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Birth weight is an important predictor of perinatal complications and long‐term health outcomes of offspring. Fetal programming influenced by maternal obesity, overnutrition, and hyperglycemia has been proposed as the fuel overload hypothesis. Recent investigations related with fetal body composition have revealed that neonatal adiposity can be predicted by fetal fat mass, and that maternal insulin resistance and serum leptin level are indicators of fetal adiposity. Based on the current evidence, the origins of obesity can partly be traced back into the fetal life. Further clarification of the determinants of fetal fat mass may lead to the clinical interventions and treatment strategies for fetal growth and development. This effort potentially leads to the elucidation of pathological conditions related with long‐term health outcomes and the primary prevention of childhood obesity and early onset metabolic syndrome. [ABSTRACT FROM AUTHOR]

Key points Fetal undernutrition establishes the foundations for hypertension development, with oxidative stress being a key hallmark. A growing interest in nutraceuticals for treating hypertension and environmental waste concerns prompted the present study aiming to evaluate whether supplementation with a polyphenol enriched extract from cocoa shell (CSE), a by‐product from the chocolate industry with antioxidant properties, reduces hypertension of developmental origin, thus improving mesenteric resistance artery (MRA) vasodilatation. Adult male and female offspring from rats exposed to 50% food restriction from mid‐gestation (maternal undernutrition, MUN) and controls were used. Supplementation was given through a gelatine (vehicle, VEH) or containing CSE (250 mg kg−1 day−1) 5 days week−1 for 3 weeks. Systolic blood pressure (SBP) was assessed by tail‐cuff plethysmography. MRA function was studied by wire myography, and superoxide anion and nitric oxide were investigated by fluorescent indicators and confocal microscopy. Compared to control‐VEH, MUN‐VEH males showed significantly higher SBP, reduced MRA as well as relaxation to ACh, sodium nitroprusside and the AMPK agonist 5‐aminoimidazole‐4‐carboxamide riboside, but not to isoproterenol. In MUN males, endothelial endothelium‐derived hyperpolarizing factor and nitric oxide were unaltered, but MRA released a vasoconstrictor prostanoid and produced higher levels of superoxide anion. CSE normalized blood pressure and improved all above‐mentioned MRA alterations in MUN males without an effect on control counterparts, except the reduction of superoxide anion. MUN‐VEH females were normotensive and only showed a tendency towards larger superoxide anion production, which was abolished by CSE. CSE supplementation reduces SBP improving endothelium‐dependent and independent MRA vasodilatation, related to local superoxide anion reduction, being a potential nutraceutical ingredient to counteract hypertension, in addition to contributing to the circular economy. Fetal undernutrition induces hypertension in males associated with deficient resistance artery vasodilatation, being normalized by cocoa shell extract (CSE). Release of a cyclooxygenase‐derived contractile factor is the main endothelial alteration, which is abolished by CSE. AMPK and soluble guanylyl cyclase‐mediated relaxation are also reduced in smooth muscle cells from maternal undernutrition resistance arteries, being improved by CSE. Vascular oxidative damage caused by excess superoxide anion generation can account for impaired vasodilatation, which is improved by CSE. The capacity of CSE to improve relaxation is probably related to its antioxidant bioactive factors, and thus cocoa shell is a potential food by‐product to treat hypertension. [ABSTRACT FROM AUTHOR]

Background: To mitigate the growing burden of non-communicable diseases, doctors training to become paediatricians should be equipped with concepts and knowledge regarding Developmental Origins of Health and Disease (DOHaD). Methods: We assessed the knowledge, attitudes, and practices (KAP) of medical officers, resident physicians, as well as junior and senior residents practising in the paediatric department of a tertiary women's and children's hospital. This was done through a cross-sectional online survey, with questions developed after focused group discussions with domain experts, and responses based on a 5-point Likert scale. Results: A total of 95 physicians met the inclusion criteria, grouped into Medical Officers (MOs) and Registrars (REGs), and we received a 100% response rate. Results showed that few physicians (n = 22, 23.2%) knew the term DOHaD, and majority rated their colleagues to be inadequately informed (n = 84, 88.4%). Among the physicians, one third (n = 32, 33.7%) were not confident in their ability to counsel patients about initiating healthy feeding practices to prevent future metabolic diseases in their children. However, there was a readiness to be better equipped with DOHaD principles and knowledge, and 95.8% (n = 91) strongly acknowledged the physician's responsibility to optimise early life determinants of cardiometabolic health. Conclusion: In conclusion, the findings suggest a poor translation of DOHaD concepts, indicating that bridging the gap between DOHaD research knowledge and clinical application represents an unmet need. These principles should be inculcated early in the professional training of all healthcare providers. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Insufficient evidence regarding how maternal undernutrition affects craniofacial bone development persists. With its unique focus on the impact of gestational protein restriction on calvaria and mandible osteogenesis, this study aims to fill, at least in part, this gap. Female mice were mated and randomized into NP (normal protein) or LP (low protein) groups. On the 18th gestational day (GD), male embryos were collected and submitted to microtomography (µCT), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), PCR, and autophagy dynamic analyses. The study shows that the LP offspring exhibited lower body mass than the NP group, with µCT analysis revealing no volumetric differences in fetus's head. EDS analysis showed lower calcium and higher phosphorus percentages in mandibles and calvaria. SEM assessment evidenced higher hydroxyapatite crystal-like (HC) deposition on the calvaria surface in LP fetus. Conversely, lower HC deposition was observed on the mandible surface, suggesting delayed matrix mineralization in LP fetuses with a higher percentage of collagen fibers in the mandible bone. The autophagy process was reduced in the mesenchyme of LP fetuses. PCR array analysis of 84 genes revealed 27 genes with differential expression in the LP progeny—moreover, increased mRNA levels of Akt1, Mtor, Nfkb, and Smad1 in the LP offspring. In conclusion, the results suggest that gestational protein restriction anticipated bone differentiation in utero, before 18GD, where this process is reduced compared to the control, leading to the reduction in bone area at 15 postnatal day previously observed. These findings provide insights into the molecular and cellular mechanisms of mandible development and suggest potential implications for the Developmental Origins of Health and Disease (DOHaD). [ABSTRACT FROM AUTHOR]

The disciplinary integration of biology and economy is taking new forms in the postgenomic era, transforming long-standing exchanges between human biology and economics. In this article, we first describe how an emerging area of research in development and health economics has embraced, stabilized, and expanded the emerging field of the Developmental Origins of Health and Disease (DOHaD). We map the global expansion of this literature particularly in the Global South. Via an analysis of shifting models of health in human capital, we argue that as economists draw on DOHaD theories, their increasing focus on marginalized groups in postcolonial settings produces a darker model of health deficit. Based on notions of accumulated shocks, this model questions the generalizable expansion of the economization of life and speaks to a wider and more sombre range of figures. Health models in economics reflect the double nature of biological and developmental plasticity caught between agency and passivity, change, and near-permanency. [ABSTRACT FROM AUTHOR]

