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Over the last few years, during the pandemic, the Brazilian population has suffered several problems, ranging from health to socioeconomic impacts. When we consider Brazilian science, there has been an undeniable scientific delay generated by the pandemic, especially in areas that are not related to the coronavirus. In this context, with the aim of fostering collaboration among researchers in the field of Developmental Origins of Health and Diseases (DOHaD) and enhancing the potential for implementing public health strategies to prevent noncommunicable chronic diseases, the Brazilian Association of Developmental Origins of Health and Diseases (DOHaD Brazil) was established in 2020. In this narrative, we explore the effects of the COVID-19 pandemic in Brazil, focusing on its impacts on scientific research conducted in universities. Additionally, we underscore the significance of the DOHaD Brazil Association, particularly from the perspective of young researchers engaged in DOHaD research in Brazil.

Few population studies have sufficient follow-up period to examine early-life exposures with later life diseases. A critical question is whether involuntary exposure to tobacco smoke from conception to adulthood increases the risk of cardiometabolic diseases (CMD) in midlife. In the Collaborative Perinatal Project, serum-validated maternal smoking during pregnancy (MSP) was assessed in the 1960s. At a mean age of 39 years, 1623 offspring were followed-up for the age at first physician-diagnoses of any CMDs, including diabetes, heart disease, hypertension, or hyperlipidemia. Detailed information on their exposure to environmental tobacco smoke (ETS) in childhood and adolescence was collected with a validated questionnaire. Cox regression was used to examine associations of in utero exposure to MSP and exposure to ETS from birth to 18 years with lifetime incidence of CMD, adjusting for potential confounders. We calculated midlife cumulative incidences of hyperlipidemia (25.2%), hypertension (14.9%), diabetes (3.9%), and heart disease (1.5%). Lifetime risk of hypertension increased by the 2 nd -trimester exposure to MSP (adjusted hazard ratio: 1.29, 95% confidence interval: 1.01-1.65), ETS in childhood (1.11, 0.99-1.23) and adolescence (1.22, 1.04-1.44). Lifetime risk of diabetes increased by joint exposures to MSP and ETS in childhood (1.23, 1.01-1.50) or adolescence (1.47, 1.02-2.10). These associations were stronger in males than females, in never-daily smokers than lifetime ever smokers. In conclusion, early-life involuntary exposure to tobacco smoke increases midlife risk of hypertension and diabetes in midlife.

The developmental origins of health and disease (DOHaD) framework has highlighted the importance of the early life period on disease risk in later life with impacts that can span generations. A primary focus to date has been around maternal health and the 'First Thousand Days' as a key developmental window whereby an adverse environment can have lasting impacts on both mother and offspring. More recently, the impact of paternal health has gathered increasing traction as a key window for early life developmental programming. However, to date, adolescents, the next generation of parents, have attracted less attention as a key DOHaD window although many behavioural traits become entrained during adolescence and track into adulthood. This systematic review examined literature focused on identifying adolescent understanding of DOHaD concepts. Consistent across the eligible articles was that overall understanding of DOHaD-related concepts in adolescents was low. Three key themes emerged: 1. Individual-level awareness of DOHaD concepts (cognitive engagement and action of the adolescents themselves); 2. Interpersonal communication and social awareness of DOHaD concepts (cognitive engagement and communication of the DOHaD concepts to family and wider community); and 3. Health literacy and the promotion of adolescence as a key DOHaD life stage. These findings highlight the need to develop strategic approaches to increase DOHaD awareness that are not only appealing to adolescents but can also support sustained changes in health behaviour. Investment in today's adolescents has the potential to act as a NCD 'circuit breaker' and thus will yield significant dividends for future generations.

The aim of this study was to evaluate whether high-fat (HF) diet intake during puberty can program obesity as well as generate glucose imbalance and hepatic metabolic dysfunctions in adult life. Male Wistar rats were randomly assigned into two groups: rats fed standard chow (NF) and rats fed a HF from postnatal 30-day-old (PND30) until PND60. Then, both groups were fed a standard chow from PND60 until PND120. Euthanasia and samples collections occurred at PND120. HF animals were overweight (+11%) and had increased adiposity, hyperphagia (+12%), hyperglycaemia (+13%), hyperinsulinemia (+69%), and hypertriglyceridemia (+34%). Plasma glucose levels during intravenous glucose tolerance test (ivGTT) and intraperitoneal insulin tolerance test (ipITT) were also higher in the HF group, whereas K itt was significantly lower (-34%), suggesting reduced insulin sensitivity. In the same sense, HF animals present pancreatic islets hypertrophy and high β-cell mass. HF animals also had a significant increase in blood glucose levels during pyruvate tolerance test, indicating increased gluconeogenesis. Hepatic morphology analyses showed an increase in lipid inclusion in the HF group. Moreover, PEPCK and FAS protein expression were higher in the livers of the HF animals (+79% and + 37%, respectively). In conclusion, HF during puberty causes obese phenotype leading to glucose dyshomeostasis and nonalcoholic fatty liver disease, which can be related to the overexpression of proteins PEPCK and FAS.

