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Early life nutrition is associated with the development and metabolism in later life, which is known as the Developmental Origin of Health and Diseases (DOHaD). Epigenetics have been proposed as an important explanation for this link between early life malnutrition and long-term diseases. Non-coding RNAs (ncRNAs) may play a role in this epigenetic programming. The expression of ncRNAs (such as long non-coding RNA H19, microRNA-122, and circular RNA-SETD2) was significantly altered in specific tissues of offspring exposed to maternal malnutrition. Changes in these downstream targets of ncRNAs lead to abnormal development and metabolism. This review aims to summarize the existing knowledge on ncRNAs linking the maternal nutrition condition and offspring metabolic diseases, such as obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD).

Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring. [ABSTRACT FROM AUTHOR]

Maternal nutrition and health status in the peri-pregnancy period are closely related to offspring health. Currently, population studies are unable to provide quantitative relationships and effective measures of peri-pregnancy high-fat diet and offspring myocardial remodeling due to the difficulty of obtaining human samples. This study aimed to establish the mouse models of maternal obesity and high-fat diet supplementation and deprivation during pregnancy. The effects of obesity, periconceptional high-fat diet window, fetal weight, sex, and placental weight on myocardial remodeling in the offspring were measured by single-factor and multiple-factor regression analyses. Moreover, the relationship between perinatal high-fat diet/fetal weight and offspring myocardial remodeling was explored using the mediation analysis model. The multivariate analysis showed that the heart weight to body weight (HW/BW) ratio of the offspring decreased by −1.6525 mg/g for every 1-g increase in fetal weight. The offspring HW/BW increased by 1.1967 mg/g if pregnant women were exposed to a high-fat diet throughout pregnancy. The mediation analysis model of a perinatal high-fat diet for the myocardial remodeling of offspring revealed that fetal weight had a suppression effect on the myocardial weight of offspring, accounting for 60.70%; also, it had a mediating effect on the HW/BW of offspring, accounting for 17.10%. Moreover, subgroup analysis showed an interaction between offspring sex and HW/BW in a maternal high-fat diet during pregnancy. Additionally, a quantitative real-time polymerase chain reaction experiment further proved that a perinatal high-fat diet could change the important indicators of myocardial remodeling in offspring. In conclusion, this study found that a high-fat diet in the periconceptional period influenced factors in offspring myocardial remodeling. Moreover, maternal high-fat diet deprivation attenuated the changes in offspring myocardial remodeling. In addition, the role of fetal weight in mediating maternal high-fat diet-mediated offspring myocardial remodeling was quantified. Our study showed that a sensible and healthy diet during the perinatal period, especially during pregnancy, played a positive role in the health of the offspring. [ABSTRACT FROM AUTHOR]

Animal models are very important for biomedical research. Rodents and lagomorphs are the most commonly used species to study the developmental origins of health and disease or DOHaD but larger species such as sheep are essential due to their gestation period and fetal physiological characteristics. In addition, the use of animal models allows the identification of the window(s) of vulnerability such as the preconception, peri-implantation, gestational and/or lactation periods. Disturbances in the maternal environment (nutritional or metabolic environment, exposure to environmental contaminants) during these different critical periods impact on the phenotype of the offspring. These studies also make it possible to evaluate or anticipate long-term effects on the offspring, whereas explorations remain limited via human cohorts due to the intergenerational time step. Finally, this chapter will discuss the interest of these models for testing interventional therapies before their implementation in humans. [ABSTRACT FROM AUTHOR]