Introduction: Using a non-human primate (NHP) model of maternal Westernstyle diet (mWSD) feeding during pregnancy and lactation, we previously reported altered offspring beta:alpha cell ratio in vivo and insulin hypersecretion ex vivo. Mitochondria are known to maintain beta-cell function by producing ATP for insulin secretion. In response to nutrient stress, the mitochondrial network within beta cells undergoes morphological changes to maintain respiration and metabolic adaptability. Given that mitochondrial dynamics have also been associated with cellular fate transitions, we assessed whether mWSD exposure was associated with changes in markers of beta-cell maturity and/or mitochondrial morphology that might explain the offspring islet phenotype. Methods: We evaluated the expression of beta-cell identity/maturity markers (NKX6.1, MAFB, UCN3) via florescence microscopy in islets of Japanese macaque pre-adolescent (1 year old) and peri-adolescent (3-year-old) offspring born to dams fed either a control diet or WSD during pregnancy and lactation and weaned onto WSD. Mitochondrial morphology in NHP offspring beta cells was analyzed in 2D by transmission electron microscopy and in 3D using super resolution microscopy to deconvolve the beta-cell mitochondrial network. Results: There was no difference in the percent of beta cells expressing key maturity markers in NHP offspring from WSD-fed dams at 1 or 3 years of age; however, beta cells of WSD-exposed 3 year old offspring showed increased levels of NKX6.1 per beta cell at 3 years of age. Regardless of maternal diet, the beta-cell mitochondrial network was found to be primarily short and fragmented at both ages in NHP; overall mitochondrial volume increased with age. In utero and lactational exposure to maternal WSD consumption may increase mitochondrial fragmentation. Discussion: Despite mWSD consumption having clear developmental effects on offspring beta:alpha cell ratio and insulin secretory response to glucose, this does not appear to be mediated by changes to beta-cell maturity or the beta-cell mitochondrial network. In general, the more fragmented mitochondrial network in NHP beta cells suggests greater ability for metabolic flexibility. [ABSTRACT FROM AUTHOR]

The placenta operates during gestation as the primary communication organ between the mother and fetus. It is essential for gas, nutrient exchange, and fetal waste transfer. The placenta also produces a wide range of hormones and other factors that influence maternal physiology, including survival and activity of the corpus luteum of the ovary, but the means whereby the placenta shapes fetal development remain less clear, although the fetal brain is thought to be dependent upon the placenta for factors that play roles in its early differentiation and growth, giving rise to the term "placenta–brain axis". Placental hormones transit via the maternal and fetal vasculature, but smaller placental molecules require protection from fetal and maternal metabolism. Such biomolecules include small RNA, mRNA, peptides, lipids, and catecholamines that include serotonin and dopamine. These compounds presumably shuttle to maternal and fetal systems via protective extracellular vesicles (EVs). Placental EVs (pEVs) and their components, in particular miRNA (miRs), are known to play important roles in regulating maternal systems, such as immune, cardiovascular, and reproductive functions. A scant amount is known about how pEVs affect fetal cells and tissues. The composition of pEVs can be influenced by gestational diseases. This review will provide critical insight into the roles of pEVs as the intermediary link between maternal and fetal systems, the impact of maternal pathologies on pEV cargo contents, and how an understanding of biomolecular changes within pEVs in health and disease might be utilized to design early diagnostic and mitigation strategies to prevent gestational diseases and later offspring disorders. [ABSTRACT FROM AUTHOR]

Pregnancy is an opportunistic time for dietary intake to influence future disease susceptibility in offspring later in life. The ORIGINS Project was established to identify the factors that contribute to 'a healthy start to life' through a focus supporting childhood health and preventing disease (including non-communicable diseases). We aim to describe the dietary intakes of pregnant women in this cohort and to compare these to the Nutrient Reference Values (NRVs) and Australian Recommended Food Score (ARFS). The usual food and nutrient intakes of women were collected using the Australian Eating Survey (AES), a semi-quantitative food frequency questionnaire (FFQ). A total of 374 women completed the AES FFQ at both 20 weeks and 36 weeks of gestation between December 2016 and January 2023. Macronutrient, micronutrient, and food group intake were explored using descriptive statistics. Overall, it was found that the energy contribution from carbohydrates was low, while that from fat and saturated fat was high; participants were not meeting the recommendations for several key micronutrients (calcium, iron, iodine, and folate); and they had low diet quality scores for all food groups. These findings suggest that despite the ongoing promotion of healthy eating during pregnancy, further exploration into why dietary guidelines during pregnancy are not being adhered to is warranted. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals (EDCs) have become so pervasive in our environment and daily lives that it is impossible to avoid contact with such compounds, including pregnant women seeking to minimize exposures to themselves and their unborn children. Developmental exposure of humans and rodent models to bisphenol A (BPA) and other EDCs is linked to increased anxiogenic behaviors, learning and memory deficits, and decreased socio-sexual behaviors. Prenatal exposure to BPA and other EDCs leads to longstanding and harmful effects on gut microbiota with reductions in beneficial bacteria, i.e., gut dysbiosis, and such microbial changes are linked to host changes in fecal metabolites, including those involved in carbohydrate metabolism and synthesis, and neurobehavioral alterations in adulthood, in particular, social and cognitive deficits. Gut dysbiosis is increasingly being recognized as a key driver of a myriad of diseases, ranging from metabolic, cardiovascular, reproductive, and neurobehavioral disorders via the gut-microbiome–brain axis. Thus, EDCs might induce indirect effects on physical and mental health by acting as microbiome-disrupting chemicals. Findings raise the important question as to whether pregnant women should consume a probiotic supplement to mitigate pernicious effects of EDCs, especially BPA, on themselves and their unborn offspring. Current studies investigating the effects of maternal probiotic supplementation on pregnant women's health and that of their unborn offspring will be reviewed. Data will inform on the potential application of probiotic supplementation to reverse harmful effects of EDCs, especially BPA, in pregnant women unwittingly exposed to these compounds and striving to give their offspring the best start in life. [ABSTRACT FROM AUTHOR]

Abstract Background To mitigate the growing burden of non-communicable diseases, doctors training to become paediatricians should be equipped with concepts and knowledge regarding Developmental Origins of Health and Disease (DOHaD). Methods We assessed the knowledge, attitudes, and practices (KAP) of medical officers, resident physicians, as well as junior and senior residents practising in the paediatric department of a tertiary women’s and children’s hospital. This was done through a cross-sectional online survey, with questions developed after focused group discussions with domain experts, and responses based on a 5-point Likert scale. Results A total of 95 physicians met the inclusion criteria, grouped into Medical Officers (MOs) and Registrars (REGs), and we received a 100% response rate. Results showed that few physicians (n = 22, 23.2%) knew the term DOHaD, and majority rated their colleagues to be inadequately informed (n = 84, 88.4%). Among the physicians, one third (n = 32, 33.7%) were not confident in their ability to counsel patients about initiating healthy feeding practices to prevent future metabolic diseases in their children. However, there was a readiness to be better equipped with DOHaD principles and knowledge, and 95.8% (n = 91) strongly acknowledged the physician’s responsibility to optimise early life determinants of cardiometabolic health. Conclusion In conclusion, the findings suggest a poor translation of DOHaD concepts, indicating that bridging the gap between DOHaD research knowledge and clinical application represents an unmet need. These principles should be inculcated early in the professional training of all healthcare providers.