The maternal metabolic environment can be detrimental to the health of the offspring. In a previous work, we showed that maternal high-fat (HH) feeding in rabbit induced sex-dependent metabolic adaptation in the fetus and led to metabolic syndrome in adult offspring. As early development representing a critical window of susceptibility, in the present work we aimed to explore the effects of the HH diet on the oocyte, preimplantation embryo and its microenvironment. In oocytes from females on HH diet, transcriptomic analysis revealed a weak modification in the content of transcripts mainly involved in meiosis and translational control. The effect of maternal HH diet on the embryonic microenvironment was investigated by identifying the metabolite composition of uterine and embryonic fluids collected in vivo by biomicroscopy. Metabolomic analysis revealed differences in the HH uterine fluid surrounding the embryo, with increased pyruvate concentration. Within the blastocoelic fluid, metabolomic profiles showed decreased glucose and alanine concentrations. In addition, the blastocyst transcriptome showed under-expression of genes and pathways involved in lipid, glucose and amino acid transport and metabolism, most pronounced in female embryos. This work demonstrates that the maternal HH diet disrupts the in vivo composition of the embryonic microenvironment, where the presence of nutrients is increased. In contrast to this nutrient-rich environment, the embryo presents a decrease in nutrient sensing and metabolism suggesting a potential protective process. In addition, this work identifies a very early sex-specific response to the maternal HH diet, from the blastocyst stage.

Most human studies investigating the relationship between maternal diet in pregnancy and infant epigenetic state have focused on macro- and micro-nutrient intake, rather than the whole diet. This makes it difficult to translate the evidence into practical prenatal dietary recommendations.To review the evidence on how the prenatal diet relates to the epigenetic state of infants measured in the first year of life via candidate gene or genome-wide approaches.Following the PRISMA guidelines, this systematic literature search was completed in August 2020, and updated in August 2021 and April 2022. Studies investigating dietary supplementation were excluded. Risk of bias was assessed, and the certainty of results was analysed with consideration of study quality and validity.Seven studies were included, encompassing 6852 mother-infant dyads. One study was a randomised controlled trial and the remaining six were observational studies. There was heterogeneity in dietary exposure measures. Three studies used an epigenome-wide association study (EWAS) design and four focused on candidate genes from cord blood samples. All studies showed inconsistent associations between maternal dietary measures and DNA methylation in infants. Effect sizes of maternal diet on DNA methylation ranged from very low (< 1%) to high (> 10%). All studies had limitations and were assessed as having moderate to high risk of bias.The evidence presented here provides very low certainty that dietary patterns in pregnancy relate to epigenetic state in infants. We recommend that future studies maximise sample sizes and optimise and harmonise methods of dietary measurement and pipelines of epigenetic analysis.

Melatonin supplementation to obese mothers during gestation and lactation might benefit the pancreatic islet cellular composition and beta-cell function in male offspring adulthood. C57BL/6 females (mothers) were assigned to two groups ( n = 20/each) based on their consumption in control (C 17% kJ as fat) or high-fat diet (HF 49% kJ as fat). Mothers were supplemented with melatonin (Mel) (10 mg/kg daily) during gestation and lactation, or vehicle, forming the groups ( n = 10/each): C, CMel, HF, and HFMel. The male offspring were studied, considering they only received the C diet after weaning until three months old. The HF mothers and their offspring showed higher body weight, glucose intolerance, insulin resistance, and low insulin sensitivity than the C ones. However, HFMel mothers and their offspring showed improved glucose metabolism and weight loss than the HF ones. Also, the offspring's higher expressions of pro-inflammatory markers and endoplasmic reticulum (ER) stress were observed in HF but reduced in HFMel. Contrarily, antioxidant enzymes were less expressed in HF but improved in HFMel. In addition, HF showed increased beta-cell mass and hyperinsulinemia but diminished in HFMel. Besides, the beta-cell maturity and identity gene expressions diminished in HF but enhanced in HFMel. In conclusion, obese mothers supplemented with melatonin benefit their offspring's islet cell remodeling and function. In addition, improving pro-inflammatory markers, oxidative stress, and ER stress resulted in better glucose and insulin levels control. Consequently, pancreatic islets and functioning beta cells were preserved in the offspring of obese mothers supplemented with melatonin.

Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant's fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.

The COVID-19 pandemic has exposed several inequalities worldwide, including the populations' access to healthcare systems and economic differences that impact the access to vaccination, medical resources, and health care services. Scientific research activities were not an exception, such that scientific research was profoundly impacted globally. Research trainees and early career researchers (ECRs) are the life force of scientific discovery around the world, and their work and progress in research was dramatically affected by the COVID-19 pandemic. ECRs are a particularly vulnerable group as they are in a formative stage of their scientific careers, any disruptions during which is going to likely impact their lifelong career trajectory. To understand how COVID-19 impacted lives, career development plans, and research of Developmental Origins of Health and Disease (DOHaD) ECRs, the International DOHaD ECR committee formed a special interest group comprising of ECR representatives of International DOHaD affiliated Societies/Chapters from around the world (Australia and New Zealand, Canada, French Speaking DOHaD, Japan, Latin America, Pakistan and USA). The anecdotal evidence summarized in this brief report, provide an overview of the findings of this special interest group, specifically on the impact of the evolving COVID-19 pandemic on daily research activities and its effects on career development plans of ECRs. We also discuss how our learnings from these shared experiences can strengthen collaborative work for the current and future generation of scientists.

Globally, mortality of Indigenous persons is greater than that of their non-Indigenous counterparts, which has been shown to be disproportionately attributable to non-communicable diseases. The historically subordinate position that Indigenous Knowledge (IK) held in comparison to Western science has shifted over the last several decades, with the credibility and importance of IK now being internationally recognized. Herein, we examine how Marsahall's (2014) Two-Eyed Seeing can foster collaborative and culturally relevant Developmental Origins of Health and Disease (DOHaD) studies for health and well-being by using '..the best in Indigenous ways of knowing…[and] the best in Western (or mainstream) ways of knowing…and learn to use both these eyes for the benefit of all.' At its core, Two-Eyed Seeing also includes the principles of ownership, control, access and possession, and Community-Based Participatory Research, which further reinforces the critical role of Indigenous peoples taking active roles in DOHaD research. Additionally, we also present a partnership model for working with Indigenous communities that includes the principles of respect, equity and empowerment. As researchers begin to fill the gap in Indigenous health, we outline how Two-Eyed Seeing should form the basis of DOHaD studies involving Indigenous communities. This model can be used to develop and guide projects that result in robust and meaningful participatory partnerships that have impactful uptake of research findings.

The COVID-19 pandemic has shone a spotlight on how health outcomes are unequally distributed among different population groups, with disadvantaged communities and individuals being disproportionality affected in terms of infection, morbidity and mortality, as well as vaccine access. Recently, there has been considerable debate about how social disadvantage and inequality intersect with developmental processes to result in a heightened susceptibility to environmental stressors, economic shocks and large-scale health emergencies. We argue that DOHaD Society members can make important contributions to addressing issues of inequality and improving community resilience in response to COVID-19. In order to do so, it is beneficial to engage with and adopt a social justice framework. We detail how DOHaD can align its research and policy recommendations with a social justice perspective to ensure that we contribute to improving the health of present and future generations in an equitable and socially just way.

Perinatal light exposure predisposes towards health and behaviour in adulthood. Season of birth is associated with psychiatric, allergic, cardiovascular and metabolic problems. It has been proposed that early-life environmental light disrupts the development of biological rhythms which, in turn, influence later-life health. However, the mechanisms linking perinatal seasonal light to later-life biological rhythm and health in humans are unknown. In this study, we investigated the association between season of birth and epigenome-wide DNA methylation of two postmortem human brain regions (16 hypothalamus, 14 temporal cortex). We did not find statistically significant differences at the whole epigenome level, either because we lacked statistical power or that no association exists. However, when we examined 24 CpG sites that had the highest significance or differential methylation, we identified regions which may be associated with circadian rhythm entrainment, cholinergic neurotransmission and neural development. Amongst methylation of the core clock genes, we identified that hypothalamus Neuronal PAS Domain Protein 2 (NPAS2) gene has hypermethylated regions in long photoperiod-born individuals. In addition, we found nominal associations between season of birth and genes linked to chronotype and narcolepsy. Season of birth-related brain DNA methylation profile was different than a previously reported blood methylation profile, suggesting a tissue-specific mechanism of perinatal light programming. Overall, we are the first to analyse the relationship between season of birth and human brain DNA methylation. Further studies with larger sample sizes are required to confirm an imprinting effect of perinatal light on the circadian clock.