Most historiographies of the crossroads of environmental and reproductive health in 20th century start and end with the case of thalidomide. Despite its global scope, thalidomide today stands for sharp contrasts: in the numbers of victims, in institutional responses to the disaster, and also—more generally—in regulatory approaches to potential risks and national cultures of reproductive justice and disability rights. This paper takes a closer look at two countries that have been seen as emblematic of this divide in regulatory frameworks, despite similarities and interconnections in other areas, such as (pharma)industrial production, science, and robust feminist environmental health movements: the U.S. and West Germany. It argues that thalidomide needs to be historically contextualized within a broad framework of concepts and models of environment from research on exogenous reproductive effects. To do so, it reconstructs what counted as environment in research on reproductive health and birth defects in these two national settings in the postwar decades. It looks at transformations made across multifaceted initiatives, studying collective landscapes and workplaces as potentially dangerous "outer worlds," as well as smaller scale and more individualized environments, i.e., the maternal metabolism, uterus, lifestyle, or social interactions. The article thereby aims to explicate concepts and debates about the environment that influenced later national divisions in politics of science and technology, hinting of the democratic challenges these posed. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the effect of the ketone β-hydroxybutyrate (βOHB) on preimplantation mouse embryo development, metabolism, epigenetics and post-transfer viability? SUMMARY ANSWER In vitro βOHB exposure at ketogenic diet (KD)-relevant serum concentrations significantly impaired preimplantation mouse embryo development, induced aberrant glycolytic metabolism and reduced post-transfer fetal viability in a sex-specific manner. WHAT IS KNOWN ALREADY A maternal KD in humans elevates gamete and offspring βOHB exposure during conception and gestation, and in rodents is associated with an increased time to pregnancy, and altered offspring organogenesis, post-natal growth and behaviour, suggesting a developmental programming effect. In vitro exposure to βOHB at supraphysiological concentrations (8–80 mM) perturbs preimplantation mouse embryo development. STUDY DESIGN, SIZE, DURATION A mouse model of embryo development and viability was utilized for this laboratory-based study. Embryo culture media were supplemented with βOHB at KD-relevant concentrations, and the developmental competence, physiology, epigenetic state and post-transfer viability of in vitro cultured βOHB-exposed embryos was assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS Mouse embryos were cultured in vitro with or without βOHB at concentrations representing serum levels during pregnancy (0.1 mM), standard diet consumption (0.25 mM), KD consumption (2 mM) and diabetic ketoacidosis (4 mM). The impact of βOHB exposure on embryo development (blastocyst formation rate, morphokinetics and blastocyst total, inner cell mass and trophectoderm (TE) cell number), physiology (redox state, βOHB metabolism, glycolytic metabolism), epigenetic state (histone 3 lysine 27 β-hydroxybutyrylation, H3K27bhb) and post-transfer viability (implantation rate, fetal and placental development) was assessed. MAIN RESULTS AND THE ROLE OF CHANCE All βOHB concentrations tested slowed embryo development (P  <   0.05), and βOHB at KD-relevant serum levels (2 mM) delayed morphokinetic development, beginning at syngamy (P  <   0.05). Compared with unexposed controls, βOHB exposure reduced blastocyst total and TE cell number (≥0.25 mM; P  <   0.05), reduced blastocyst glucose consumption (2 mM; P  <   0.01) and increased lactate production (0.25 mM; P  <   0.05) and glycolytic flux (0.25 and 2 mM; P  <   0.01). Consumption of βOHB by embryos, mediated via monocarboxylate transporters, was detected throughout preimplantation development. Supraphysiological (20 mM; P  <   0.001), but not physiological (0.25–4 mM) βOHB elevated H3K27bhb levels. Preimplantation βOHB exposure at serum KD levels (2 mM) reduced post-transfer viability. Implantation and fetal development rates of βOHB-treated embryos were 50% lower than controls (P < 0.05), and resultant fetuses had a shorter crown-rump length (P  <   0.01) and placental diameter (P  <   0.05). A strong sex-specific effect of βOHB was detected, whereby female fetuses from βOHB-treated embryos weighed less (P  <   0.05), had a shorter crown-rump length (P  <   0.05), and tended to have accelerated ear development (P  <   0.08) compared with female control fetuses. LIMITATIONS, REASONS FOR CAUTION This study only assessed embryo development, physiology and viability in a mouse model utilizing in vitro βOHB exposure; the impact of in vivo exposure was not assessed. The concentrations of βOHB utilized were modelled on blood/serum levels as the true oviduct and uterine concentrations are currently unknown. WIDER IMPLICATIONS OF THE FINDINGS These findings indicate that the development, physiology and viability of mouse embryos is detrimentally impacted by preimplantation exposure to βOHB within a physiological range. Maternal diets which increase βOHB levels, such as a KD, may affect preimplantation embryo development and may therefore impair subsequent viability and long-term health. Consequently, our initial observations warrant follow-up studies in larger human populations. Furthermore, analysis of βOHB concentrations within human and rodent oviduct and uterine fluid under different nutritional states is also required. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the University of Melbourne and the Norma Hilda Schuster (nee Swift) Scholarship. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Polyphenols are compounds found in plants that have been extensively studied due to the health benefits of its consumption in adulthood. Meanwhile, recent evidence suggests that polyphenol consumption during pregnancy may not be safe for the fetus. The goal of this study was to evaluate the effect of naringenin supplementation during pregnancy on brain redox homeostasis and mitochondrial activity of the newborn rat. Adult female Wistar rats were divided into two groups: (1) vehicle (1 mL/Kg p.o.) or (2) naringenin (50 mg/Kg p.o.). Naringenin was administered once a day during pregnancy. The offspring were euthanized on postnatal day 7, as well the dams, and brain regions were dissected. The offspring cerebellum was the most affected region, presenting increased activity of the mitochondrial electron transport system, allied to increased reactive species levels, lipid peroxidation, and glutathione concentration. The nitric oxide levels suffered structure-dependent alteration, with decreased levels in the pups' cerebellum and increased in the hippocampus. The offspring parietal cortex was not affected, as well as the parameters evaluated in the dams' brains. Maternal consumption of naringenin alters offspring cerebellar redox homeostasis, which could be related to adverse effects on the motor and cognitive development in the descendants. [ABSTRACT FROM AUTHOR]

Metabolic disorders can start in utero. Maternal transmission of metabolic phenotypes may increase the risks of adverse metabolic outcomes, such as nonalcoholic fatty liver disease (NAFLD); effective intervention is essential to prevent this. The gut microbiome plays a crucial role in fat storage, energy metabolism, and NAFLD. We investigated the therapeutic use of probiotic Lactobacillus reuteri and postbiotic butyrate gestation in the prevention of perinatal high-fat diet-induced programmed hepatic steatosis in the offspring of pregnant Sprague–Dawley rats who received regular chow or a high-fat (HF) diet 8 weeks before mating. L. reuteri or sodium butyrate was administered via oral gavage to the gestated rats until their sacrifice on day 21 of gestation. Both treatments improved liver steatosis in pregnant dams; L. reuteri had a superior effect. L. reuteri ameliorated obesity and altered the metabolic profiles of obese gravid dams. Maternal L. reuteri therapy prevented maternal HF diet-induced fetal liver steatosis, and reformed placental remodeling and oxidative injury. Probiotic therapy can restore lipid dysmetabolism in the fetal liver, modulate nutrient-sensing molecules in the placenta, and mediate the short-chain fatty acid signaling cascade. The therapeutic effects of maternal L. reuteri on maternal NAFLD and NAFLD reprogramming in offspring should be validated for further clinical translation. [ABSTRACT FROM AUTHOR]

(1) Background: Albeit the main focus remains largely on mothers, in recent years Developmental Origins of Health and Disease (DOHaD) scientists, including epigeneticists, have started to examine how a father's environment affects disease risk in children and argued that more attention needs to be given to father's health-related behaviors for their influence on offspring at preconception (i.e., sperm health) as well as paternal lifestyle influences over the first 1000 days. This research ushers in a new paternal origins of health and disease (POHaD) paradigm and is considered a welcome equalization to the overemphasis on maternal influences. Epigeneticists are excited by the possibilities of the POHaD paradigm but are also cautious about how to interpret data and avoid biased impression of socio-biological reality. (2) Methods: We review sociological and historical literatures on the intersection of gender, food and diet across different social and historical contexts to enrich our understanding of the father; (3) Results: Sociological and historical research on family food practices and diet show that there are no "fathers" in the abstract or vacuum, but they are differently classed, racialized and exist in socially stratified situations where choices may be constrained or unavailable. This confirms that epigeneticists researching POHaD need to be cautious in interpreting paternal and maternal dietary influences on offspring health; (4) Conclusions: We suggest that interdisciplinary approach to this new paradigm, which draws on sociology, history and public health, can help provide the social and historical context for interpreting and critically understanding paternal lifestyles and influences on offspring health. [ABSTRACT FROM AUTHOR]

While a dramatic increase in obesity and related comorbidities is being witnessed, the underlying mechanisms of their spread remain unresolved. Epigenetic and other non-genetic mechanisms tend to be prominent candidates involved in the establishment and transmission of obesity and associated metabolic disorders to offspring. Here, we review recent findings addressing those candidates, in the context of maternal and paternal influences, and discuss the effectiveness of preventive measures. [ABSTRACT FROM AUTHOR]