Maternal adverse childhood experiences (ACEs) are robust predictors of mental health for both the exposed individual and the next generation; however, the pathway through which such intergenerational risk is conferred remains unknown. The current study evaluated the association between maternal ACEs and infant brain development, including an a priori focus on circuits implicated in emotional and sensory processing. The sample included 101 mother-infant dyads from a longitudinal study. Maternal ACEs were assessed with the Adverse Childhood Questionnaire dichotomized into low (0 or 1) and high (≥2) groups. White matter microstructure, as indexed by fractional anisotropy (FA), was assessed using structural magnetic resonance imaging in infants (41.6–46.0 weeks' postconceptional age) within a priori tracts (the cingulum, fornix, uncinate, inferior frontal occipital fasciculus, and inferior longitudinal fasciculus). Exploratory analyses were also conducted across the whole brain. High maternal ACEs (≥2) were associated with decreased infant left inferior longitudinal fasciculus (ILF) FA (F (1,94) = 7.78, p <.006) relative to infants of low ACE mothers. No group difference was observed within the right ILF following correction for multiple comparisons (F (1,95) = 4.29, p <.041). Follow-up analyses within the left ILF demonstrated associations between high maternal ACEs and increased left radial diffusivity (F (1,95) = 5.10, p <.006). Exploratory analyses demonstrated preliminary support for differences in visual processing networks (e.g., optic tract) as well as additional circuits less frequently examined in the context of early life adversity exposure (e.g., corticothalamic tract). Maternal ACEs predict neural circuit development of the inferior longitudinal fasciculus. Findings suggest that early developing sensory circuits within the infant brain are susceptible to maternal adverse childhood experiences and may have implications for the maturation of higher-order emotional and cognitive circuits. • We assessed maternal adverse childhood experiences on infant white matter development. • Among 101 infants we measured white matter microstructure using fractional anisotropy. • Maternal ACEs predicted lower inferior longitudinal fasciculus fractional anisotropy. • Sensory circuitry development within the infant brain is susceptible to maternal ACEs. [ABSTRACT FROM AUTHOR]

Abstract Background We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle. Results Focusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, our approach identifies 217 cattle CoRSIVs, a subset of which we independently validate by bisulfite pyrosequencing. Similar to human CoRSIVs, those in cattle are strongly associated with genetic variation. Also as in humans, we show that establishment of DNA methylation at cattle CoRSIVs is particularly sensitive to early embryonic environment, in the context of embryo culture during assisted reproduction. Conclusions Our data indicate that CoRSIVs exist in cattle, as in humans, suggesting these systemic epigenetic variants may be common to mammals in general. To the extent that individual epigenetic variation at cattle CoRSIVs affects phenotypic outcomes, assessment of CoRSIV methylation at birth may become an important tool for optimizing agriculturally important traits. Moreover, adjusting embryo culture conditions during assisted reproduction may provide opportunities to tailor agricultural outcomes by engineering CoRSIV methylation profiles.

Background: An association between birth weight and cardiovascular disease (CVD) in adulthood has been observed in many countries; however, only a few studies have been conducted in Asian populations. Methods: We used data from the baseline survey (2011–2016) of the Japan Public Health Center-based Prospective Study for the Next Generation Cohort, which included 114,105 participants aged 40–74 years. Adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) were calculated from the prevalence of present and past histories of CVD and other lifestyle-related diseases, including hypertension, diabetes, hyperlipidemia, and gout, by birth weight, using Poisson regression. Results: The prevalence of CVD increased with lower birth weight, with the highest prevalence among those with birth weight under 1,500 grams (males 4.6%; females 1.7%) and the lowest one among those with birth weight at or over 4,000 g (males 3.7%: females 0.8%). Among 88,653 participants (41,156 males and 47,497 females) with complete data on possible confounders, birth weight under 1,500 g was associated with a higher prevalence of CVD (aPR 1.76; 95% CI, 1.37–2.26), hypertension (aPR 1.29; 95% CI, 1.17–1.42), and diabetes (aPR 1.53; 95% CI, 1.26–1.86) when a birth weight of 3,000–3,999 grams was used as the reference. Weaker associations were observed for birth weight of 1,500–2,499 grams and 2,500–2,999 grams, while no significant associations were observed for birth weight at or over 4,000 grams. The association between birth weight and the prevalence of hyperlipidemia was less profound, and no significant association was observed between birth weight and gout. Conclusion: Lower birth weight was associated with a higher prevalence of CVD, hypertension, and diabetes in the Japanese population.

Abstract Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome‐wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English‐language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross‐sectional studies, 13.4% animal studies, 4.8% genome‐wide studies, 5.8% epigenome‐wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long‐term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early‐life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome‐wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long‐term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW‐associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

Recent studies have highlighted the impact of disrupted maternal gut microbiota on the colonization of offspring gut microbiota, with implications for offspring developmental trajectories. The extent to which offspring inherit the characteristics of altered maternal gut microbiota remains elusive. In this study, we employed a mouse model where maternal gut microbiota disruption was induced using non-absorbable antibiotics. Systematic chronological analyses of dam fecal samples, offspring luminal content, and offspring gut tissue samples revealed a notable congruence between offspring gut microbiota profiles and those of the perturbed maternal gut microbiota, highlighting the profound influence of maternal microbiota on early-life colonization of offspring gut microbiota. Nonetheless, certain dominant bacterial genera in maternal microbiota did not transfer to the offspring, indicating a bacterial taxonomy-dependent mechanism in the inheritance of maternal gut microbiota. Our results embody the vertical transmission dynamics of disrupted maternal gut microbiota in an animal model, where the gut microbiota of an offspring closely mirrors the gut microbiota of its mother.