In many human populations, especially those living in regions with pronounced climatic differences between seasons, the most sensitive (prenatal and neonatal) developmental stages occur in contrasting conditions depending on the season of conception. The difference in prenatal and postnatal environments may be a factor significantly affecting human development and risk for later life chronic diseases. Factors potentially contributing to this kind of developmental programming include nutrition, outdoor temperature, infectious exposures, duration of sunlight, vitamin D synthesis, etc. Month of birth is commonly used as a proxy for exposures which vary seasonally around the perinatal period. Season-of-birth patterns have been identified for many chronic health outcomes. In this review, the research evidence for the seasonality of birth in adult-life disorders is provided and potential mechanisms underlying the phenomenon of early life seasonal programming of chronic disease and longevity are discussed.

Nutrition during the periconceptional period influences postnatal cardiovascular health. We determined whether in vitro embryo culture and transfer, which are manipulations of the nutritional environment during the periconceptional period, dysregulate postnatal blood pressure and blood pressure regulatory mechanisms. Embryos were either transferred to an intermediate recipient ewe (ET) or cultured in vitro in the absence (IVC) or presence of human serum (IVCHS) and a methyl donor (IVCHS+M) for 6 days. Basal blood pressure was recorded at 19-20 weeks after birth. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after varying doses of phenylephrine (PE). mRNA expression of signaling molecules involved in blood pressure regulation was measured in the renal artery. Basal MAP did not differ between groups. Baroreflex sensitivity, set point, and upper plateau were also maintained in all groups after PE stimulation. Adrenergic receptors alpha-1A (αAR1A), alpha-1B (αAR1B), and angiotensin II receptor type 1 (AT1R) mRNA expression were not different from controls in the renal artery. These results suggest there is no programmed effect of ET or IVC on basal blood pressure or the baroreflex control mechanisms in adolescence, but future studies are required to determine the impact of ET and IVC on these mechanisms later in the life course when developmental programming effects may be unmasked by age.

Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.

Mono-2-ethylhexyl phthalate (MEHP) is the primary metabolite of the ubiquitous plasticizer and toxicant, di-2-ethylhexyl phthalate. MEHP exposure has been linked to abnormal development, increased oxidative stress, and metabolic syndrome in vertebrates. Nuclear factor, Erythroid 2 Like 2 (Nrf2), is a transcription factor that regulates gene expression in response to oxidative stress. We investigated the role of Nrf2a in larval steatosis following embryonic exposure to MEHP. Wild-type and nrf2a mutant (m) zebrafish embryos were exposed to 0 or 200 μg/l MEHP from 6 to either 96 (histology) or 120 hours post fertilization (hpf). At 120 hpf, exposures were ceased and fish were maintained in clean conditions until 15 days post fertilization (dpf). At 15 dpf, fish lengths and lipid content were examined, and the expression of genes involved in the antioxidant response and lipid processing was quantified. At 96 hpf, a subset of animals treated with MEHP had vacuolization in the liver. At 15 dpf, deficient Nrf2a signaling attenuated fish length by 7.7%. MEHP exposure increased hepatic steatosis and increased expression of peroxisome proliferator-activated receptor alpha target fabp1a1. Cumulatively, these data indicate that developmental exposure alone to MEHP may increase risk for hepatic steatosis and that Nrf2a does not play a major role in this phenotype.

Muscle and bone have been considered a functional unit that grows together early in life, deteriorates with aging, and can cause osteosarcopenia. Due to its importance in public health, detecting risk factors in early life is desirable. This study examined whether birth weight (BW) was associated with muscle-bone unit using dual energy X-ray absorptiometry (DXA) parameters in young women from the Nutritionists' Health Study (NutriHS), a cohort study of undergraduates and Nutrition graduates. This cross-sectional analysis included 170 young healthy women who answered early life events-questionnaire, and had anthropometric, muscle tests and DXA-determined body composition and bone densitometry (iDXA-Lunar®). A blood sample was obtained for a subsample of 148 participants. Appendicular skeletal muscle mass index (ASMI) was calculated. BW was categorized in quartiles (BWq) and variables of interest compared by ANOVA. Associations of BWq with calf circumference (CC), handgrip, muscle performance tests, ASMI, bone mineral density and content (BMD and BMC), and plasma glucose, lipids, insulin, and 25-hydroxyvitamin D were performed using multiple linear regression and directed acyclic graph-recommended adjustments. Mean values of age, body mass index, and BW were 23.0 years (20.0-28.0), 22.9 ± 2.9 kg/m2, and 3199 ± 424 g, respectively. Comparing variables across BWq, significant differences in CC, handgrip, ASMI, and total body BMC were detected. Regression models adjusted for confounders showed associations of BWq with CC (β = 0.72, p = 0.005), handgrip (β = 1.53, p = 0.001), ASMI (β = 0.16, p = 0.022), total body BMC (β = 64.8, p = 0.005), total femur BMC (β = 0.70, p = 0.041), total body BMD (β = 0.02, p = 0.043), and lumbar spine BMD (β = 0.03, p = 0.028). We conclude that BW is associated with muscle-bone unit using DXA-parameters in Brazilian young healthy women from the NutriHS, suggesting a role for intrauterine environment for musculoskeletal health.

