Lactoferrin Supplementation during Pregnancy and Lactation Protects Adult Male Rat Offspring from Hypertension Induced by Maternal Adenine Diet.

Lactoferrin, a glycoprotein derived from breastmilk, is recognized for its health benefits in infants and children; however, its protective effects when administered during gestation and lactation against offspring hypertension remain unclear. This study aimed to investigate whether maternal lactoferrin supplementation could prevent hypertension in offspring born to mothers with chronic kidney disease (CKD), with a focus on nitric oxide (NO), renin-angiotensin system (RAS) regulation, and alterations in gut microbiota and short-chain fatty acids (SCFAs). Prior to pregnancy, female rats were subjected to a 0.5% adenine diet for 3 weeks to induce CKD. During pregnancy and lactation, pregnant rats received one of four diets: normal chow, 0.5% adenine diet, 10% lactoferrin diet, or adenine diet supplemented with lactoferrin. Male offspring were euthanized at 12 weeks of age (n = 8 per group). Supplementation with lactoferrin during gestation and lactation prevented hypertension in adult offspring induced by a maternal adenine diet. The maternal adenine diet caused a decrease in the index of NO availability, which was restored by 67% with maternal LF supplementation. Additionally, LF was related to the regulation of the RAS, as evidenced by a reduced renal expression of renin and the angiotensin II type 1 receptor. Combined maternal adenine and LF diets altered beta diversity, shifted the offspring's gut microbiota, decreased propionate levels, and reduced the renal expression of SCFA receptors. The beneficial effects of lactoferrin are likely mediated through enhanced NO availability, rebalancing the RAS, and alterations in gut microbiota composition and SCFAs. Our findings suggest that maternal lactoferrin supplementation improves hypertension in offspring in a model of adenine-induced CKD, bringing us closer to potentially translating lactoferrin supplementation clinically for children born to mothers with CKD.

Maternal Malnutrition and Elevated Disease Risk in Offspring.

US populations have seen dramatic increases in the prevalence of chronic disease over the past three generations. Rapid increases in type 2 diabetes and obesity have occurred in all the states but have been particularly striking in the Deep South. These increases have contributed to decreases in life expectancy and to painful elevations in health care costs. The causes of worsening population health are complex and incompletely understood. However, there is strong evidence that vulnerability to chronic conditions is determined in early life. Most chronic diseases are developmentally driven. There are specific stressors experienced in early life that influence epigenetic and structural changes during development. These include malnutrition, severe levels of social stress, toxic chemicals, and low oxygen levels. Most US populations have experienced a decrease in the quality of the food they consume as industrial foods have replaced garden-grown foods. Thus, the consumption of too few nutrients before and during pregnancy and during lactation influences the growth of the placenta and fetal organs and their level of resilience when faced with stresses in postnatal life and particularly as adults. Animal studies have shown that the effects of poor nutrition can be passed on to future generations. The most powerful way that the current epidemics of obesity and insulin resistance can be reversed is by providing key nutrients to prospective mothers and those already pregnant.

Chondroitin Sulfate Ameliorates Hypertension in Male Offspring Rat Born to Mothers Fed an Adenine Diet.

Pregnant women with chronic kidney disease (CKD) face increased risks of adverse outcomes in their adult offspring. Offspring rats born to dams fed an adenine diet develop hypertension, coinciding with dysregulated hydrogen sulfide (H2S) and nitric oxide (NO) pathways, as well as alterations in gut microbiota. Chondroitin sulfate (CS) is a multifunctional food known for its diverse bioactivities. As a sulfate prebiotic, CS has shown therapeutic potential in various diseases. Here, we investigated the protective effects of maternal CS supplementation against hypertension in offspring induced by an adenine diet. Mother rats were administered regular chow, 0.5% adenine, 3% CS, or a combination throughout gestation and lactation. Maternal CS supplementation effectively protected offspring from hypertension induced by the adenine diet. These beneficial effects of CS were connected with increased renal mRNA and protein levels of 3-mercaptopyruvate sulfurtransferase, an enzyme involved in H2S production. Furthermore, maternal CS treatment significantly enhanced alpha diversity and altered beta diversity of gut microbiota in adult offspring. Specifically, perinatal CS treatment promoted the abundance of beneficial microbes such as Roseburia hominis and Ruminococcus gauvreauii. In conclusion, perinatal CS treatment mitigates offspring hypertension associated with maternal adenine diet, suggesting that early administration of sulfate prebiotics may hold preventive potential. These findings warrant further translational research to explore their clinical implications.