Lead (Pb) is widely used as a raw material for various daily necessities in human civilization. However, Pb is a major toxicant and Pb poisoning has long been a global health concern. A large body of evidence has revealed that exposure to Pb causes a variety of adverse health effects. Meanwhile, experimental studies on the developmental effects caused by trace amounts of Pb remain to be fully conducted. Therefore, we aimed to provide direct experimental evidence of the adverse developmental effects of Pb exposure below the occupational regulatory standard concentrations using a zebrafish model. We also attempted to investigate the cellular stress response caused by such a trace amount of Pb at the individual level. Fertilized zebrafish eggs were exposed to 100 ppb Pb from 6 to 72 h post fertilization (hpf), the developmental period included within the mammalian implantation to birth. The embryos exposed to Pb did not show superficially evident morphological alterations or differences in viability compared with the controls until 72 hpf; however, they hatched earlier and were significantly shorter in body length than the controls at 48 and 72 hpf. Larvae that were exposed to Pb until 72 hpf and then cultured until 7 days post fertilization without Pb exhibited edema and inflation defects in the swim bladder. The reactive oxygen species level in the Pb-exposed embryos was similar at 24 hpf, slightly but significantly higher at 48 hpf, and lower than half that of the control at 72 hpf. Accordingly, the expression levels of oxidative stress response-related genes were analyzed, and five out of seven tested genes were upregulated in Pb-exposed embryos at 48 and 72 hpf. In addition, the endoplasmic reticulum (ER) stress related genes were upregulated at 48 hpf. These results indicate that exposure of embryos to trace amounts of Pb induces a transient increase in oxidative- and ER-stresses and results in weak hypotrophy and subsequent abnormalities later in development. Our findings may be key to understanding the total health effects of Pb exposure, and indicate that the zebrafish model is suitable for the investigation of developmental toxicity of pollutants such as Pb. [ABSTRACT FROM AUTHOR]

Objectives: Recent tests of the relationship between enamel defects, an indicator of early life stress, and fluctuating asymmetry (FA), a measure of cumulative developmental instability, have produced equivocal results. This may be because they use methods that underestimate the number of defects. We reinvestigate this relationship using high‐resolution microscopy images of tooth surfaces. Further, we test the hypothesis that developmental stresses during the earliest period of tooth development have a greater impact on FA than stresses during subsequent periods. Materials and Methods: The sample consists of 48 individuals from two colonial‐era cemeteries in Mexico City. Using one canine from each individual, we created photomontages using a 2D light microscope. Tooth crowns were divided into three developmental periods. Defects were identified as widely spaced perikymata using moving z‐scores. We compared defect presence, frequency, and timing to FA calculated from 11 landmarks using geometric morphometrics from 3D models of each cranium. Results: Both the presence and frequency of enamel defects are significantly associated with an increase in FA. Contrary to our expectations, defects that formed in the latest developmental period (4–5.5 years) were uniquely associated with an increase in FA, relative to the other two periods. Discussion: The presence and frequency of stress during childhood increases developmental instability. The time between 4 and 5.5 years may be a sensitive window of development in which disruptions to growth have a long‐lasting effect on developmental instability. Results indicate that research on developmental stress should consider the timing and frequency of stress events to more fully understand their impact on later life. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Maternal exposure to particulate matter with an aerodynamic diameter ≤ 2.5 μm (PM 2.5 ) is believed to be a risk factor of developmental origins of health and disease (DOHaD), but its effect on offspring's susceptibility to obesity, a common target disease of DOHaD, remains controversial. To pinpoint the effect of maternal PM 2.5 exposure on offspring's energy homeostasis, female C57BL/6J mice were exposed to filtered air (FA) or concentrated ambient PM 2.5 (CAP) for 12 weeks and mated with normal male mice to produce offspring. After parturition, a cross-fostering strategy was exploited to determine whether prenatal and/or postnatal mothering by CAP-exposed dams program offspring's energy homeostasis and susceptibility to obesity. Moreover, oocytes were collected from FA- or CAP-exposed mice and subjected to in vitro fertilization (IVF) to determine whether maternal pre-conceptional exposure to PM 2.5 programs energy homeostasis. Results showed that prenatal mothering by CAP-exposed dams increased suckling's milk intake and weight gain, decreased normal diet (ND)-fed offspring's adulthood food intake and body weight, and did not influence offspring's diet-induced obesity (DIO). Postnatal mothering by CAP-exposed dams did not influence suckling's milk intake and weight gain, increased ND-fed offspring's adulthood food intake and body weight and did not influence offspring's DIO. Prenatal plus postnatal mothering by CAP-exposed dams increased suckling's milk intake and weight gain, increased ND-fed offspring's adulthood food intake and body weight, and aggravated offspring's DIO. IVF study revealed that male offspring derived from CAP-exposed mice versus controls had significantly decreased adulthood food intake and body weight. RNA sequencing showed that CAP exposure influenced oocyte estrogen signaling and histone methylation. This study thus clearly reveals that timing determines programming of energy homeostasis by maternal PM 2.5 exposure., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Ltd.)

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.