Developmental origins of health and disease research have cemented relationships between the early-life environment and later risk of non-communicable diseases (NCDs). However, there is limited translation of this knowledge in developing-economy nations, such as the Cook Islands, that carry exceptionally high NCD burdens. Considering the evidence, Cook Islands leaders identified a need for increased community awareness of the importance of early-life nutrition. Using a community-based participatory research approach, this study aimed to engage Cook Islands community representatives in the co-construction of a contextually relevant early-life nutrition resource. A booklet distributed to mothers in Australia and New Zealand was used as a starting point. Ten semi-structured focus groups (n = 60) explored views regarding the existing resource and options for contextual adaptation. Three core themes were identified: knowledge of the importance of early-life nutrition, recognition of the need for an early-life nutrition resource and the importance of resources being context specific. A draft booklet was created based on these discussions. Participants were invited to give feedback via a second round of focus groups. This confirmed that the voice of the community was represented in the draft booklet. Suggestions for additional material not included in the original resource were also identified. We report on the process and outcomes of the co-construction with community representatives of a resource that has the potential to be used to stimulate community-level discussion about the importance of early-life nutrition. It is crucial that communities have an active voice in research and in making decisions about interventions for their population.

The Developmental Origins of Health and Disease (DOHaD) states that intrauterine maternal environment influences postnatal life by programming offspring's metabolism. Intrauterine milieu induced by exercise during pregnancy promotes long-lasting benefits to the offspring's health and seems to offer some resistance against chronic diseases in adult life. Alzheimer's disease is a public health concern with limited treatment options. In the present study, we assessed the potential of maternal exercise during pregnancy in long-term programming of young adult male rat offspring's cerebellar metabolism in conferring neuroprotection against amyloid-β (Aβ) neurotoxicity. Female Wistar rats were submitted to a swimming protocol 1 week prior mating and throughout pregnancy (five sessions/a week lasting 30 min). Aβ oligomers were infused bilaterally in the brain ventricles of 60-day-old male offspring. Fourteen days after surgery, we measured parameters related to redox state, mitochondrial function, and the immunocontent of proteins related to synaptic function. We found that maternal exercise during pregnancy attenuated several parameters in the offspring's male rat cerebellum, such as the reactive species rise, the increase of inducible nitric oxide synthase immunocontent and tau phosphorylation induced by Aβ oligomers, increased mitochondrial fission indicated by dynamin-related protein 1 (DRP1), and protein oxidation identified by carbonylation. Strikingly, we find that maternal exercise promotes changes in the rat offspring's cerebellum that are still evident in young adult life. These favorable neurochemical changes in offspring's cerebellum induced by maternal exercise may contribute to a protective phenotype against Aβ-induced neurotoxicity in young adult male rat offspring.

Chronic hypoxia during gestation induces greater occurrence of perinatal complications such as intrauterine growth restriction, fetal hypoxia, newborn asphyxia, and respiratory distress, among others. This condition may also cause a failure in the transition of the fetal to neonatal circulation, inducing pulmonary arterial hypertension of the neonate (PAHN), a syndrome that involves pulmonary vascular dysfunction, increased vasoconstrictor tone and pathological remodeling. As this syndrome has a relatively low prevalence in lowlands (~7 per 1000 live births) and very little is known about its prevalence and clinical evolution in highlands (above 2500 meters), our understanding is very limited. Therefore, studies on appropriate animal models have been crucial to comprehend the mechanisms underlying this pathology. Considering the strengths and weaknesses of any animal model of human disease is fundamental to achieve an effective and meaningful translation to clinical practice. The sheep model has been used to study the normal and abnormal cardiovascular development of the fetus and the neonate for almost a century. The aim of this review is to highlight the advances in our knowledge on the programming of cardiopulmonary function with the use of high-altitude newborn sheep as a translational model of PAHN.

