolic dysfunction, but the mechanism regulating this association is unclear. We investigated how paternal diet-induced obesity impacted placental vascular development, associated cellular stress pathways, and markers of placental endocrine function and macronutrient transport across gestation in a murine model. We found that paternal obesity is associated with placental hypoxia as measured by CAIX and HIF1α at E14.5 which persisted to E18.5. Hypoxia was associated with increased VEGF protein levels, as well as its pro-angiogenic receptor, VEGFR2 in male and female E14.5 placentae, although, this increase was apparent only in females at E18.5. The proportion of placental tissue that was immunopositive for the endothelial cell marker CD31 was increased in female but not male E18.5 placentae. Paternal obesity was associated with cellular stress as measured by the three branches of the unfolded protein response (UPR): ATF6, PERK, and IRE1α. However, despite increased phosphorylation of PERK and IRE1α in placental tissue derived from obese fathers, there was no impact on downstream signal transducers. Pro-apoptotic Bcl2 family members’ transcript levels were reduced at E18.5 in placentae from obese fathers, but this did not correspond to any changes in cleaved casp-3 protein levels. Placental lactogen and macronutrient transporter transcript levels were similar between groups across gestation, although Igf2 transcripts were increased in female placenta from obese fathers at both mid and late gestation. Thus, paternal obesity results in placental hypoxia and VEGF mediated sex specific changes in vascularization with a pro-angiogenic response occurring in females. Future studies will investigate whether paternal obesity impairs early placental implantation, resulting in poor vascularization and hypoxia at E18.5. / Thesis / Master of Science (MSc)

Adult exposure to high fat diet (HFD) has been linked to increased risk of musculoskeletal, cardiovascular, and metabolic diseases; however, the contribution of gestational HFD to elevated oxidative stress (OS), perinatal cardiovascular, skeletal, and metabolic dysfunction as well as long-term effects on adult offspring are incompletely understood. Pathophysiologic mechanisms linking gestational HFD, OS, and insulin resistance to perinatal development and adult-onset chronic diseases are explored in the present study, and maternal antioxidant (quercetin) is offered as a potential preventive dietary supplement to reduce fetal and maternal sequelae of HFD. Female C57BL/6 mice were fed "cafeteria-style" HFD (including 32.1% saturated fat to mimic a typical fast food menu) with or without quercetin for one month prior to conception, and throughout gestation. HFD dams developed gestational diabetes with significantly increased placental OS and vasculopathy. Neonates were smaller at birth than age-matched controls, and surviving offspring developed type 2 diabetes, hypertension and osteoporosis during adulthood, despite having been fed healthy diet throughout their postnatal life. Additional measures of bone using three-dimensionally reconstructed computed tomographic image analysis (microCT) revealed microarchitectural changes of bone at birth, and at 6 and 12 months postnatally. Fetuses from HFD dams displayed diminished bone mineral density (BMD) and disrupted endochondral and intramembranous ossification with significantly shortened distal limb lengths, as compared to offspring of standard rodent chow dams. Skeletal malformation persisted into adulthood despite the fact that both control and HFD offspring were fed conventional rodent chow throughout postnatal life. The offspring gestationally exposed to HFD showed significant decreased femoral BMD at 6 months of age and dysregulation of distal femoral trabecular architecture at 12 months of age, indicating development of osteoporosis. We were able to reduce incidence of placental vasculopathy, fetal maldevelopment and adult-onset type 2 diabetes, hypertension and osteoporosis with concurrent maternal quercetin supplementation during pregnancy. Collectively, these data suggested that maternal HFD increases placental OS and vascular damage during pregnancy, which are associated with fetal malformation and elevated adult-onset multisystemic chronic diseases. Maternal quercetin supplementation must be further explored as a potential dietary intervention for improved placental integrity, fetal development and lifelong health. / Ph. D.