Study Question: Is early embryonic size and growth in the first trimester of pregnancy associated with adverse birth outcomes?, Summary Answer: Larger embryonic crown-rump length (CRL) and embryonic volume (EV) are associated with lower odds of adverse birth outcomes, especially small for gestational age (SGA)., What Is Already Known: Preterm birth, SGA, and congenital anomalies are the most prevalent adverse birth outcomes with lifelong health consequences as well as high medical and societal costs. In the late first and second trimesters of pregnancy, fetuses at risk for adverse birth outcomes can be identified using 2-dimensional ultrasonography (US)., Study Design, Size, Duration: Between 2009 and 2018, singleton pregnancies were enrolled in this ongoing prospective Rotterdam Periconception Cohort., Participants/materials, Setting, Methods: This study included 918 pregnant women from a tertiary hospital in the Netherlands. Pregnancy dating was based on either a regular menstrual cycle (for natural pregnancies) or a conception date (for ART pregnancies). CRL and EV were measured using Virtual Reality software on 3-dimensional (3D) ultrasound scans, repeatedly performed around 7, 9, and 11 weeks of gestation. The main outcome measure was adverse birth outcome, defined as the composite of SGA (birth weight <10th percentile), preterm birth (<37th week of gestation), congenital anomalies (Eurocat criteria), stillbirth (>16th week of pregnancy), or early neonatal mortality (≤7 days of life). Reference curves for CRL and EV were constructed. Cross-sectional (CRL/EV <20th percentile at 7, 9, and 11 weeks of gestation) and longitudinal (CRL/EV growth trajectories between 6th and 13th weeks) regression analyses were performed, with adjustments for the participants' educational level, smoking, parity, age, BMI, geographical background, mode of conception, and fetal sex., Main Results and the Role of Chance: Of the 918 pregnant women included, the median age was 32.3 years, and 404 (44%) pregnancies had been conceived via ART. In 199 (22%) pregnancies, there was an adverse birth outcome. Regression analyses showed that at 7 weeks of gestation onwards, embryos with a CRL <20th percentile had an ∼2-fold increased odds of adverse birth outcome (adjusted odds ratio (aOR) 2.03, 95% CI 1.21-3.39, P = 0.007). Similar associations were found for EV <20th percentile but were not statistically significant. These findings were mainly driven by the strong association between embryonic size and SGA (e.g. 7-week CRL: aOR 2.18 (1.16-4.09), P = 0.02; 9-week EV: aOR 2.09 (1.10-3.97, P = 0.02). Longitudinal growth trajectories of CRL, but not of EV, were associated with adverse birth outcomes. Both CRL and EV growth trajectories were associated with SGA., Limitations, Reasons for Caution: The tertiary hospital population and the availability of sophisticated 3D-ultrasound techniques limit the generalizability of this study to general populations and settings., Wider Implications of the Findings: Already very early in the first trimester of pregnancy, embryos with increased risks of an adverse birth outcome can be identified by using 3D-US and Virtual Reality. This expands the window of opportunity to enable the development of future interventions to potentially improve pregnancy outcomes and offspring health during their life-course., Study Funding/competing Interest(s): This work was funded by the Department of Obstetrics and Gynecology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. The authors declare no conflicts of interest., Trial Registration Number: NL4115., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Biological age (BA), reflecting aging-related health decline beyond chronological age, varies among individuals. While previous research explored associations of maternal pregnancy-related body size with offspring health outcomes, its implications for BA in young adults remain unclear. Utilizing longitudinal data of 1,148 mother-offspring pairs from the Jerusalem Perinatal Study, we analyzed associations of maternal pre-pregnancy BMI and gestational weight gain (GWG) with offspring Klemera-Doubal method (KDM)-based BA at age 32, and potential familial life-course underlying mechanisms. Maternal pregnancy-related body size, adjusted for sociodemographic/lifestyle factors was associated with offspring BA (βmaternal pre-pregnancy BMI=0.183,95%CI:0.098,0.267;βGWG=0.093,95%CI:0.021,0.165). Association of GWG with BA was largely direct (90%,95%CI,44%,100%), while association with maternal pre-pregnancy BMI was partially mediated through adolescent BMI (36%,95%CI=18%,75%), with both associations eliminated after adjustment for offspring adult BMI. Associations persisted after adjusting for offspring polygenic risk score for BMI (βmaternal pre-pregnancy BMI=0.128;95%CI=0.023,0.234; βGWG=0.102;95%CI=0.006,0.198), and somewhat altered after adjustment for maternal cardiometabolic conditions (βmaternal pre-pregnancy BMI=0.144,95%CI=0.059, 0.230). Impact on GWG associations was negligible. Thus, perinatal obesogenic environment contributes to offspring BA beyond sociodemographic factors and maternal cardiometabolic history, yet intergenerational transmission of obesity seems to underlie these associations. Nonetheless, the period between adolescence and young adulthood could be targeted for weight-reducing interventions, ultimately promoting healthy aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Pregnant women are daily exposed to environmental contaminants, including endocrine disruptors that can impact the offspring's health. This study aimed to evaluate the effects of maternal oral exposure to a mixture of contaminants at a dose mimicking women's exposure, during folliculogenesis and/or preimplantation period (FED and ED groups, respectively) on the fetoplacental phenotype in a rabbit model. The mixture (DEHP, pp'DDE, β-HCH, HCB, BDE-47, BPS, PFOS, PFOA) was defined based on data from HELIX and INMA cohorts. FED and ED females or unexposed females (control) were inseminated, their embryos were collected and transferred to unexposed control recipient rabbits at 80 h post-insemination. The effects of maternal FED and ED exposure were evaluated on fetoplacental growth and development by ultrasound, fetoplacental biometry, fetal metabolism, placental structure and function. The results demonstrated that the mixture weakly affected ultrasound measurements, as only placental volume increased significantly in FED vs ED. Analysis of placental structure demonstrated that the volume fraction of the maternal blood space was increased in FED vs control. Pre- and/or periconception exposure did not affect biometric at the end of gestation, but affected FED fetal biochemistry. Plasma triglyceride concentration was reduced compared to control. However, total cholesterol, urea, ASAT and ALAT in fetal blood were affected in both exposed groups. Multiple factor analysis, including biometric, biochemical, and stereological datasets, indicated that the three groups were significantly different. Additionally, several placental genes were differentially expressed between groups, compared two by two, in a sex-specific manner, with more difference in females than in males. The differentially expressed genes were involved in lipid, cholesterol, and drug/xenobiotic metabolism in both sexes. These results indicate that maternal exposure to environmental contaminants during crucial developmental windows only mildly impaired fetoplacental development but disturbed fetal blood biochemistry and placental gene expression with potential long-term effects on offspring phenotype., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations., Methods: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504)., Results: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10 -5 ). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10 -33 ) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10 -9 ) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (-0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (-0.043±0.013 kg, p=0.0011) in the combined cohorts., Conclusions: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers., Funding: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332., Competing Interests: WD, NC, NC, SA, Rd, AL, KM, SA, PS, ST, TM, KT, PM, MA, ES, GP, SA No competing interests declared, (© 2024, Deng et al.)

Ghrelin has effects that range from the maturation of the central nervous system to the regulation of energy balance. The production of ghrelin increases significantly during the first weeks of life. Studies have addressed the metabolic effects of liver-expressed antimicrobial peptide 2 (LEAP2) in inhibiting the effects evoked by ghrelin, mainly in glucose homeostasis, insulin resistance, and lipid metabolism. Despite the known roles of ghrelin in the postnatal development, little is known about the long-term metabolic influences of modulation with the endogenous expressed growth hormone secretagogue receptor (GHSR) inverse agonist LEAP2. This study aimed to evaluate the contribution of GHSR signalling during perinatal phases, to neurodevelopment and energy metabolism in young animals, under inverse antagonism by LEAP2[1-14]. For this, two experimental models were used: (i) LEAP2[1-14] injections in female rats during the pregnancy. (ii) Postnatal modulation of GHSR with LEAP2[1-14] or MK677. Perinatal GHSR modulation by LEAP2[1-14] impacts glucose homeostasis in a sex and phase-dependent manner, despite no effects on body weight gain or food intake. Interestingly, liver PEPCK expression was remarkably impacted by LEAP2 injections. The observed results suggests that perinatal LEAP2 exposure can modulate liver metabolism and systemic glucose homeostasis. In addition, these results, although not expressive, may just be the beginning of the metabolic imbalance that will occur in adulthood.