Early-life chronic exposure to environmental contaminants, such as bisphenol-A, particulate matter air pollution, organophosphorus pesticides, and pharmaceutical drugs, among others, may affect central tissues, such as the hypothalamus, and peripheral tissues, such as the endocrine pancreas, causing inflammation and apoptosis with severe implications to the metabolism. The Developmental Origins of Health and Disease (DOHaD) concept articulates events in developmental phases of life, such as intrauterine, lactation, and adolescence, to later-life metabolism and health. These developmental phases are more susceptible to environmental changes, such as those caused by environmental contaminants, which may predispose individuals to obesity, metabolic syndrome, and chronic noncommunicable diseases later in life. Alterations in the epigenome are explored as an underlying mechanism to the programming effects on metabolism, as the expression of key genes related with central and peripheral metabolic functions may be altered in response to environmental disturbances. Studies show that environmental contaminants may affect gene expressions in mammals, especially when exposed to during the developmental phases of life, leading to metabolic disorders in adulthood. In this review, we discuss the current obesity epidemics, the DOHaD concept, pollutants' toxicology, environmental control, and the role of environmental contaminants in the central and peripheral programming of obesity and metabolic syndrome. Improving environmental monitoring may directly affect the quality of life of the population and help protect the future generations from metabolic diseases.

Gestational nutrition is widely recognized to affect an offspring's future risk of lifestyle-related diseases, suggesting the involvement of epigenetic mechanisms. As folic acid (FA) is a nutrient essential for modulating DNA methylation, we sought to determine how maternal FA intake during early pregnancy might influence tumor sensitivity in an offspring. Dams were maintained on a FA-depleted (FA(-)) or normal (2 mg FA/kg; FA(+)) diet from 2 to 3 days before mating to 7 days post-conception, and their offspring were challenged with chemical tumorigenesis using 7,12-dimethylbenz[a)anthracene and phorbol 12-myristate 13-acetate for skin and 4-nitroquinoline N-oxide for tongue. In both squamous tissues, tumorigenesis was more progressive in the offspring from FA(-) than FA(+) dams. Notably, in the skin of FA(-) offspring, the expression and activity of cylindromatosis (Cyld) were decreased due to the altered DNA methylation status in its promoter region, which contributed to increased tumorigenesis coupled with inflammation in the FA(-) offspring. Thus, we conclude that maternal FA insufficiency during early pregnancy is able to promote neoplasm progression in the offspring through modulating DNA methylation, such as Cyld. Moreover, we propose, for the first time, "innate" utero nutrition as the third cause of tumorigenesis besides the known causes-hereditary predisposition and acquired environmental factors.

Evidence supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis indicates that improving early life environments can reduce non-communicable disease risks and improve health over the lifecourse. A widespread understanding of this evidence may help to reshape structures, guidelines and individual behaviors to better the developmental conditions for the next generations. Yet, few efforts have yet been made to translate the DOHaD concept beyond the research community. To understand why, and to identify priorities for DOHaD Knowledge Translation (KT) programs, we review here a portion of published descriptions of DOHaD KT efforts and critiques thereof. We focus on KT targeting people equipped to apply DOHaD knowledge to their everyday home or work lives. We identified 17 reports of direct-to-public DOHaD KT that met our inclusion criteria. Relevant KT programs have been or are being initiated in nine countries, most focusing on secondary school students or care-workers-in-training; few target parents-to-be. Early indicators suggest that such programs can empower participants. Main critiques of DOHaD KT suggest it may overburden mothers with responsibility for children's health and health environments, minimizing the roles of other people and institutions. Simultaneously, though, many mothers-to-be seek reliable guidance on prenatal health and nutrition, and would likely benefit from engagement with DOHaD KT. We thus recommend emphasizing solidarity, and bringing together people likely to one day become parents (youth), people planning pregnancies, expecting couples, care workers and policymakers into empowering conversation about DOHaD and about the importance and complexity of early life environments.

Adverse exposures during fetal life and the postnatal period influence physical, cognitive and emotional development, and predispose to an increased risk of various chronic diseases throughout the life course. Findings from large observational studies in various populations and experimental animal studies have identified different modifiable risk factors in early life. Adverse maternal lifestyle factors, including overweight, unhealthy diet, sedentary behavior, smoking, alcohol consumption and stress in the preconception period and during pregnancy, are the most common modifiable risk factors leading to a suboptimal in-utero environment for fetal development. In the postnatal period, breastfeeding, infant growth and infant dietary intake are important modifiable factors influencing long-term offspring health outcomes. Despite the large amount of findings from observational studies, translation to lifestyle interventions seems to be challenging. Currently, randomized controlled trials focused on the influence of lifestyle interventions in these critical periods on short-term and long-term maternal and offspring health outcomes are scarce, have major limitations and do not show strong effects on maternal and offspring outcomes. New and innovative approaches are needed to move from describing these causes of ill-health to start tackling them using intervention approaches. Future randomized controlled lifestyle intervention studies and innovative observational studies, using quasi-experimental designs, are needed focused on the effects of an integrated lifestyle advice from preconception onwards on pregnancy outcomes and long-term health outcomes in offspring on a population level.