Introduction:Maternal obstructive sleep apnea (OSA) during pregnancy is the risk factor for impaired fetal growth with low birth weight in the offspring. However, it is unclear whether gestational intermittent hypoxia (IH, a hallmark of maternal OSA) has long-term detrimental consequences on the skeletal development of offspring. This study aimed to investigate postnatalmaxillofacial bone growth and cartilage metabolism in male and female offspring that were exposed to gestational IH. Methods: Mother rats underwent IH at 20 cycles/h (nadir, 4% O2; peak, 21% O2; 0% CO2) for 8 h per day during gestational days (GD) 7-20, and their male and female offspring were analyzed postnatally at 5 and 10 weeks of age. Allmale and female offspring were born and raised under normoxic conditions. Results: There was no significant difference in whole-body weight and tibial length between the IH male/female offspring and their control counterparts. In contrast, the mandibular condylar length was significantly shorter in the IH male offspring than in the control male offspring at 5 and 10 weeks of age, while there was no significant difference in the female offspring. Real-time polymerase chain reaction (PCR) showed that gestational IH significantly downregulated the mRNA level of SOX9 (a chondrogenesismarker) and upregulated themRNA level of HIF- 1α (a hypoxia-inducible factor marker) in the mandibular condylar cartilage of male offspring, but not in female offspring. Conclusion: Gestational IH induced underdeveloped mandibular ramus/condyles and reduced mRNA expression of SOX9, while enhancing mRNA expression of HIF-1α in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Introduction: Early life growth restriction significantly increases the risk of adulthood physical inactivity and thereby chronic disease incidence. Improvements in motor skill acquisition could result in greater physical activity engagement in the growth-restricted population, thus reducing chronic disease risk. The purpose of this study was to implement an early life motor training intervention to improve physical activity engagement in control and growth-restricted mice. Methods: Mice were growth restricted in early life utilizing a validated nutritive model or remained fully nourished in early life as a control. All mice were tested throughout early life for various components of motor skill acquisition. On postnatal day 10,mice were randomly assigned to engage in an early life motor skill intervention daily until postnatal day 21 or remained as a sedentary control. All mice were given access to an in-cage running wheel from postnatal days 45-70. Results: Growth-restricted group (PGR) mice had impaired trunk and postural control, coordination/vestibular development, and hindlimb strength in early life compared with control mice. There were no differences in wheel running behavior between the trained and sedentary mice, although control mice ran at a faster average speed compared with PGR mice. Control female mice ran more than PGR female mice during the week 2 dark cycle. Conclusions: Early life growth restriction reduced motor skill attainment throughout early life, which may be associated with reduced ability to engage in physical activity in adulthood. The early life motor skill intervention did not elicit changes in body weight or physical activity engagement in control or PGR mice, indicating that a more intense/different intervention specifically targeting skeletal muscle may be necessary to counteract the detrimental effects of early life growth restriction. [ABSTRACT FROM AUTHOR]

The Barcelona Life Study Cohort (BiSC) is a research project that aims to investigate the impact of environmental factors on maternal and child health and development. The cohort consists of 1080 pregnant women who were recruited between October 2018 and April 2021 in Barcelona, Spain. Data collection includes a wide range of demographic, lifestyle, and exposure information, as well as mental and physical health outcomes. The study conducts multiple follow-ups with participants during pregnancy and postnatal periods, collecting comprehensive data on various variables. The data collected includes information on sociodemographic characteristics, exposures and lifestyle, medical history, clinical data, mental health, physical examination, biological samples, home characteristics, and cognitive tests. The study also collects data during home visits, including information on air pollution, noise, temperature, humidity, physical activity, and geolocation. The study has a high participation rate, with 828 participants remaining in the cohort at the 18-month follow-up. The data collected in the study is valuable for researchers studying various aspects of health and environmental factors in Barcelona. The study faced challenges due to the COVID-19 pandemic, resulting in missing data and limitations in data collection, but it also provided an opportunity to evaluate the interaction between socio-environmental factors and maternal and child health. The BiSC data is available for external collaborations, and interested parties can request access through the BiSC website. The study was funded by the European Research Council and the Health Effects Institute, among others. [Extracted from the article]

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno‐miR‐184 and rno‐miR‐141‐3p in the ventral prostate (VP) of offspring. Here, rno‐miR‐184 and rno‐miR‐141‐3 expressions were obtained by RT‐qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21‐F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 μg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1‐treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers. [ABSTRACT FROM AUTHOR]

Introduction: Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed. Methods: Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences. Results: We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2). Conclusions: These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility. [ABSTRACT FROM AUTHOR]

The exponential increase in global plastic usage has led to the emergence of nano- and microplastic (NMP) pollution as a pressing environmental issue due to its implications for human and other mammalian health. We have developed methodologies to extract solid materials from human tissue samples by saponification and ultracentrifugation, allowing for highly specific and quantitative analysis of plastics by pyrolysis-gas chromatography and mass spectrometry (Py-GC-MS). As a benchmark, placenta tissue samples were analyzed using fluorescence microscopy and automated particle count, which demonstrated the presence of >1-micron particles and fibers, but not nano-sized plastic particles. Analyses of the samples (n  = 10) using attenuated total reflectance-Fourier transform infrared spectroscopy indicated presence of rayon, polystyrene, polyethylene, and unclassified plastic particles. By contrast, among 62 placenta samples, Py-GC-MS revealed that microplastics were present in all participants' placentae, with concentrations ranging widely from 6.5 to 685 µg NMPs per gram of placental tissue, averaging 126.8 ± 147.5 µg/g (mean±SD). Polyethylene was the most prevalent polymer, accounting for 54% of total NMPs and consistently found in nearly all samples (mean 68.8 ± 93.2 µg/g placenta). Polyvinyl chloride and nylon each represented approximately 10% of the NMPs by weight, with the remaining 26% of the composition represented by 9 other polymers. Together, these data demonstrate advancements in the unbiased quantitative resolution of Py-GC-MS applied to the identification and quantification of NMP species at the maternal-fetal interface. This method, paired with clinical metadata, will be pivotal to evaluating potential impacts of NMPs on adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Large-scale production and waste of plastic materials have resulted in widespread environmental contamination by the breakdown product of bulk plastic materials to micro- and nanoplastics (MNPs). The small size of these particles enables their suspension in the air, making pulmonary exposure inevitable. Previous work has demonstrated that xenobiotic pulmonary exposure to nanoparticles during gestation leads to maternal vascular impairments, as well as cardiovascular dysfunction within the fetus. Few studies have assessed the toxicological consequences of maternal nanoplastic (NP) exposure; therefore, the objective of this study was to assess maternal and fetal health after a single maternal pulmonary exposure to polystyrene NP in late gestation. We hypothesized that this acute exposure would impair maternal and fetal cardiovascular function. Pregnant rats were exposed to nanopolystyrene on gestational day 19 via intratracheal instillation. 24 h later, maternal and fetal health outcomes were evaluated. Cardiovascular function was assessed in dams using vascular myography ex vivo and in fetuses in vivo function was measured via ultrasound. Both fetal and placental weight were reduced after maternal exposure to nanopolystyrene. Increased heart weight and vascular dysfunction in the aorta were evident in exposed dams. Maternal exposure led to vascular dysfunction in the radial artery of the uterus, a resistance vessel that controls blood flow to the fetoplacental compartment. Function of the fetal heart, fetal aorta, and umbilical artery after gestational exposure was dysregulated. Taken together, these data suggest that exposure to NPs negatively impacts maternal and fetal health, highlighting the concern of MNPs exposure on pregnancy and fetal development. [ABSTRACT FROM AUTHOR]