ABSTRACT Objective: Intrauterine environment can induce fetal metabolic programming that predisposes to adiposity-related chronic diseases in its lifespan. We examined the associations of parental nutritional status and gestational weight gain with offspring body composition in early adulthood. Materials and methods: This is cross-sectional analysis of female participants of the NutriHS who were submitted to questionnaires, clinical examinations and body composition assessed by DXA. Association of pre-conception parental BMI and maternal gestational weight gain (exposures) with body composition measurements (outcomes) were analyzed using multiple linear models adjusted for Directed Acyclic Graphs-based covariables (maternal and paternal educational level, maternal age, and tobacco, alcohol and/or drugs use). The sample included 124 women (median 28 (24-31) years) with a mean BMI of 25.4 ± 4.7 kg/m2. Results: No association between previous paternal BMI and offspring’s body composition was detected. In the fully adjusted linear regression model, maternal BMI was associated with offspring’s total lean mass (β = 0.66, p = 0.001), appendicular skeletal muscle mass index (ASMI) (β = 0.11, p = 0.003) and fat mass index (FMI) (β = 0.03, p = 0.039). Gestational weight gain was associated with increased offspring’s BMI (OR 1.12 [95% CI 1.02-1.20], p = 0.01). The linear regression model adjusted for maternal age and maternal and paternal education levels showed associations of gestational weight gain with offspring’s ASMI (β = 0.42, p = 0.046), FMI (β = 0.22, p = 0.005) and android-to-gynoid fat ratio (β = 0.09, p = 0.035). Conclusion: Our findings suggest that preconception maternal BMI could influence lean mass and general adiposity of young adult female offspring and that gestational weight gain could be useful for predicting centrally distributed adiposity.

Background: Developmental exposure to airborne particulate matter (PM) may increase children’s risk of developing autism spectrum disorder. We quantified the impact of reducing PM exposure during pregnancy on the development of autistic traits in children. We also assessed associations between indoor fine PM (PM2.5) concentrations during pregnancy and autistic traits. Methods: In this parallel-group randomized controlled trial, we randomized 540 non-smoking pregnant women to receive HEPA filter air cleaners or to a control group, which did not receive air cleaners. We administered the Social Responsiveness Scale (SRS-2) to caregivers when children were a median of 48 months (range: 48 to 51 months). Our primary outcome was the SRS-2 total T-score. We imputed missing data using multiple imputation with chained equations and our primary analysis was by intention to treat. In secondary analyses, we estimated associations between full pregnancy and trimester-specific indoor PM2.5 concentrations and T-scores. Results: We enrolled participants at a median of 11 weeks’ gestation. Our analysis included 478 children (233 control, 245 intervention). The intervention reduced average indoor PM2.5 concentrations by 29 % (95 % CI: 21, 37 %). The mean SRS-2 total T-score was 0.5 units lower (95 % CI: −2.5, 1.5) among intervention participants, with evidence of larger benefits for children at the high end of the T-score distribution. An interquartile range (9.6 µg/m3) increase in indoor PM2.5 during pregnancy was associated with 1.8-unit (95 % CI: 0.3, 3.2) increase in mean SRS-2 total T-score. Effect estimates for PM2.5 concentrations by trimester were smaller and confidence intervals spanned no effect. Conclusion: Reducing indoor PM during pregnancy had little impact on mean autism-related behavior scores in children. However, indoor PM2.5 concentrations during pregnancy were associated with higher scores. Exposure to particulate matter during pregnancy may influence the development of autistic traits in childhood.Trial registration: ClinicalTrials.gov: NCT01741051.

IntroductionIn rats, a maternal high-fat diet (HFD) leads to adverse metabolic changes in the adult offspring, similar to the children of mothers with obesity during pregnancy. Supplementation with a high dose of fish oil (FO) to pregnant rats fed a HFD has been shown to prevent the development of insulin resistance in adult offspring. However, the effects of supplementation at a translationally relevant dose remain unknown.AimTo determine whether supplementation with a human-relevant dose of FO to pregnant rats can prevent the long-term adverse metabolic and cardiovascular effects of a maternal HFD on adult offspring.MethodsFemale rats (N = 100, 90 days of age) were assigned to HFD (45% kcal from fat) or control diet (CD) for 14 days prior to mating and throughout pregnancy and lactation. Following mating, dams received a gel containing 0.05 ml of FO (human equivalent 2–3 ml) or a control gel on each day of pregnancy. This produced 4 groups, CD with control gel, CD with FO gel, HFD with control gel and HFD with FO gel. Plasma and tissue samples were collected at day 20 of pregnancy and postnatal day 2, 21, and 100. Adult offspring were assessed for insulin sensitivity, blood pressure, DXA scan, and 2D echocardiography.ResultsThere was an interaction between maternal diet and FO supplementation on insulin sensitivity (p = 0.005) and cardiac function (p < 0.01). A maternal HFD resulted in impaired insulin sensitivity in the adult offspring (p = 0.005 males, p = 0.001 females). FO supplementation in the context of a maternal HFD prevented the reduction in insulin sensitivity in offspring (p = 0.05 males, p = 0.0001 females). However, in dams consuming CD, FO supplementation led to impaired insulin sensitivity (p = 0.02 males, p = 0.001 females), greater body weight and reduced cardiac ejection fraction.ConclusionThe effects of a human-relevant dose of maternal FO on offspring outcomes were dependent on the maternal diet, so that FO was beneficial to the offspring if the mother consumed a HFD, but deleterious if the mother consumed a control diet. This study suggests that supplementation with FO should be targeted to women expected to have abnormalities of metabolism such as those with overweight and obesity.

It has been long known that the environment plays a critical role in the etiology of disease. However, it is still unclear how the large variety of environmental factors humans are exposed to interact with each other to lead to disease. Metabolic disorders are just one example of human disorders that have been associated with environmental exposures. Obesity and type 2 diabetes have become a health and economic burden worldwide as the number of affected people has tripled in the last 40 years. Animal and human studies have shown a strong association between exposure to environmental chemicals during critical windows of susceptibility such as periconception, prenatal, and early life, whose effect can persist through development and across generations. However, little is known about the mechanisms driving this persistence. Here, we review historical and current knowledge on the effect of exposure to environmental factors during in utero development and discuss mechanisms for these disorders to be propagated across generations.

