Exposure to toxins causes lasting damaging effects on the body. Numerous studies in humans and animals suggest that diet has the potential to modify the epigenome and these modifications can be inherited transgenerationally, but few studies investigate how diet can protect against negative effects of toxins. Potential evidence in the primary literature supports that caloric restriction, high-fat diets, high protein-to-carbohydrate ratios, and dietary supplementation protect against environmental toxins and strengthen these effects on their offspring's epigenome. Most notably, the timing when dietary interventions are given - during a parent's early development, pregnancy, and/or lifetime - result in similar transgenerational epigenetic durations. This implies the existence of multiple opportunities to strategically fortify the epigenome. This narrative review explores how to best utilize dietary modifications to modify the epigenome to protect future generations against negative health effects of persistent environmental toxins. Furthermore, by suggesting an ideal diet with specific micronutrients, macronutrients, and food groups, epigenetics can play a key role in the field of preventive medicine. Based on these findings, longitudinal research should be conducted to determine if a high protein, high-fat, and low-carbohydrate diet during a mother's puberty or pregnancy can epigenetically protect against alcohol, tobacco smoke, and air pollution across multiple generations.

Hormones mediate life-history trade-offs. In female mammals, such trade-offs have been studied predominantly in the contexts of oestrogen, progesterone and prolactin. We evaluate the hypothesis that prenatal and postnatal testosterone levels structure and regulate trade-offs in females involving components of reproduction and survival. This hypothesis is predicated on the observation that testosterone confers competition-related and survival-related benefits, but also reproduction-related costs, to female mammals. The hypothesis is supported by field and laboratory data from diverse non-human animals, and data from healthy women. Most broadly, relatively low testosterone level in females has been associated with earlier, faster and higher offspring production, greater attractiveness to males, and reduced dominance or competitiveness, whereas higher testosterone level is associated with delayed and reduced reproduction but increased dominance, status, aggression, and resource accrual. The magnitude of testosterone-mediated trade-offs is expected to depend upon the strength of female-female competition, which represents some function of species-specific ecology, behaviour and mating system. Testosterone-associated trade-offs have, until now, been virtually ignored in studies of female life history, reproductive physiology, evolutionary endocrinology, and female-limited disease, probably due to researcher biases towards conceptualizing androgens as hormones with effects mainly restricted to males.

Background: Chronic venous disease (CVD) is a vascular disorder common among pregnant women, due to the impairment in the venous function associated with the mechanical, hemodynamical, and hormonal changes that occur during pregnancy. CVD is linked to venous hypertension, inflammation, oxidative stress, and hypoxia, which alter placental structure and function, as demonstrated in previous works. The placenta fulfills several roles in fetal development and maternal well-being by mediating nutrient exchange; acting as a mechanical, chemical, and immunological shield; and producing essential hormones, making it crucial to investigate the effects of CVD in this organ. Patients and methods: This work specifically analyzes the gene expression of circadian markers (CLOCK, BMAL1, PER1, and PER2), epigenetic regulators (HAT1 and associated molecules like histones H3, H4, RBBP7, and ASF1), and the anti-aging protein KLOTHO in placental tissue of pregnant women with CVD (CVD-PW, N = 98) compared to healthy pregnant controls (HC-PW, N = 82), using RT-qPCR and immunohistochemistry (IHC) to determine protein expression. Results: Our study demonstrates that the placentas of CVD-PW exhibit the reduced gene and protein levels of circadian regulators (clock, bmal1, per1, and per2), increased expression of hat1 and related proteins (h3, h4, rbbp7, and asf1), and decreased klotho expression, indicative of accelerated aging. Conclusions: These findings highlight profound molecular disturbances in the placentas of women with CVD, offering insights into the disease's pathophysiology and potential implications for maternofetal well-being. While this study deepens our understanding of the relationship between CVD and placental dysfunction, further research is required to fully elucidate these mechanisms and their long-term effects.

The early life growth period, from conception to ~2 years of age, has proven crucial for later health. We hypothesized that early life growth could explain variations in pubertal growth and timing, and adult height.

This retrospective, population-based study was conducted in Sweden. A subgroup, including individuals of all gestational ages and birth sizes (n = 4700, 50% males), from the longitudinal GrowUp1974&1990Gothenburg cohorts was used. QEPS variables were analyzed in univariate and multivariate linear regression models, separately per sex; Q-function throughout all growth periods, and specific E- and P-functions, for early life growth and pubertal growth, respectively.

In multivariate models, early life growth explained 37-38% of the variability in specific pubertal growth, but less so the variability in pubertal timing. Variability in adult height was explained by birth size (57-62%), early growth (66-67%), childhood growth (65-69%), and to a lesser degree by mid-parental height (35-39%). The change in height during puberty explained 8-9% of the variation in adult height.

This study indicates that early life growth is strongly associated with the variability in pubertal growth, and adult height, but not with the timing of pubertal growth.