Sex-Specific Associations between Prenatal Exposure to Bisphenols and Phthalates and Infant Epigenetic Age Acceleration.

We examined whether prenatal exposure to two classes of endocrine-disrupting chemicals (EDCs) was associated with infant epigenetic age acceleration (EAA), a DNA methylation biomarker of aging. Participants included 224 maternal-infant pairs from a Canadian pregnancy cohort study. Two bisphenols and 12 phthalate metabolites were measured in maternal second trimester urines. Buccal epithelial cell cheek swabs were collected from 3 month old infants and DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The Pediatric-Buccal-Epigenetic tool was used to estimate EAA. Sex-stratified robust regressions examined individual chemical associations with EAA, and Bayesian kernel machine regression (BKMR) examined chemical mixture effects. Adjusted robust models showed that in female infants, prenatal exposure to total bisphenol A (BPA) was positively associated with EAA (B = 0.72, 95% CI: 0.21, 1.24), and multiple phthalate metabolites were inversely associated with EAA (Bs from -0.36 to -0.66, 95% CIs from -1.28 to -0.02). BKMR showed that prenatal BPA was the most important chemical in the mixture and was positively associated with EAA in both sexes. No overall chemical mixture effects or male-specific associations were noted. These findings indicate that prenatal EDC exposures are associated with sex-specific deviations in biological aging, which may have lasting implications for child health and development.

Developmental origins of exceptional health and survival: A four-generation family cohort study.

Background: Previous researched has demonstrated potent health and survival advantages across three-generations in longevity-enriched families. However, the survival advantage associated with familial longevity may manifest earlier in life than previously thought. Methods: We conducted a matched cohort study comparing early health trajectories in third-generation grandchildren (n = 5,637) and fourth-generation great-grandchildren (n = 14,908) of longevity-enriched sibships to demographically matched births (n = 41,090) in Denmark between 1973 and 2018. Results: Lower risk was observed across a range of adverse early life outcomes in the grandchildren, including infant mortality (Hazard Ratio (HR) = 0.53, 95% CI [0.36, 0.77]), preterm birth (Odds Ratio (OR) = 0.82, [0.72, 0.93]), small for gestational age (OR = 0.83, [0.76, 0.90]) and neonatal respiratory disorders (OR = 0.77, [0.67, 0.88]). Relative advantages in parental education and maternal smoking were observed in both generations to a similar degree. However, a much smaller reduction in infant mortality was observed in the great-grandchildren (HR = 0.90, [0.70, 1.17]) and benefits across other outcomes were also less consistent, despite persisting socioeconomic and behavioural advantages. Lastly, maternal, and paternal lines of transmission were equipotent in the transmission of infant survival advantages. Conclusions: Descendants of longevity-enriched sibships exhibit a broad health advantage manifesting as early the perinatal period. However, this effect is strongly diluted over successive generations. Our findings suggest that exceptional health and survival may have early developmental components and implicate heritable genetic and or epigenetic factors in their specific transmission.

Promoting Glutathione Synthesis: A Possibility for Treating Cardiomyopathy Induced by a Maternal Western Diet.