Objectives: Historical evidence from 18th‐ and 19th‐century England suggests that industrialization's impacts on health were largely negative, especially among marginalized groups. However, available documentary evidence is often biased toward adult men and rarely sheds light on the experiences of other members of the population, such as women and children. Craniofacial fluctuating asymmetry (FA) can serve as a proxy measurement of developmental instability and stress during development. This study examines the associations among age, sex, socioeconomic status (SES), and FA in skeletal samples from industrial‐era England. Materials and Methods: The sample for this study comes from four industrial‐era cemeteries from England (A.D. 1711–1857). Geometric morphometric analyses of three‐dimensional landmark coordinate data were used to generate a measure of FA for each individual (Mahalanobis distance). A three‐way ANOVA was used to evaluate the impacts of sex, SES, and FA scores on adult age at death (n = 168). Results: Significant associations existed between age at death and SES (p = 0.004) and FA scores (p = 0.094). Comparisons of the estimated means indicated that age at death was consistently higher among high SES individuals and individuals with FA scores less than one standard deviation from the mean. Conclusions: This study supports findings from previous studies that have suggested that the differences in resource access and environmental buffering generated by socioeconomic inequality can impact longevity and patterns of mortality among socioeconomic status groups. Likewise, stress in early life—evinced by craniofacial fluctuating asymmetry—can influence observed patterns of longevity in adults decades later. [ABSTRACT FROM AUTHOR]

Recent evidence indicates that the human womb is contaminated with a variety of particulate contaminants. Microplastics (MPs, tiny plastic particles, 0.1 – 5000 µm) generated by the breakdown of larger plastic products in the environment) accumulation in human placenta has recently been described. In addition, recent evidence has correlated the number of air pollution particulates in term placentas to the loading of these particles in dust from the gestational parent home. The current study sought to characterize the accumulation of plastic and non-plastic particles (NPP) within the term human placenta. Placenta tissues were collected from healthy, singleton pregnancies following vaginal (n = 5) and caesarean section (n = 5) deliveries at a tertiary care centre located in an urban Canadian city (Ottawa, ON), with particles detected and characterized by Raman micro-spectroscopy. Both plastic and non-plastic particles were identified in all placentas examined, with an average of 1 ± 1.2 MPs /g and 4 ± 2.9 NPP /g of tissue. Similar tissue concentrations of MPs and NNP were identified in all regions of the placenta (basal plate, chorionic villous, chorionic plate), and did not differ according to mode of delivery. MPs ranged in size (2 – 60 μm), with the most abundant MPs being polyethylene (PE), polypropylene (PP), polystyrene (PS) and polyvinyl chloride (PVC). The most abundantly identified NPP were carbon, graphite, and lead oxide. Collectively, these results demonstrate the accumulation of foreign particles, including MPs, throughout the human placenta. Given the vital functions of the placenta in supporting fetal growth and development, and a potential for MPs to induce toxicity, further investigations into the potential harmful effects of these environmental toxicants on maternal and fetal health is warranted.

Introduction The ORIGINS Project ("ORIGINS") is a longitudinal, population-level birth cohort with data and biosample collections that aim to facilitate research to reduce non-communicable diseases (NCDs) and encourage 'a healthy start to life'. ORIGINS has gathered millions of datapoints and over 400,000 biosamples over 15 timepoints, antenatally through to five years of age, from mothers, non-birthing partners and the child, across four health and wellness domains: 'Growth and development', 'Medical, biological and genetic', 'Biopsychosocial and cognitive', 'Lifestyle, environment and nutrition'. Methods Mothers, non-birthing partners and their offspring were recruited antenatally (between 18 and 38 weeks' gestation) from the Joondalup and Wanneroo communities of Perth, Western Australia from 2017 to 2024. Data come from several sources, including routine hospital antenatal and birthing data, ORIGINS clinical appointments, and online self-completed surveys comprising several standardised measures. Data are merged using the Medical Record Number (MRN), the ORIGINS Unique Identifier and the ORIGINS Pregnancy Number, as well as additional demographic data (e.g. name and date of birth) when necessary. Results The data are held on an integrated data platform that extracts, links, ingests, integrates and stores ORIGINS' data on an Amazon Web Services (AWS) cloud-based data warehouse. Data are linked, transformed for cleaning and coding, and catalogued, ready to provide to sub-projects (independent researchers that apply to use ORIGINS data) to prepare for their own analyses. ORIGINS maximises data quality by checking and replacing missing and erroneous data across the various data sources. Conclusion As a wide array of data across several different domains and timepoints has been collected, the options for future research and utilisation of the data and biosamples are broad. As ORIGINS aims to extend into middle childhood, researchers can examine which antenatal and early childhood factors predict middle childhood outcomes. ORIGINS also aims to link to State and Commonwealth data sets (e.g. Medicare, the National Assessment Program -- Literacy and Numeracy, the Pharmaceutical Benefits Scheme) which will cater to a wide array of research questions.

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 p0.05) 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.

Abstract Fetal exposure to prenatal stress can have significant consequences on short- and long-term health. Epigenetic mechanisms, especially DNA methylation (DNAm), are a possible process how these adverse environmental events could be biologically embedded. We evaluated candidate gene as well as epigenome-wide association studies associating prenatal stress and DNAm changes in peripheral tissues; however, most of these findings lack robust replication. Prenatal stress-associated epigenetic changes have also been linked to child health including internalizing problems, neurobehavioral outcomes and stress reactivity. Future studies should focus on refined measurement and definition of prenatal stress and its timing, ideally also incorporating genomic as well as longitudinal information. This will provide further opportunities to enhance our understanding of the biological embedding of prenatal stress exposure.

ABSTRACTEpigenetic modifications, including DNA methylation, are proposed mechanisms explaining the impact of parental exposures to foetal development and lifelong health. Micronutrients including folate, choline, and vitamin B12 provide methyl groups for the one-carbon metabolism and subsequent DNA methylation processes. Placental DNA methylation changes in response to one-carbon moieties hold potential targets to improve obstetrical care. We conducted a systematic review on the associations between one-carbon metabolism and human placental DNA methylation. We included 22 studies. Findings from clinical studies with minimal ErasmusAGE quality score 5/10 (n = 15) and in vitro studies (n = 3) are summarized for different one-carbon moieties. Next, results are discussed per study approach: (1) global DNA methylation (n = 9), (2) genome-wide analyses (n = 4), and (3) gene specific (n = 14). Generally, one-carbon moieties were not associated with global methylation, although conflicting outcomes were reported specifically for choline. Using genome-wide approaches, few differentially methylated sites associated with S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), or dietary patterns. Most studies taking a gene-specific approach indicated site-specific relationships depending on studied moiety and genomic region, specifically in genes involved in growth and development including LEP, NR3C1, CRH, and PlGF; however, overlap between studies was low. Therefore, we recommend to further investigate the impact of an optimized one-carbon metabolism on DNA methylation and lifelong health.

BackgroundGenetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example at methylation quantitative trait loci (mQTL). We present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation, which we call correlated regions of systemic interindividual variation (CoRSIVs). These can be assayed in blood DNA and do not reflect interindividual variation in cellular composition.ResultsWe use target-capture bisulfite sequencing to assess DNA methylation at 4086 CoRSIVs in multiple tissues from each of 188 donors in the NIH Gene-Tissue Expression (GTEx) program. At CoRSIVs, DNA methylation in peripheral blood correlates with methylation and gene expression in internal organs. We also discover unprecedented mQTL at these regions. Genetic influences on CoRSIV methylation are extremely strong (median R2=0.76), cumulatively comprising over 70-fold more human mQTL than detected in the most powerful previous study. Moreover, mQTL beta coefficients at CoRSIVs are highly skewed (i.e., the major allele predicts higher methylation). Both surprising findings are independently validated in a cohort of 47 non-GTEx individuals. Genomic regions flanking CoRSIVs show long-range enrichments for LINE-1 and LTR transposable elements; the skewed beta coefficients may therefore reflect evolutionary selection of genetic variants that promote their methylation and silencing. Analyses of GWAS summary statistics show that mQTL polymorphisms at CoRSIVs are associated with metabolic and other classes of disease.ConclusionsA focus on systemic interindividual epigenetic variants, clearly enhanced in mQTL content, should likewise benefit studies attempting to link human epigenetic variation to the risk of disease.

In mammals, pregnancy is a process that involves normal physiological adaptations in mother's body that allows the growth of a new individual. It is well known for proper organ development and growth of the fetus it must be an equilibrium between maternal and environmental factors. However, in the last decades has been observed that pregnant women exposed to unfavorable environments, such as undernutrition, may bring adverse effects not only to mother's health but also can induce a hostile intrauterine environment, which may conduct to the development of chronic-degenerative diseases, since birth even in the adulthood. This is why the developmental programming concept (DOHaD: Developmental Origins of Health and Disease), has focused on explaining the relationship between exposure to environmental and social factors during fetal life and the development of several pathologies after birth. This review aims to offer a general overview of how an individual may be susceptible to metabolic diseases due to the various environmental factors that the mother could be exposed to during vulnerable stages of life, and how is that the high-fat diets consumption during pregnancy can be detrimental to the progeny, emphasizing the importance of care during pregnancy in terms of physical, psychosocial and nutritional aspects, all this with the only purpose of awareness to the general population about the importance that pregnant women have a healthy environment. [ABSTRACT FROM AUTHOR]

Consumption of obesogenic (OB) diets increases the prevalence of maternal obesity worldwide, causing major psychological and social burdens in women. Obesity not only impacts the mother's health and fertility but also elevates the risk of obesity and metabolic disorders in the offspring. Family lifestyle is mostly persistent through generations, possibly contributing to the growing prevalence of obesity. We hypothesized that offspring metabolic health is dependent on both maternal and offspring diet and their interaction. We also hypothesized that the sensitivity of the offspring to the diet may be influenced by the match or mismatch between offspring and maternal diets. To test these hypotheses, outbred Swiss mice were fed a control (C, 10% fat, 7% sugar, and n = 14) or OB diet (60% fat, 20% sugar, and n = 15) for 7 weeks and then mated with the same control males. Mice were maintained on the same corresponding diet during pregnancy and lactation, and the offspring were kept with their mothers until weaning. The study focused only on female offspring, which were equally distributed at weaning and fed C or OB diets for 7 weeks, resulting in four treatment groups: C-born offspring fed C or OB diets (C » C and C » OB) and OBborn offspring fed C or OB diets (OB » C and OB » OB). Adult offspring's systemic blood profile (lipid and glucose metabolism) and muscle mitochondrial features were assessed. We confirmed that the offspring's OB diet majorly impacted the offspring's health by impairing the offspring's serum glucose and lipid profiles, which are associated with abnormal muscle mitochondrial ultrastructure. Contrarily, maternal OB diet was associated with increased expression of mitochondrial complex markers and mitochondrial morphology in offspring muscle, but no additive effects of (increased sensitivity to) an offspring OB diet were observed in pups born to obese mothers. In contrast, their metabolic profile appeared to be healthier compared to those born to lean mothers and fed an OB diet. These results are in line with the thrifty phenotype hypothesis, suggesting that OB-born offspring are better adapted to an environment with high energy availability later in life. Thus, using a murine outbred model, we could not confirm that maternal obesogenic diets contribute to female familial obesity in the following generations. [ABSTRACT FROM AUTHOR]

Probiotic supplementation has been identified as a potential target to reduce inflammatory mediators associated with obesity. Therefore, this study assessed the effect of probiotic Lacticaseibacillus rhamnosus LB1.5 on anxiety-like behavior, gene expression in the prefrontal cortex, and neuroinflammation in the cerebral cortex and hippocampus of male mice fed a high-fat diet. Mice aged 21 days were divided into four groups: control (CONT), control plus probiotic (CONT + PROB), high-fat diet (HFD), and high-fat diet plus probiotic (HFD + PROB), and fed for 13 weeks. The probiotic Lact. rhamnosus 1.5 (3.1 × 108 CFU/mL, derived from raw buffalo milk) was administered by gavage three times a week. Probiotic supplementation provided an anxiolytic effect in CONT and HFD. The IL-6 showed lower levels after probiotic supplementation in the HFD. Regarding immunoreactivity for GFAP in the cerebral cortex, we demonstrated that animals HFD-fed had a reduction in cells number compared to CONT. In the hippocampus, we found an interaction between diet and supplementation, as well as an effect of probiotic supplementation. A higher number of Th positive cells was observed in the cerebral cortex in mice fed HFD. Lact. rhamnosus LB1.5 supplementation decreased serum IL-6 levels in HFD-fed mice and promoted a reduction in anxiety-like behavior. [ABSTRACT FROM AUTHOR]

Asthma is the most common chronic disease among children, with more than 300 million cases worldwide. Over the past several decades, asthma incidence has grown, and epidemiological studies identify the modernized lifestyle as playing a strong contributing role in this phenomenon. In particular, lifestyle factors that modify the maternal gut microbiome during pregnancy, or the infant microbiome in early life, can act as developmental programming events which determine health or disease susceptibility later in life. Microbial colonization of the gut begins at birth, and factors such as delivery mode, breastfeeding, diet, antibiotic use, and exposure to environmental bacteria influence the development of the infant microbiome. Colonization of the gut microbiome is crucial for proper immune system development and disruptions to this process can predispose a child to asthma development. Here, we describe the importance of early‐life events for shaping immune responses along the gut‐lung axis and why they may provide a window of opportunity for asthma prevention. [ABSTRACT FROM AUTHOR]