The developmental origin of health and disease (DOHaD) hypothesis refers to the adverse effects of suboptimal developmental environments during embryonic and early fetal stages on the long-term health of offspring. Intrauterine metabolic perturbations can profoundly impact organogenesis in offspring, particularly affecting cardiac development and giving rise to potential structural and functional abnormalities. In this discussion, we contemplate the existing understanding regarding the impact of maternal metabolic disorders, such as obesity, diabetes, or undernutrition, on the developmental and functional aspects of the offspring’s heart. This influence has the potential to contribute to the susceptibility of offspring to cardiovascular health issues. Alteration in the nutritional milieu can influence mitochondrial function in the developing hearts of offspring, while also serving as signaling molecules that directly modulate gene expression. Moreover, metabolic disorders can exert influence on cardiac development-related genes epigenetically through DNA methylation, levels of histone modifications, microRNA expression, and other factors. However, the comprehensive understanding of the mechanistic underpinnings of these phenomena remains incomplete. Further investigations in this domain hold profound clinical significance, as they can contribute to the enhancement of public health and the prevention of cardiovascular diseases.

The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother–child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.

Informed by the theory of developmental origins of health and disease, we conducted a survey among 66,854 mother–preschooler dyads in all kindergartens within the Longhua District of Shenzhen in China for exploring the combined effect of prenatal mosquito coil smoke (MCS) exposure and early postnatal nutritional status on obesity in preschoolers. A self-administered questionnaire was completed by mothers to collect parents’ and children’s socio-demographic characteristics, prenatal MCS exposure, child nutritional status at 1–3 years, etc., and children’s heights and weights were measured at the same time. After controlling for potential confounders, a series of logistic regression models and cross-over analyses were used to examine the independent and combination effects of prenatal MCS exposure and postnatal nutritional status on preschoolers’ obesity. We found that prenatal MCS exposure significantly increased the risk of preschoolers’ obesity (AOR = 1.14, 95%CI = 1.08–1.21). Additionally, early postnatal well-nourished nutritional status also increased the risk of preschoolers’ obesity (AOR = 1.56, 95%CI = 1.47–1.66). The cross-over analysis showed that the combination of prenatal MCS exposure with early general postnatal nutrition status (AOR = 1.22, 95%CI = 1.10–1.36) and early postnatal well-nourished nutrition status (AOR = 1.81, 95%CI = 1.65–1.97), respectively, increased the risk of preschoolers’ obesity. Our results indicated that prenatal MCS exposure and early postnatal nutritional status can independently and jointly increase the risk of preschoolers’ obesity.

Changes in the activities of some metabolic factors have been suggested to increase the risk of conditions associated with the Developmental Origins of Health and Disease (DOHaD). We examined changes in oxytocin (OT), a metabolic factor, and OT receptor (OTR) mRNA levels throughout the developmental period in rats of intrauterine undernutrition. Pregnant rats were divided into two groups: a maternal normal nutrition (mNN) and maternal undernutrition (mUN) group. Serum OT concentrations and hypothalamic mRNA levels of OT and OTR were measured in both offspring at various postnatal stages. Both offspring showed significant increases in serum OT concentrations during the neonatal period, significant reductions around the pubertal period, and significant increases in adulthood. Hypothalamic OT mRNA expression levels gradually increased from the neonatal to pubertal period and decreased in adulthood in both offspring. In the pre-weaning period, hypothalamic OT mRNA expression levels were significantly lower in the mUN offspring than in the mNN offspring. In the mUN offspring, hypothalamic OTR mRNA expression levels transiently increased during the neonatal period, decreased around the pubertal period, and increased again in adulthood, whereas transient changes were not detected in mNN offspring. These changes could affect nutritional and metabolic regulation systems in later life and play a role in the mechanisms underlying DOHaD.

Early life gut microbiota-influencing factors may play an important role in programming individuals long-term health and substantial efforts have been devoted into studying the development of the gut microbiota in relation to early life events. This study aimed to examine in a single study, the persistence of associations between 20 factors occurring in the early life and the gut microbiota at 3.5 years of 798 children from two French nationwide birth cohorts, EPIPAGE 2 (very preterm children) and ELFE (late preterm and full-term children). Gut microbiota profiling was assessed using 16S rRNA gene sequencing-based method. Upon thorough adjustment of confounding factors, we demonstrated that gestational age was one of the factors most associated with gut microbiota differences with a noticeable imprint of prematurity at 3.5 years of age. Children born by cesarean section harbored lower richness and diversity and a different overall gut microbiota composition independently of preterm status. Children who had ever received human milk were associated with a Prevotella-driven enterotype (P_type) compared to those who had never received human milk. Living with a sibling was associated with higher diversity. Children with siblings and those attending daycare centers were associated with a P_type enterotype. Maternal factors including the country of birth and preconception maternal body mass index were associated with some microbiota characteristics: children born to overweight or obese mothers showed increased gut microbiota richness. This study reveals that multiple exposures operating from early life imprint the gut microbiota at 3.5 years that is a pivotal age when the gut microbiota acquires many of its adult characteristics.

Growing evidence has demonstrated that maternal artificial sweetener (AS) consumption may not be a beneficial alternative when compared to sugar-sweetened beverages and potentially leads to metabolic dysfunction in adult offspring. Compromised skin integrity and wound healing associated with type 2 diabetes can lead to complications such as diabetic pressure injury (PI). In this context, the skin plays an important role in the maintenance of metabolic homeostasis, yet there is limited information on the influence of sugar- or AS-sweetened beverages during pregnancy on developmental programming and offspring skin homeostasis. This study examined the impact of maternal fructose or acesulfame-k consumption on offspring wound healing. Female C57Bl/6 mice received a chow diet ad libitum with either water (CD), fructose (FR; 34.7 mM fructose), or AS (AS; 12.5 mM Acesulfame-K) throughout pregnancy and lactation. PIs were induced in offspring at 9 weeks of age (n = 6/sex/diet). PIs and healthy skin biopsies were collected for later analysis. Maternal AS intake increased skin inflammatory markers in healthy biopsies while an FR diet increased Tgfb expression, and both diets induced subtle changes in inflammatory markers post-wound inducement in a sex-specific manner. Furthermore, a maternal FR diet had a significant effect on pressure wound severity and early wound healing delay, while AS maternal diet had a sex-specific effect on the course of the healing process. This study demonstrates the need for a better understanding of developmental programming as a mediator of later-life skin integrity and wound responsiveness.