Early life growth is important as it can serve as a marker for future growth, development, and health. The association between length growth during fetal life and infancy and pubertal growth and timing, and adult height, is only partly understood. Using the QEPS growth model, specific early life growth (E-function) and specific pubertal growth (P-function), including individual variations in tempo and amplitude, can be studied separately from ongoing basic growth (Q-function). This study showed that early life growth is strongly associated with and explains specific pubertal height gain and adult height but less so the timing of pubertal growth.

Maternal melatonin (MT) readily crosses the placental barrier to enter the fetal circulation, and it holds the potential to enhance hair follicle (HF) development, possibly augmented through nutritional interventions during pregnancy. However, the specific impact of maternal MT treatment on fetal HF development remains largely unexplored. In this study, we implanted pregnant rabbits with 10 mg of MT-containing and non-MT-containing silica gel microcapsules. We then assessed HF density and the extent of HF cell apoptosis in the neonatal rabbits. Our findings revealed that maternal MT implantation significantly reduced HF cell apoptosis and promoted an increased HF density in the neonates. Mechanistically, this process involved MT downregulating the expression of JUN/FOS and AP-1, while concurrently upregulating equol expression and reducing norepinephrine levels. Analysis of key protein expression within the MAPK pathway indicated that maternal MT activated this pathway. These results suggest that maternal MT treatment promotes beneficial HF development in offspring. Notably, the transcriptional regulation of JUN/FOS members of the AP-1 complex emerges as a pivotal factor mediating the beneficial effects of MT on neonatal hair follicle development.

The use of selective serotonin reuptake inhibitors (SSRIs) has increased over time. Several studies indicate that paternal use of medication may adversely affect the developing fetus. Only a few studies have investigated the association between preconceptional paternal exposure to SSRIs and the risks of adverse health outcomes in children.

This study aimed to assess adverse birth outcomes and adverse early life events in children fathered by men using SSRIs prior to conception.

All live-born singleton children born in Denmark from 1997 until 2019 and their parents were included. The exposed cohort comprised all children fathered by men using SSRIs 3 months prior to conception and the unexposed cohort comprised all other children. We estimated the odds ratios for adverse birth outcomes: small for gestational age (SGA), preterm birth, low Apgar score, and major congenital malformations. Furthermore, we estimated the hazard ratios for adverse early life events of infections and hospitalizations within 1 year from birth. We also examined adverse birth outcomes and the adverse early life events according to SSRI subgroups.

There was a statistically significantly increased odds ratio 1.15 (confidence interval, CI: 1.06-1.23) for preterm birth. No significant results were found for SGA, low Apgar score, and major congenital malformations. The adjusted hazard ratios for hospitalizations and infections were 1.06 (CI: 1.02-1.11) and 1.02 (CI: 0.97-1.07), respectively. There was a statistically significantly increased odds ratio for preterm birth with respect to the SSRI subgroups citalopram and escitalopram, and for hospitalizations with respect to citalopram.

Although the risks of certain adverse birth and adverse early life outcomes were statistically significantly increased, the ratios were small and may have limited clinical importance. Paternal use of SSRI was in general safe in the preconceptual period.

Childhood obesity increases the risk of developing metabolic diseases in adulthood, since environmental stimuli during critical windows of development can impact on adult metabolic health. Studies demonstrating the effect of prepubertal diet on adult metabolic disease risk are still limited. We hypothesized that a prepubertal control diet (CD) protects the adult metabolic phenotype from diet-induced obesity (DIO), while a high-fat diet (HFD) would predispose to adult metabolic alterations. Sprague-Dawley male rats were fed either a CD or a HFD during the prepubertal period (day 30-40 of age) and subsequently a chronic HFD or CD, respectively, until adulthood (day 220 of age). As controls, rats aged 30 days were exclusively fed a CD or a HFD until adulthood. Body weight and composition, metabolic rate, biochemical and hormonal plasma measurements, hepatic gene expression and methylation and hydroxymethylation levels were analyzed at ages 30, 40 and 220 days. The prepubertal CD prevented fat mass accumulation, lean mass loss and metabolic inflexibility, showed lower insulin, leptin and cholesterol concentrations in adulthood despite the chronic HFD. Notably, the prepubertal CD led to higher hepatic Lxrα expression, lower hepatic global DNA methylation and higher hydroxymethylation in adulthood despite a chronic HFD. Conversely, a prepubertal HFD decreased adult metabolic flexibility, increased serum cholesterol, and decreased Lxrα expression and global DNA hydroxymethylation, while also increasing DNA methylation levels despite a chronic CD. In summary, a prepubertal CD protected the adult metabolic phenotype from high cholesterol concentrations associated with increased hepatic Lxrα expression and lower hepatic global DNA methylation in adulthood, despite exposure to a chronic HFD. Conversely, a prepubertal HFD altered the adult metabolic phenotype.