In Australia, there are two distinct populations, each with vastly disparate health outcomes: Aboriginal and Torres Strait Islander People and non-Aboriginal Australians. Aboriginal Australians have significantly higher rates of health and socioeconomic disadvantage, and Aboriginal babies are also more likely to be born low birth weight or growth restricted. The Developmental Origins of Health and Disease (DOHaD) hypothesis advocates that a sub-optimal intrauterine environment, often manifested as diminished foetal growth, during critical periods of foetal development has the potential to alter the risk of non-communicable disease in the offspring. A better understanding of the role of the intrauterine environment and subsequent developmental programming, in response to both transgenerational and immediate stimuli, in Aboriginal Australians remains a relatively unexplored field and may provide insights into the prevailing health disparities between Aboriginal and non-Aboriginal children. This narrative review explores the role of DOHaD in explaining the ongoing disadvantage experienced by Aboriginal People in today's society through a detailed discussion of the literature on the association between foetal growth, as a proxy for the quality of the intrauterine environment, and outcomes in the offspring including perinatal health, early life development and childhood education. The literature largely supports this hypothesis and this review therefore has potential implications for policy makers not only in Australia but also in other countries that have minority and Indigenous populations who suffer disproportionate disadvantage such as the United States, Canada and New Zealand.

Non-communicable diseases (NCDs) are a major problem as they are the leading cause of death and represent a substantial economic cost. The 'Developmental Origins of Health and Disease Hypothesis' proposes that adverse stimuli at different life stages can increase the predisposition to these diseases. In fact, adverse in utero programming is a major origin of these diseases due to the high malleability of embryonic development. This review provides a comprehensive analysis of the scientific literature on in utero programming and NCDs highlighting potential medical strategies to prevent these diseases based upon this programming. We fully address the concept and mechanisms involved in this programming (anatomical disruptions, epigenetic modifications and microbiota alterations). We also examine the negative role of in utero programming on the increased predisposition of NCDs in the offspring, which introduces the passive medical approach that consists of avoiding adverse stimuli including an unhealthy diet and environmental chemicals. Finally, we extensively discuss active medical approaches that target the causes of NCDs and have the potential to significantly and rapidly reduce the incidence of NCDs. These approaches can be classified as direct in utero programming modifications and personalized lifestyle pregnancy programs; they could potentially provide transgenerational NCDs protection. Active strategies against NCDs constitute a promising tool for the reduction in NCDs.

Small Island Developing States (SIDS) are island nations that experience specific social, economic and environmental vulnerabilities associated with small populations, isolation and limited resources. Globally, SIDS exhibit exceptionally high rates of non-communicable disease (NCD) risk and incidence. Despite this, there is a lack of context-specific research within SIDS focused on life course approaches to NCD prevention, particularly the impact of the early-life environment on later disease risk as defined by the Developmental Origins of Health and Disease (DOHaD) framework. Given that globalization has contributed to significant nutritional transitions in these populations, the DOHaD paradigm is highly relevant. SIDS in the Pacific region have the highest rates of NCD risk and incidence globally. Transitions from traditional foods grown locally to reliance on importation of Western-style processed foods high in fat and sugar are common. The Cook Islands is one Pacific SIDS that reports this transition, alongside rising overweight/obesity rates, currently 91%/72%, in the adult population. However, research on early-life NCD prevention within this context, as in many low- and middle-income countries, is scarce. Although traditional research emphasizes the need for large sample sizes, this is rarely possible in the smaller SIDS. In these vulnerable, high priority countries, consideration should be given to utilizing 'small' sample sizes that encompass a high proportion of the total population. This may enable contextually relevant research, crucial to inform NCD prevention strategies that can contribute to improving health and well-being for these at-risk communities.

Evidence in support of the Developmental Origins of Health and Disease (DOHaD) hypothesis has reached the level where it can appropriately be used to inform practice. DOHaD informed interventions supporting primary noncommunicable disease risk reduction should target the pre- and periconceptional periods, pregnancy, lactation, childhood and adolescence. Such interventions are dependent on a health workforce (including dietitians, nurses, midwives, doctors, and nutrition teachers), that has a deep understanding of DOHaD concepts. This study assessed development of awareness of DOHaD concepts during undergraduate health professional training programs. Using a cross-sectional design, a standardized questionnaire was completed by Year 1-4 undergraduate students studying nutrition in Japan (n=309) and Year 1-3 nursing students in New Zealand (n=151). On entry to undergraduate study, most students had no awareness of the terms 'DOHaD' or 'First 1000 Days'. While awareness reached 60% by Year 3 in courses that included DOHaD-related teaching, this remains inadequate. More than 95% of Year 1 undergraduates in both countries demonstrated an appreciation of associations between maternal nutrition and fetal health. However, awareness of associations between parental health status and/or nutritional environment and later-life health was low. While levels of awareness increased across program years, overall awareness was less than optimal. These results indicate evidence of some focus on DOHaD-related content in curricula. We argue that DOHaD principles should be one pillar around which health training curricula are built. This study indicates a need for the DOHaD community to engage with faculties in curriculum development.