Prematurity is a risk factor for dysbiosis of the gut microbiota due to particular birth conditions and frequent prolonged hospitalization of neonates. Although gut microbiota colonization after birth and its establishment during the hospitalization period have been studied in preterm infants, data on gut microbiota following discharge, particularly during early childhood, are scarce. The present study investigated the relationship between gut microbiota at 1 month after birth (hospitalization period) and 3.5 years of age in 159 preterm children belonging to the French EPIFLORE prospective observational cohort study. Analysis using bacterial 16S rRNA gene sequencing showed that the gut microbiota of preterm neonates at 1 month was highly variable and characterized by six distinct enterotypes. In contrast, the gut microbiota of the same children at 3.5 years of age showed less variability, with only two discrete enterotypes. An absence of association between enterotypes at 1 month and 3.5 years of age was observed. While the alpha diversity of gut microbiota significantly increased between 1 month and 3.5 years of age, for both alpha and beta diversities, there was no correlation between the 1-month and 3.5-years time points. Comparison at 3.5 years between children born either preterm (n = 159) or full-term (n = 200) showed no differences in terms of enterotypes, but preterm children harbored a lower Shannon diversity index and a different overall composition of microbiota than full-term children. This study suggests that the characteristics of the early gut microbiota of preterm children are not predictive of the microbial community composition at 3.5 years of age. However, the impact of gestational age is still noticeable on the gut microbiota up to 3.5 years of age. [ABSTRACT FROM AUTHOR]

The intestinal microbiota is involved in many physiological processes. However, the effects of microbiota in metabolic programming still unknow. We evaluated whether the transplantation of fecal microbiota during early life can program health or disease during adulthood in a model of lean and obese male and female Wistar rats. Parental obesity were induced using a small litter (SL, 3 pups/dam) model. At 90 d old, normal litter (NL, 9 pups/dam) and SL males and females (parents) from different litters were mated: NL male vs. NL female; SL male vs. SL female. After birth, male and female offspring rats were also standardized in normal litters or small litters. From the 10th until 25th d of life, the NL and SL male and female offspring received via gavage of a solution containing the diluted feces of the opposite dam (fecal microbiota, M) or saline solution (S). At 90 d of age, biometric and biochemical parameters were assessed. NLM male rats transplanted with obese microbiota showed increased body weight, and fat pad deposition, hyperinsulinemia, glucose intolerance and dyslipidemia. SLM male rats transplanted with lean microbiota had decreased retroperitoneal and mesenteric fat, triglycerides and VLDL levels and improvement of glucose tolerance. Despite SLM female rats showed higher visceral fat, microbiota transplantation in female rats caused no changes in these parameters compared with control groups. Fecal microbiota transplantation during lactation induces long-term effects on the metabolism of male Wistar rats. However, female rats were resistant to metabolic alterations caused by the treatment. [ABSTRACT FROM AUTHOR]

Objective: To assess the impact of fetal exposure to cannabis on adiposity and glucose-insulin traits in early life. Research Design and Methods: We leveraged a subsample of 103 mother-child pairs from Healthy Start, an ethnically diverse Colorado-based cohort. Twelve cannabinoids/metabolites of cannabis (including Δ9-tetrahydrocannabinol and cannabidiol) were measured in maternal urine collected at ~27 weeks' gestation. Fetal exposure to cannabis was dichotomized as exposed (any cannabinoid > limit of detection [LOD]) and not exposed (all cannabinoids < LOD). Fat mass and fat-free mass were measured via air displacement plethysmography at follow-up (mean age: 4.7 years). Glucose and insulin were obtained after an overnight fast. Generalized linear models estimated the associations between fetal exposure to cannabis with adiposity measures (fat mass [kg], fat-free mass [kg], adiposity [fat mass percentage], body mass index [BMI], and BMI z-scores) and metabolic measures (glucose [mg/dL], insulin [uIU/mL], and homeostatic model assessment of insulin resistance [HOMA-IR]). Results: Approximately 15% of the women had detectable levels of any cannabinoid, indicating fetal exposure to cannabis. Exposed offspring had higher fat mass (1.0 kg; 95% CI, 0.3-1.7), fat-free mass (1.2 kg; 95% CI, 0.4-2.0), adiposity (2.6%; 95% CI, 0.1-5.2), and fasting glucose (5.6 mg/dL; 95% CI, 0.8-10.3) compared with nonexposed offspring. No associations were found with fasting insulin (in the fully adjusted model), HOMA-IR, BMI, or BMI z-scores. Conclusions: We provide novel evidence to suggest an association between fetal exposure to cannabis with increased adiposity and fasting glucose in childhood, a finding that should be validated in other cohorts. [ABSTRACT FROM AUTHOR]

Adverse birth outcomes, such as early gestational age and low birth weight, can have lasting effects on morbidity and mortality, with impacts that persist into adulthood. Identifying the maternal factors that contribute to adverse birth outcomes in the next generation is thus a priority. Epigenetic clocks, which have emerged as powerful tools for quantifying biological aging and various dimensions of physiological dysregulation, hold promise for clarifying relationships between maternal biology and infant health, including the maternal factors or states that predict birth outcomes. Nevertheless, studies exploring the relationship between maternal epigenetic age and birth outcomes remain few. Here, we attempt to replicate a series of analyses previously reported in a US-based sample, using a larger similarly aged sample (n = 296) of participants of a long-running study in the Philippines. New pregnancies were identified prospectively, dried blood spot samples were collected during the third trimester, and information was obtained on gestational age at delivery and offspring weight after birth. Genome-wide DNA methylation was assessed with the Infinium EPIC array. Using a suite of 15 epigenetic clocks, we only found one significant relationship: advanced age on the epigenetic clock trained on leptin predicted a significantly earlier gestational age at delivery (β = − 0.15, p = 0.009). Of the other 29 relationships tested predicting gestational age and offspring birth weight, none were statistically significant. In this sample of Filipino women, epigenetic clocks capturing multiple dimensions of biology and health do not predict birth outcomes in offspring. [ABSTRACT FROM AUTHOR]

Underpinning the theory "developmental origins of health and disease" (DOHaD), evidence is accumulating to suggest that the risks of adult disease are in part programmed by exposure to environmental factors during the highly plastic "first 1,000 days of life" period. An elucidation of the mechanisms involved in this programming is challenging as it would help developing new strategies to promote adult health. The intestinal microbiome is proposed as a long-lasting memory of the neonatal environment. This proposal is supported by indisputable findings such as the concomitance of microbiota assembly and the first 1,000-day period, the influence of perinatal conditions on microbiota composition, and the impact of microbiota composition on host physiology, and is based on the widely held but unconfirmed view that the microbiota is long-lastingly shaped early in life. In this review, we examine the plausibility of the gut microbiota being programmed by the neonatal environment and evaluate the evidence for its validity. We highlight that the capacity of the pioneer bacteria to control the implantation of subsequent bacteria is supported by both theoretical principles and statistical associations, but remains to be demonstrated experimentally. In addition, our critical review of the literature on the long-term repercussions of selected neonatal modulations of the gut microbiota indicates that sustained programming of the microbiota composition by neonatal events is unlikely. This does not exclude the microbiota having a role in DOHaD due to a possible interaction with tissue and organ development during the critical windows of neonatal life. [ABSTRACT FROM AUTHOR]