BACKGROUND: The adverse effects of a Western diet on obesity and diabetes among reproductive-aged women pose a significant threat to the cardiovascular health of their offspring. Given the crucial role of glutathione metabolism and glutathione-related antioxidant defense systems in cardiovascular diseases through scavenging ROS and maintaining redox homeostasis, further exploration of their specific influence is imperative to develop therapeutic strategies for cardiomyopathy induced by a maternal Western diet. METHODS: We developed a prenatal maternal Western diet exposure model in C57/B6 mice to investigate cardiac morphology and function through histological analysis and echocardiography. RNA sequencing and analysis were utilized to elucidate the mechanisms underlying the impact of a maternal Western diet and N-acetylcysteine treatment on cardiomyopathy. Additionally, ELISAs, transmission electron microscopy, and flow cytometry were employed to assess the antioxidant defense system and mitochondrial ROS levels in progenitor cardiomyocytes. RESULTS: N-acetylcysteine significantly mitigated cardiomyocyte hypertrophy, myocardial interstitial fibrosis, collagen type I accumulation, and left ventricular remodeling induced by a maternal Western diet, particularly in male offspring. Furthermore, N-acetylcysteine reversed the increase in apoptosis and the increase in the ß/α-MyHC ratio in the myocardium of offspring that results from a maternal Western diet. RNA sequencing and GSEA revealed that the beneficial effects of N-acetylcysteine were linked to its ability to modulate oxidative phosphorylation pathways. Additionally, N-acetylcysteine treatment during pregnancy can markedly elevate glutathione levels, augment glutathione peroxidase (GPx) activity, and mitigate the accumulation of mitochondrial ROS caused by a maternal Western diet. CONCLUSIONS: N-acetylcysteine mitigated cardiomyopathy induced by a maternal Western diet by bolstering glutathione synthesis and enhancing GPx activity, thereby scavenging mitochondrial ROS and modulating oxidative phosphorylation pathways.

Prenatal exposure to an environmentally relevant phthalate mixture alters serum cytokine levels and inflammatory markers in the F1 mouse ovary.

Phthalates are used as plasticizers and solvents in consumer products. Virtually 100% of the US population has measurable exposure levels to phthalates, however, the mechanisms by which prenatal exposure to phthalate mixtures affects reproductive health in the offspring remain unclear. Thus, this study tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture promotes inflammation in F1 ovarian tissue. Pregnant CD-1 dams were dosed orally with vehicle control (corn oil) or phthalate mixture (20 µg/kg/d, 200 µg/kg/d, 200 mg/kg/d, 500 mg/kg/d). Pregnant dams delivered pups naturally and ovaries and sera from the F1 females were collected at postnatal day (PND) 21, PND 60, 3 mo, and 6 mo. Sera were used to measure levels of C-reactive protein (CRP). Ovaries and sera were used for cytokine array analysis. RNA was isolated from F1 ovaries and used to quantify expression of selected cytokine genes. Prenatal exposure to the mixture significantly increased the levels of CRP at 200 µg/kg/d on PND 21 compared with controls. The mixture altered 6 immune factors in sera at PND 21 and 33 immune factors in the ovary and sera at 6 mo compared with controls. The mixture increased ovarian expression of cytokines at PND 21 and decreased ovarian expression of cytokines at 6 mo compared with controls. These data suggest that prenatal exposure to a phthalate mixture interferes with the immune response in F1 female mice long after initial exposure.

The oral microbiome is associated with HPA axis response to a psychosocial stressor.

Intense psychosocial stress during early life has a detrimental effect on health-disease balance in later life. Simultaneously, despite its sensitivity to stress, the developing microbiome contributes to long-term health. Following stress exposure, HPA-axis activation regulates the "fight or flight" response with the release of glucose and cortisol. Here, we investigated the interaction between the oral microbiome and the stress response. We used a cohort of 115 adults, mean age 24, who either experienced institutionalisation and adoption (n = 40) or were non-adopted controls (n = 75). Glucose and cortisol measurements were taken from participants following an extended socially evaluated cold pressor test (seCPT) at multiple time points. The cohort´s oral microbiome was profiled via 16S-V4 sequencing on microbial DNA from saliva and buccal samples. Using mixed-effect linear regressions, we identified 12 genera that exhibited an interaction with host's cortisol-glucose response to stress, strongly influencing intensity and clearance of cortisol and glucose following stress exposure. Particularly, the identified taxa influenced the glucose and cortisol release profiles and kinetics following seCPT exposure. In conclusion, our study provided evidence for the oral microbiome modifying the effect of stress on the HPA-axis and human metabolism, as shown in glucose-cortisol time series data.

Venom gland organogenesis in the common house spider.