Stress-induced fetal programming diminishes β2 adrenergic tone, which coincides with intrauterine growth restriction (IUGR) and lifelong metabolic dysfunction. We determined if stimulating β2 adrenergic activity in IUGR-born lambs would improve metabolic outcomes. IUGR lambs that received daily injections of saline or the β2 agonist clenbuterol from birth to 60 days were compared with controls from pair-fed thermoneutral pregnancies. As juveniles, IUGR lambs exhibited systemic inflammation and robust metabolic dysfunction, including greater (p < 0.05) circulating TNFα, IL-6, and non-esterified fatty acids, increased (p < 0.05) intramuscular glycogen, reduced (p < 0.05) circulating IGF-1, hindlimb blood flow, glucose-stimulated insulin secretion, and muscle glucose oxidation. Daily clenbuterol fully recovered (p < 0.05) circulating TNFα, IL-6, and non-esterified fatty acids, hindlimb blood flow, muscle glucose oxidation, and intramuscular glycogen. Glucose-stimulated insulin secretion was partially recovered (p < 0.05) in clenbuterol-treated IUGR lambs, but circulating IGF-1 was not improved. Circulating triglycerides and HDL cholesterol were elevated (p < 0.05) in clenbuterol-treated IUGR lambs, despite being normal in untreated IUGR lambs. We conclude that deficient β2 adrenergic regulation is a primary mechanism for several components of metabolic dysfunction in IUGR-born offspring and thus represents a potential therapeutic target for improving metabolic outcomes. Moreover, benefits from the β2 agonist were likely complemented by its suppression of IUGR-associated inflammation. [ABSTRACT FROM AUTHOR]

Glyphosate-based herbicides (GBH) are the most widely used pesticides globally. Studies have indicated that they may increase the risk of various organic dysfunctions. Herein, we verified whether exposure to GBH during puberty increases the susceptibility of male and female mice to obesity when they are fed a high-fat diet (HFD) in adulthood. From the 4th–7th weeks of age, male and female C57Bl/6 mice received water (CTL group) or 50 mg GBH /kg body weight (BW; GBH group). From the 8th–21st weeks of age, the mice were fed a standard diet or a HFD. It was found that pubertal GBH exposure exacerbated BW gains and hyperphagia induced by HFD, but only in female GBH-HFD mice. These female mice also exhibited high accumulation of perigonadal and subcutaneous fat, as well as reduced lean body mass. Both male and female GBH-HFD displayed hypertrophic white adipocytes. However, only in females, pubertal GBH exposure aggravated HFD-induced fat accumulation in brown adipocytes. Furthermore, GBH increased plasma cortisol levels by 80% in GBH-HFD males, and 180% in GBH-HFD females. In conclusion, pubertal GBH exposure aggravated HFD-induced obesity, particularly in adult female mice. This study provides novel evidence that GBH misprograms lipid metabolism, accelerating the development of obesity when individuals are challenged by a second metabolic stressor, such as an obesogenic diet. [ABSTRACT FROM AUTHOR]

Fetal exposure to prenatal stress can have significant consequences on short- and long-term health. Epigenetic mechanisms, especially DNA methylation (DNAm), are a possible process how these adverse environmental events could be biologically embedded. We evaluated candidate gene as well as epigenome-wide association studies associating prenatal stress and DNAm changes in peripheral tissues; however, most of these findings lack robust replication. Prenatal stress-associated epigenetic changes have also been linked to child health including internalizing problems, neurobehavioral outcomes and stress reactivity. Future studies should focus on refined measurement and definition of prenatal stress and its timing, ideally also incorporating genomic as well as longitudinal information. This will provide further opportunities to enhance our understanding of the biological embedding of prenatal stress exposure. [ABSTRACT FROM AUTHOR]

IntroductionUsing a non-human primate (NHP) model of maternal Western-style diet (mWSD) feeding during pregnancy and lactation, we previously reported altered offspring beta:alpha cell ratio in vivo and insulin hyper-secretion ex vivo. Mitochondria are known to maintain beta-cell function by producing ATP for insulin secretion. In response to nutrient stress, the mitochondrial network within beta cells undergoes morphological changes to maintain respiration and metabolic adaptability. Given that mitochondrial dynamics have also been associated with cellular fate transitions, we assessed whether mWSD exposure was associated with changes in markers of beta-cell maturity and/or mitochondrial morphology that might explain the offspring islet phenotype.MethodsWe evaluated the expression of beta-cell identity/maturity markers (NKX6.1, MAFB, UCN3) via florescence microscopy in islets of Japanese macaque pre-adolescent (1 year old) and peri-adolescent (3-year-old) offspring born to dams fed either a control diet or WSD during pregnancy and lactation and weaned onto WSD. Mitochondrial morphology in NHP offspring beta cells was analyzed in 2D by transmission electron microscopy and in 3D using super resolution microscopy to deconvolve the beta-cell mitochondrial network.ResultsThere was no difference in the percent of beta cells expressing key maturity markers in NHP offspring from WSD-fed dams at 1 or 3 years of age; however, beta cells of WSD-exposed 3 year old offspring showed increased levels of NKX6.1 per beta cell at 3 years of age. Regardless of maternal diet, the beta-cell mitochondrial network was found to be primarily short and fragmented at both ages in NHP; overall mitochondrial volume increased with age. In utero and lactational exposure to maternal WSD consumption may increase mitochondrial fragmentation.DiscussionDespite mWSD consumption having clear developmental effects on offspring beta:alpha cell ratio and insulin secretory response to glucose, this does not appear to be mediated by changes to beta-cell maturity or the beta-cell mitochondrial network. In general, the more fragmented mitochondrial network in NHP beta cells suggests greater ability for metabolic flexibility.

IntroductionLimited knowledge exists regarding the impact of paternal smoking and alcohol exposure on the development of allergic rhinitis in offspring. Our study aimed to investigate the potential association between preconception paternal smoking and alcohol exposure and the likelihood of children allergic rhinitis.MethodsA retrospective case-control study of 556 prepubertal children aged 3–12 years was performed. The participants were 278 children with allergic rhinitis and 278 healthy controls matched for age and gender. Self-administered questionnaires were distributed and collected on-site, focusing on various factors related to the children's fathers, mothers, and the children themselves during the first year of life and the past 12 months, from March to October 2022.ResultsMultivariate analysis demonstrated that paternal smoking, paternal alcohol consumption prior to conception, paternal allergic diseases, children with a family history of allergies, maternal allergic diseases and pregnancy complications were identified as independent risk factors for allergic rhinitis in their offspring. Moreover, after considering confounding factors, it was observed that paternal smoking exceeding 5 cigarettes per day in the year preceding pregnancy and exceeding 11 years significantly elevated the likelihood of allergic rhinitis in children (OR = 2.009 and 2.479, respectively). Furthermore, the consumption of alcohol by the father at intervals of less than one month in the year prior to pregnancy and a duration of alcohol consumption exceeding 11 years prior to pregnancy are both associated with a significantly increased risk of allergic rhinitis in children (OR = 2.005 and 3.149, respectively).ConclusionsPaternal smoking and alcohol consumption prior to conception contribute to an increased risk of allergic rhinitis in children, with the risk being dependent on the dosage and duration of exposure. Therefore, it is important to not only focus on personal and maternal environmental exposures when considering the occurrence risk of allergic rhinitis in children, but also to consider paternal detrimental exposures prior to conception.

IntroductionEmerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed.MethodsHere, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences.ResultsWe found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2).ConclusionsThese findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility.

Abstract Background Serotonin (5-hydroxytryptamine, 5-HT) signaling is involved in neurodevelopment, mood regulation, energy metabolism, and other physiological processes. DNA methylation plays a significant role in modulating the expression of genes responsible for maintaining 5-HT balance, such as 5-HT transporter (SLC6A4), monoamine oxidase A (MAOA), and 5-HT receptor type 2A (HTR2A). Maternal metabolic health can influence long-term outcomes in offspring, with DNA methylation mediating these effects. We investigated associations between maternal metabolic parameters—pre-pregnancy body mass index (pBMI), gestational weight gain (GWG), and glucose tolerance status (GTS), i.e., gestational diabetes mellitus (GDM) versus normal glucose tolerance (NGT)—and cord blood methylation of SLC6A4, MAOA, and HTR2A in participants from our PlaNS birth cohort. CpG sites (15, 9, and 2 in each gene, respectively) were selected based on literature and in silico data. Methylation levels were quantified by bisulfite pyrosequencing. We also examined the stability of methylation patterns in these genes in circulating blood cells from birth to adolescence using longitudinal DNA methylation data from the ARIES database. Results None of the 203 PlaNS mothers included in this study had preexisting diabetes, 99 were diagnosed with GDM, and 104 had NGT; all neonates were born at full term by planned Cesarean section. Methylation at most CpG sites differed between male and female newborns. SLC6A4 methylation correlated inversely with maternal pBMI and GWG, while methylation at HTR2A site -1665 correlated positively with GWG. None of the maternal metabolic parameters statistically associated with MAOA methylation. DNA methylation data in cord blood and peripheral blood at ages 7 and 15 years were available for 808 participants from the ARIES database; 4 CpG sites (2 in SLC6A4 and 2 in HTR2A) overlapped between the PlaNS and ARIES cohorts. A positive correlation between methylation levels in cord blood and peripheral blood at 7 and 15 years of age was observed for both SLC6A4 and HTR2A CpG sites. Conclusions Methylation of 5-HT regulating genes in cord blood cells is influenced by neonatal sex, with maternal metabolism playing an additional role. Inter-individual variations present in circulating blood cells at birth are still pronounced in childhood and adolescence.

According to the neo-functional developmental theory, newborns and infants exhibit complex psycho-bodily functioning. The Basic Experiences of the Self (BEsS) refer to how they fulfil their essential life needs by organising their psycho-bodily functions in a typical configuration. As part of our research study, we developed a prototype psychometric tool called the BEsS Assessment Form (BAF) to assess the BEsS in infants aged zero to three years. We collected video recordings of their spontaneous behaviour and used the BAF to evaluate function polarity. In the BAF, thirty pairs of words represent functions in their dyadic polarity. To estimate the level of function polarity, we used the Osgood semantic differential scale, which ranges from seven to one. The study’s results confirm that functions can be assessed by grading along the opposite polarity spectrum. Moreover, in accordance with the theory, the functions can be grouped into four domains: the emotional, postural motor, physiological, and cognitive-symbolic planes. Our findings suggest that the characteristics of BEsS are significantly influenced by the activation of the physiological and postural motor functions, which are related to the early regulation of the autonomic nervous system and can be used to evaluate infant arousal.

Abstract Background The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life on the adult gut microbial ecosystem and examine the association of famine-induced disturbance in gut microbiota with type 2 diabetes. Methods We profiled the gut microbial composition among 11,513 adults (18–97 years) from three independent cohorts and examined the association of famine exposure during early life with alterations of adult gut microbial diversity and composition. We performed co-abundance network analyses to identify keystone taxa in the three cohorts and constructed an index with the shared keystone taxa across the three cohorts. Among each cohort, we used linear regression to examine the association of famine exposure during early life with the keystone taxa index and assessed the correlation between the keystone taxa index and type 2 diabetes using logistic regression adjusted for potential confounders. We combined the effect estimates from the three cohorts using random-effects meta-analysis. Results Compared with the no-exposed control group (born during 1962–1964), participants who were exposed to the famine during the first 1000 days of life (born in 1959) had consistently lower gut microbial alpha diversity and alterations in the gut microbial community during adulthood across the three cohorts. Compared with the no-exposed control group, participants who were exposed to famine during the first 1000 days of life were associated with consistently lower levels of keystone taxa index in the three cohorts (pooled beta − 0.29, 95% CI − 0.43, − 0.15). Per 1-standard deviation increment in the keystone taxa index was associated with a 13% lower risk of type 2 diabetes (pooled odds ratio 0.87, 95% CI 0.80, 0.93), with consistent results across three individual cohorts. Conclusions These findings reveal a potential role of the gut microbiota in the developmental origins of health and disease (DOHaD) hypothesis, deepening our understanding about the etiology of type 2 diabetes.

Pregnancy is an opportunistic time for dietary intake to influence future disease susceptibility in offspring later in life. The ORIGINS Project was established to identify the factors that contribute to ‘a healthy start to life’ through a focus supporting childhood health and preventing disease (including non-communicable diseases). We aim to describe the dietary intakes of pregnant women in this cohort and to compare these to the Nutrient Reference Values (NRVs) and Australian Recommended Food Score (ARFS). The usual food and nutrient intakes of women were collected using the Australian Eating Survey (AES), a semi-quantitative food frequency questionnaire (FFQ). A total of 374 women completed the AES FFQ at both 20 weeks and 36 weeks of gestation between December 2016 and January 2023. Macronutrient, micronutrient, and food group intake were explored using descriptive statistics. Overall, it was found that the energy contribution from carbohydrates was low, while that from fat and saturated fat was high; participants were not meeting the recommendations for several key micronutrients (calcium, iron, iodine, and folate); and they had low diet quality scores for all food groups. These findings suggest that despite the ongoing promotion of healthy eating during pregnancy, further exploration into why dietary guidelines during pregnancy are not being adhered to is warranted.

Plastics found in our everyday environment are becoming an increasing concern for individual and population-level health, and the extent of exposure and potential toxic effects of these contaminants on numerous human organ systems are becoming clear. Microplastics (MPs), tiny plastic particles, appear to have many of the same biological effects as their plastic precursors and have the compounded effect of potential accumulation in different organs. Recently, microplastic accumulation was observed in the human placenta, raising important questions related to the biological effects of these contaminants on the health of pregnancies and offspring. These concerns are particularly heightened considering the developmental origins of health and disease (DOHaD) framework, which postulates that in utero exposure can programme the lifelong health of the offspring. The current review examines the state of knowledge on this topic and highlights important avenues for future investigation. [ABSTRACT FROM AUTHOR]