Insights from the Developmental Origins of Health and Disease paradigm and epigenetics are elucidating the biological pathways through which social and environmental signals affect human health. These insights prompt a serious debate about how the structure of society affects health and what the responsibility of society is to counteract health inequalities. Unfortunately, oversimplified interpretations of insights from Developmental Origins of Health and Disease and epigenetics may be (mis)used to focus on the importance of individual responsibility for health rather than the social responsibility for health. In order to advance the debate on responsibility for health, we present an ethical framework to determine the social responsibility to counteract health inequalities. This is particularly important in a time where individual responsibility often justifies a passive response from policymakers.

Intrauterine growth restriction (IUGR) and fetal growth restriction (FGR) are pregnancy complications associated with morbidity in later life. Despite a growing body of evidence from current research on developmental origins of health and disease (DOHaD), little information is currently provided to parents on long-term metabolic, cardiovascular and neurologic consequences. As parents strongly rely on internet-based health-related information, we examined the quality of information on IUGR/FGR sequelae and DOHaD in webpages used by laypersons. Simulating non-clinicians experience, we entered the terms 'IUGR consequences' and 'FGR consequences' into Google and Yahoo search engines. The quality of the top search-hits was analyzed with regard to the certification through the Health On the Net Foundation (HON), currentness of cited references, while reliability of information and DOHaD-related consequences were assessed via the DISCERN Plus score (DPS). Overall the citation status was not up-to-date and only a few websites were HON-certified. The results of our analysis showed a dichotomy between the growing body of evidence regarding IUGR/FGR-related sequelae and lack of current guidelines, leaving parents without clear directions. Furthermore, detailed information on the concept of DOHaD is not provided. These findings emphasize the responsibility of the individual physician for providing advice on IUGR/FGR-related sequelae, monitoring and follow-up.

Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic-pituitary-adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.

Exposures during the early life (periconceptional, prenatal and early postnatal) period are increasingly recognized as playing an important role in the aetiology of chronic non-communicable diseases (NCD), including coronary heart disease, stroke, hypertension, Type 2 diabetes and osteoporosis. The 'Developmental Origins of Health and Disease' (DOHaD) hypothesis states that these disorders originate through unbalanced nutrition early in life and risk is highest when there is a 'mismatch' between the early- and later-life environments. Thus, the DOHaD hypothesis would predict highest risk in countries where an excess of infants are born with low birth weight and where there is a rapid transition to nutritional adequacy or excess in adulthood. Here, I will review data from work conducted in rural Gambia, West Africa. Using demographic data dating back to the 1940s, the follow-up of randomized controlled trials of nutritional supplementation in pregnancy and the 'experiment of nature' that seasonality in this region provides, we have investigated the DOHaD hypothesis in a population with high rates of maternal and infant under-nutrition, a high burden from infectious disease, and an emerging risk of NCDs.

Endocrine disrupting chemicals (EDC) have received considerable attention as potential obesogens. Past studies examining obesogenic potential of one widespread EDC, bisphenol A (BPA), have generally focused on metabolic and adipose tissue effects. However, physical inactivity has been proposed to be a leading cause of obesity. A paucity of studies has considered whether EDC, including BPA, affects this behavior. To test whether early exposure to BPA and ethinyl estradiol (EE, estrogen present in birth control pills) results in metabolic and such behavioral disruptions, California mice developmentally exposed to BPA and EE were tested as adults for energy expenditure (indirect calorimetry), body composition (echoMRI) and physical activity (measured by beam breaks and voluntary wheel running). Serum glucose and metabolic hormones were measured. No differences in body weight or food consumption were detected. BPA-exposed females exhibited greater variation in weight than females in control and EE groups. During the dark and light cycles, BPA females exhibited a higher average respiratory quotient than control females, indicative of metabolizing carbohydrates rather than fats. Various assessments of voluntary physical activity in the home cage confirmed that during the dark cycle, BPA and EE-exposed females were significantly less active in this setting than control females. Similar effects were not observed in BPA or EE-exposed males. No significant differences were detected in serum glucose, insulin, adiponectin and leptin concentrations. Results suggest that females developmentally exposed to BPA exhibit decreased motivation to engage in voluntary physical activity and altered metabolism of carbohydrates v. fats, which could have important health implications., Competing Interests: None.