Venom is a remarkable innovation found across the animal kingdom, yet the evolutionary origins of venom systems in various groups, including spiders, remain enigmatic. Here, we investigated the organogenesis of the venom apparatus in the common house spider, Parasteatoda tepidariorum. The venom apparatus consists of a pair of secretory glands, each connected to an opening at the fang tip by a duct that runs through the chelicerae. We performed bulk RNA-seq to identify venom gland-specific markers and assayed their expression using RNA in situ hybridisation experiments on whole-mount time-series. These revealed that the gland primordium emerges during embryonic stage 13 at the chelicera tip, progresses proximally by the end of embryonic development and extends into the prosoma post-eclosion. The initiation of expression of an important toxin component in late postembryos marks the activation of venom-secreting cells. Our selected markers also exhibited distinct expression patterns in adult venom glands: sage and the toxin marker were expressed in the secretory epithelium, forkhead and sum-1 in the surrounding muscle layer, while Distal-less was predominantly expressed at the gland extremities. Our study provides the first comprehensive analysis of venom gland morphogenesis in spiders, offering key insights into their evolution and development.

Interdisciplinary fetal-neonatal neurology training improves brain health across the lifespan.

Integrated fetal, neonatal, and pediatric training constitute an interdisciplinary fetal-neonatal neurology (FNN) program. A dynamic neural exposome concept strengthens curriculum content. Trainees participate in mentoring committee selection for guidance during a proposed two-year program. Prenatal to postnatal clinical learning re-enforces early toxic stressor interplay that influences gene-environment interactions. Maternal-placental-fetal triad, neonatal, or childhood diseases require diagnostic and therapeutic decisions during the first 1,000 days when 80 % of neural connections contribute to life-course phenotypic expression. Pediatric follow-up through 3 years adjusts to gestational ages of preterm survivors. Cumulative reproductive, pregnancy, pediatric and adult exposome effects require educational experiences that emphasize a principle-to-practice approach to a brain capital strategy across the lifespan. More rigorous training during fetal, neonatal, and pediatric rotations will be offered to full time trainees. Adult neurology residents, medical students, and trainees from diverse disciplines will learn essential topics during time-limited rotations. Curriculum content will require periodic re-assessments using educational science standards that maintain competence while promoting creative and collaborative problem-solving. Continued career-long learning by FNN graduates will strengthen shared healthcare decisions by all stakeholders. Recognition of adaptive or maladaptive neuroplasticity mechanisms requires analytic skills that identify phenotypes associated with disease pathways. Developmental origins and life-course concepts emphasize brain health across the developmental-aging continuum, applicable to interdisciplinary research collaborations. Social determinants of health recognize diversity, equity, and inclusion priorities with each neurological intervention, particularly for those challenged with disparities. Diagnostic and therapeutic strategies must address resource challenges particularly throughout the Global South to effectively lower the worldwide burden of neurologic disease. Sustainable development goals proposed by the World Health Organization offer universally applicable guidelines in response to ongoing global and regional polycrises. Gender, race, ethnicity, and socio-economic equality promote effective preventive, rescue and reparative neuroprotective interventions. Global synergistic efforts can be enhanced by establishing leadership within academic teaching hubs in FNN training to assist with structure and guidance for smaller healthcare facilities in each community that will improve practice, education and research objectives. Reduced mortality with an improved quality of life must prioritize maternal-pediatric health and well-being to sustain brain health across each lifespan with transgenerational benefits.

Efficacy of Human Recombinant Growth Hormone in Females of a Non-Obese Hyperglycemic Mouse Model after Birth with Low Birth Weight.

We examined whether the administration of growth hormone (GH) improves insulin resistance in females of a non-obese hyperglycemic mouse model after birth with low birth weight (LBW), given that GH is known to increase muscle mass. The intrauterine Ischemia group underwent uterine artery occlusion for 15 min on day 16.5 of gestation. At 4 weeks of age, female mice in the Ischemia group were divided into the GH-treated (Ischemia-GH) and non-GH-treated (Ischemia) groups. At 8 weeks of age, the glucose metabolism, muscle pathology, and metabolome of liver were assessed. The insulin resistance index improved in the Ischemia-GH group compared with the Ischemia group (p = 0.034). The percentage of type 1 muscle fibers was higher in the Ischemia-GH group than the Ischemia group (p < 0.001); the muscle fiber type was altered by GH. In the liver, oxidative stress factors were reduced, and ATP production was increased in the Ischemia-GH group compared to the Ischemia group (p = 0.014), indicating the improved mitochondrial function of liver. GH administration is effective in improving insulin resistance by increasing the content of type 1 muscle fibers and improving mitochondrial function of liver in our non-obese hyperglycemic mouse model after birth with LBW.