Objectives: There is growing evidence regarding the association between rapid growth during infancy and metabolic and cardiovascular diseases later in life. We aimed to evaluate postnatal growth trajectories in extremely and very preterm infants exposed to hypertensive disorders of pregnancy (HDP) in utero.Study Design: This multicenter retrospective study used a nationwide database of preterm infants weighing ≤1,500 g born between 22 and 31 weeks of gestation between 2003 and 2015.Main Outcome Measures: The Z-scores for height and weight were evaluated at three time points (at birth, corrected age of 1.5 years, and chronological age of 3 years) in 5,144 infants (HDP, n = 1,188; non-HDP, n = 3,956). Univariate and multivariate regression analyses were performed to investigate the associations between HDP exposure and accelerated postnatal growth.Results: Male and female infants in the HDP group showed increased mean Z-scores for height and weight, whereas those in the non-HDP group showed decreased mean Z-scores. Multivariate analyses showed that HDP were associated with accelerated postnatal growth (Δ Z-scores) in weight in both male and female infants (β coefficient [95% CI]; male 0.17 [0.05-0.30], female 0.27 [0.14-0.39]), but not in height (male 0.02 [-0.09 to 0.13], female 0.04 [-0.06 to 0.15]). An interaction analysis revealed no significant differences in the effects of HDP on postnatal growth between male and female infants.Conclusions: Intrauterine exposure to HDP contributes to accelerated postnatal weight growth in extremely and very preterm infants during early childhood. In addition, no sex differences were observed in postnatal growth. [ABSTRACT FROM AUTHOR]

We examined the long-term health outcomes associated with being born small for gestational age (SGA) or large for gestational age (LGA). A total of 632 young adults aged ≈20.6 years were recruited from a longitudinal study (Chiang Mai, Thailand) in 2010: 473 born appropriate for gestational age (AGA), 142 SGA, and 17 LGA. The clinical assessments included anthropometry, blood pressure (BP), lipid profile, and an oral glucose tolerance test (OGTT). Young adults born SGA were 1.8 and 3.2 cm shorter than AGA (p = 0.0006) and LGA (p = 0.019) participants, respectively. The incidence of short stature was 8% among SGA compared with 3% in AGA and no cases among LGA participants, with the adjusted relative risk (aRR) of short stature among SGA 2.70 times higher than that of AGA counterparts (p = 0.013). SGA participants also had a 2 h glucose 7% higher than that of the AGA group (105 vs. 99 mg/dL; p = 0.006). Young adults born LGA had a BMI greater by 2.42 kg/m2 (p = 0.025) and 2.11 kg/m2 (p = 0.040) than those of SGA and AGA, respectively. Thus, the rate of overweight/obesity was 35% in the LGA group compared with 14.2% and 16.6% of SGA and AGA groups, respectively, with corresponding aRR of overweight/obesity of 2.95 (p = 0.011) and 2.50 (p = 0.017), respectively. LGA participants had markedly higher rates of BP abnormalities (prehypertension and/or hypertension) with an aRR of systolic BP abnormalities of 2.30 (p = 0.023) and 2.79 (p = 0.003) compared with SGA and AGA groups, respectively. Thai young adults born SGA had an increased risk of short stature and displayed some impairment in glucose metabolism. In contrast, those born LGA were at an increased risk of overweight/obesity and elevated blood pressure. The long-term follow-up of this cohort is important to ascertain whether these early abnormalities accentuate over time, leading to overt cardiometabolic conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Early-life events are associated with the risk of obesity and comorbidities later in life. The gut microbiota—whose composition is influenced by genetics and environmental factors—could be involved. Since the microbiota affects metabolism and fat storage, early-life insults could contribute to the occurrence of obesity driven, in part, by microbiota composition. We examined associations of gut bacteria with early-life events, nutritional status, and body composition in the Nutritionist's Health Study (NutriHS). Methods: A cross-sectional study of 114 female participants examining early-life data, body composition, and biological samples was conducted. Fecal microbiota structure was determined targeting the V4 region of the 16S rRNA gene. Principal coordinates analysis (PCoA) and permutational multivariate analysis of variance (PERMANOVA) were used to test the impact of variables on microbial diversity. Profiles were identified using the Jensen-Shannon divergence matrix and Calinski–Harabasz index. Differential abundance between the categories of exclusive breastfeeding duration and nutritional status was tested using DESeq2. Results: In the sample [median age 28 years and body mass index (BMI) 24.5 kg/m2], 2 microbiota profiles driven by the Blautia or Prevotella genus were identified. An estimated 9.1% of the variation was explained by the profiles (p < 0.001), 2.1% by nutritional status (p = 0.004), and 1.8% by exclusive breastfeeding (p = 0.012). The proportion of participants with BMI <25 kg/m2 and who were breastfed for at least 6 months was higher in the Blautia profile (p < 0.05). Conclusion: Findings in a Blautia -driven profile of healthy women reinforce that early-life events play a role in defining gut microbiota composition, confirming the importance of exclusive breastfeeding for infant gut colonization in establishing a protective profile against adiposity-related outcomes in adulthood. [ABSTRACT FROM AUTHOR]

The early developmental phase is of critical importance for human health and disease later in life. To decipher the molecular mechanisms at play, current biomedical research is increasingly relying on large quantities of diverse omics data. The integration and interpretation of the different datasets pose a critical challenge towards the holistic understanding of the complex biological processes that are involved in early development. In this review, we outline the major transcriptomic and epigenetic processes and the respective datasets that are most relevant for studying the periconceptional period. We cover both basic data processing and analysis steps, as well as more advanced data integration methods. A particular focus is given to network-based methods. Finally, we review the medical applications of such integrative analyses. [ABSTRACT FROM AUTHOR]

Abstract Background Developmental exposure to particulate matter (PM) air pollution may impair children’s behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM2.5) concentrations during pregnancy and children’s behavior. Methods This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM2.5 concentrations inside residences. Results We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m3) in first trimester PM2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old. Conclusion We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously. Trial registration ClinicalTrials.gov: NCT01741051