Sex-specific differences in the mechanisms for enhanced thromboxane A2-mediated vasoconstriction in adult offspring exposed to prenatal hypoxia.

BACKGROUND: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. METHODS: Pregnant Sprague-Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. RESULTS: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. CONCLUSIONS: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring.

Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease.

Advantageous early-life environments cushion the genetic risk for ischemic heart disease.

In one of the first papers on the impact of early-life conditions on individuals' health in older age, Barker and Osmond [Lancet, 327, 1077-1081 (1986)] show a strong positive relationship between infant mortality rates in the 1920s and ischemic heart disease in the 1970s. We merge historical data on infant mortality rates to 370,000 individual records in the UK Biobank using information on local area and year of birth. We replicate the association between the early-life infant mortality rate and later-life ischemic heart disease in our sample. We then go "beyond Barker," by showing considerable genetic heterogeneity in this association that is robust to within-area as well as within-family analyses. We find no association between the polygenic index and heart disease in areas with the lowest infant mortality rates, but a strong positive relationship in areas characterized by high infant mortality. These findings suggest that advantageous environments can cushion one's genetic disease risk.

Daily Eicosapentaenoic Acid Infusion in IUGR Fetal Lambs Reduced Systemic Inflammation, Increased Muscle ADRß2 Content, and Improved Myoblast Function and Muscle Growth.

Intrauterine growth-restricted (IUGR) fetuses exhibit systemic inflammation that contributes to programmed deficits in myoblast function and muscle growth. Thus, we sought to determine if targeting fetal inflammation improves muscle growth outcomes. Heat stress-induced IUGR fetal lambs were infused with eicosapentaenoic acid (IUGR+EPA; n = 9) or saline (IUGR; n = 8) for 5 days during late gestation and compared to saline-infused controls (n = 11). Circulating eicosapentaenoic acid was 42% less (p < 0.05) for IUGR fetuses but was recovered in IUGR+EPA fetuses. The infusion did not improve placental function or fetal O2 but resolved the 67% greater (p < 0.05) circulating TNFα observed in IUGR fetuses. This improved myoblast function and muscle growth, as the 23% reduction (p < 0.05) in the ex vivo differentiation of IUGR myoblasts was resolved in IUGR+EPA myoblasts. Semitendinosus, longissimus dorsi, and flexor digitorum superficialis muscles were 24-39% lighter (p < 0.05) for IUGR but not for IUGR+EPA fetuses. Elevated (p < 0.05) IL6R and reduced (p < 0.05) ß2 adrenoceptor content in IUGR muscle indicated enhanced inflammatory sensitivity and diminished ß2 adrenergic sensitivity. Although IL6R remained elevated, ß2 adrenoceptor deficits were resolved in IUGR+EPA muscle, demonstrating a unique underlying mechanism for muscle dysregulation. These findings show that fetal inflammation contributes to IUGR muscle growth deficits and thus may be an effective target for intervention.

In Utero Exposure to Maternal SARS-CoV-2 Infection Is Associated With Higher Left Ventricular Mass in Toddlers.

The intrauterine environment plays a critical role in shaping chronic disease risk over the life course. We prospectively evaluated cardiometabolic outcomes in toddlers born to mothers with versus without prenatal severe acute respiratory syndrome coronavirus 2 infection. Children with in utero severe acute respiratory syndrome coronavirus 2 exposure had higher left ventricular mass in association with altered maternal immunologic indices.

The future of intergenerational transmission research: A prospective, three-generation approach.

Dr. Dante Cicchetti's pioneering theory and research on developmental psychopathology have been fundamental to the proliferation of research on intergenerational transmission over the last 40 years. In part due to this foundation, much has been learned about continuities and discontinuities in child maltreatment, attachment, parenting, and psychopathology across generations. Looking towards the future, we propose that this field stands to benefit from a prospective, three-generation approach. Specifically, following established prospective, longitudinal cohorts of children over their transition to parenting the next generation will afford the opportunity to investigate the developmental origins of intergenerational transmission. This approach also can address key outstanding questions and methodological limitations in the extant literature related to the confounding of retrospective and prospective measures; examination of mediators and moderators; and investigation of the roles of biology, environment, and their interplay. After considering these advantages, we offer several considerations and recommendations for future research, many of which are broadly applicable to the study of two or more generations. We hope that this discussion will inspire the leveraging of existing prospective cohorts to carry forward Dr. Cicchetti's remarkable contributions, with the ultimate aim to inform the development of preventions and interventions that disrupt deleterious intergenerational cycles.

How to Prevent Atopic Dermatitis (Eczema) in 2024: Theory and Evidence.

Atopic dermatitis (AD) or eczema is a chronic inflammatory skin disease characterized by dry, itchy, and inflamed skin. We review emerging concepts and clinical evidence addressing the pathogenesis and prevention of AD. We examine several interventions ranging from skin barrier enhancement strategies to probiotics, prebiotics, and synbiotics; and conversely, from antimicrobial exposure to vitamin D and omega fatty acid supplementation; breastfeeding and hydrolyzed formula; and house dust mite avoidance and immunotherapy. We appraise the available evidence base within the context of the Grades of Recommendation, Assessment, Development, and Evaluation approach. We also contextualize our findings in relation to concepts relating AD and individual-patient allergic life trajectories versus a linear concept of the atopic march and provide insights into future knowledge gaps and clinical trial design considerations that must be addressed in forthcoming research. Finally, we provide implementation considerations to detect population-level differences in AD risk. Major international efforts are required to provide definitive evidence regarding what works and what does not for preventing AD.

The Yin and Yang of the oxytocin and stress systems: opposites, yet interdependent and intertwined determinants of lifelong health trajectories.

During parturition and the immediate post-partum period there are two opposite, yet interdependent and intertwined systems that are highly active and play a role in determining lifelong health and behaviour in both the mother and her infant: the stress and the anti-stress (oxytocin) system. Before attempting to understand how the environment around birth determines long-term health trajectories, it is essential to understand how these two systems operate and how they interact. Here, we discuss together the hormonal and neuronal arms of both the hypothalamic-pituitary-adrenal (HPA) axis and the oxytocinergic systems and how they interact. Although the HPA axis and glucocorticoid stress axis are well studied, the role of oxytocin as an extremely powerful anti-stress hormone deserves more attention. It is clear that these anti-stress effects depend on oxytocinergic nerves emanating from the supraoptic nucleus (SON) and paraventricular nucleus (PVN), and project to multiple sites at which the stress system is regulated. These, include projections to corticotropin releasing hormone (CRH) neurons within the PVN, to the anterior pituitary, to areas involved in sympathetic and parasympathetic nervous control, to NA neurons in the locus coeruleus (LC), and to CRH neurons in the amygdala. In the context of the interaction between the HPA axis and the oxytocin system birth is a particularly interesting period as, for both the mother and the infant, both systems are very strongly activated within the same narrow time window. Data suggest that the HPA axis and the oxytocin system appear to interact in this early-life period, with effects lasting many years. If mother-child skin-to-skin contact occurs almost immediately postpartum, the effects of the anti-stress (oxytocin) system become more prominent, moderating lifelong health trajectories. There is clear evidence that HPA axis activity during this time is dependent on the balance between the HPA axis and the oxytocin system, the latter being reinforced by specific somatosensory inputs, and this has long-term consequences for stress reactivity.

Amino Acids during Pregnancy and Offspring Cardiovascular-Kidney-Metabolic Health.

Amino acids are essential for normal pregnancy and fetal development. Disruptions in maternal amino acid metabolism have been associated with various adult diseases later in life, a phenomenon referred to as the developmental origins of health and disease (DOHaD). In this review, we examine the recent evidence highlighting the significant impact of amino acids on fetal programming, their influence on the modulation of gut microbiota, and their repercussions on offspring outcomes, particularly in the context of cardiovascular-kidney-metabolic (CKM) syndrome. Furthermore, we delve into experimental studies that have unveiled the protective effects of therapies targeting amino acids. These interventions have demonstrated the potential to reprogram traits associated with CKM in offspring. The discussion encompasses the challenges of translating the findings from animal studies to clinical applications, emphasizing the complexity of this process. Additionally, we propose potential solutions to overcome these challenges. Ultimately, as we move forward, future research endeavors should aim to pinpoint the most effective amino-acid-targeted therapies, determining the optimal dosage and mode of administration. This exploration is essential for maximizing the reprogramming effects, ultimately contributing to the enhancement of cardiovascular-kidney-metabolic health in offspring.