Depression is presented as a multi-factorial bio-psycho-social expression that has evolved primarily as an effect of stressors related to the motivational/emotional systems that regulate the BrainMind in our relationship with conspecifics. These stressors may be caused by two sources of threat, firstly, the loss of bonding with the caregiver and later with a partner and/or group which relates to the SEPARATION (PANIC/GRIEF) system, secondly, social defeat as an expression of the social competition and social dominance. The sexual maturity drives the individual to social competition and social dominance, even if the latter often occurs before sexual maturity, e.g., chickens, dogs, non-human primates, and humans. Depression is an evolutionarily conserved mechanism in mammals to terminate both separation anxiety, so as to protect the vulnerable social brain from the consequences of prolonged separation anxiety, and the stress of social competition when social defeat is predictable. Adolescence and Young adulthood are particularly susceptible to these two types of threat because of human developmental characteristics that are summarized by the term neoteny. This refers to the slowing down of growth and development, resulting in both a prolonged period of dependence on a caring/protective adult and the persistence of juvenile characteristics throughout life. Therefore, neoteny makes the transition from childhood to sexual maturity more dramatic, making the integration of the SEPARATION (PANIC/GRIEF) system with the dynamics of social competition and dominance more stressful and a source of depression. Stress is an expression of the HPA-Hypothalamic-Pituitary-Adrenal axis that articulates with other systems, mainly the autonomic nervous system and the immune-inflammatory system. The latter is believed to be one of the most significant components in the dynamics of depressive processes, connected to the prodromes of its activation in childhood, under the pressure of environmental and relational stressors which can lead to learned helplessness. The recurrence of stressors makes it easier for the immune-inflammatory system to be activated in later life, which could make a significant contribution to the establishment of a depressive disease. The possible contribution of children's identification processes with their parents' depressive personalities through observational learning is considered.

This study aimed to examine the importance assigned to assessing and considering biological maturation in thematic areas of player development and provide an overview of current practices in German football academies regarding its consideration in training and competition.

An online survey was sent to 56 elite German football academies. A total of 46 responded to the questionnaire (82% response rate). Six participants provided incomplete information resulting in a total of 40 completed surveys in the period from March to May 2022.

Only 20 of participants regularly carried out maturation assessments, despite 95% recognizing its importance for load management, 90% for player development, and 85% for injury prevention. There was no consistent approach to modifying training and competition formats based on maturity status, with a primary focus on gym-based sessions for load management.

The survey results highlight limited implementation of maturation assessment and training modification based on maturity status in German elite youth football academies. Despite recognizing the importance of load monitoring, reporting to parents, and long-term player development in considering biological maturation, practices are not widespread. The predominant use of the maturity offset method suggests an opportunity to improve accuracy by exploring alternative measurement methods and increasing assessment frequency. Moreover, a lack of established procedures for incorporating maturity status into training and competition exists, hindering comprehensive consideration of biological maturation and injury risk prevention. Further research is needed to understand the reasons for inconsistent approaches in maturation assessment and load modification during training and competition.

Objective: We investigated whether the results of leptin gene (LEP) 2548G/A (rs7799039) and leptin receptor gene (LEPR) 668 A/G (rs1137101) variants, as well as the methylation analysis of CpG regions at nucleotides -31 and -51 of the LEP gene, showed any differences between breastfed and non-breastfed children in this study. Materials and Methods: The cross-sectional study included 100 children aged 2-5 years who were attending nursery and kindergarten and had been accepted to the Department of General Paediatrics. Infants who were exclusively breastfed for the first six months after birth constituted the study group, and those who were not only breastfeed constituted the control group. Methylation percentages at CpG islands of the LEP gene were compared between exclusively breastfed and non-exclusively breastfed infants, and the statistical significance was analyzed by looking for changes in LEP -31 and -51 nt methylation and LEP 2548G/A ve LEPR 668 A/G variants. Results: Both groups were compared by feeding, and the association of LEPR and LEP gene polymorphisms and -51 nt and -31 nt methylations were analyzed. There were no significant differences between the groups regarding genotype and allele frequency for the LEPR 668 A/G, LEP 2548 G/A gene variant, -31 nt methylation, and -51 nt methylation status. Similarly, there was no significant difference in genotype and allele frequency for the LEPR 668 A/G gene variant in terms of duration of exclusive breastfeeding, total breastfeeding, body mass index, family obesity, and satiety status. However, maternal support from family elders and physical activity increased the 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. Conclusions: Maternal support from family elders and physical activity were associated with increased 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. However, there are not enough studies in this area to reach a definitive conclusion, and further research is needed.

Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with an increased risk of Parkinson's disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the α-synuclein preformed fibril and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 wk of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points-birth, 6, 12, and 36 wk old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of differential modification of cytosines with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period and disrupt critical neurodevelopmental pathways, thereby impacting risk of late-life diseases, including PD.

In 2023, the World Health Organization (WHO) published a Global Position Paper on Kangaroo Mother Care (KMC), which is applicable to all countries worldwide: from the moment of birth, every "small and sick" newborn should remain with mother in immediate and continuous skin-to-skin contact (SSC), receiving all required clinical care in that place. This was prompted by the startling results of a randomized controlled trial published in 2021: in which 1,609 infants receiving immediate SSC were compared with 1,602 controls that were separated from their mothers but otherwise received identical conventional state-of-the-art care. The intervention infants showed a 25% reduction in mortality after 28 days.

The new WHO guidelines are a significant change from earlier guidance and common clinical practice. The author presents that separating mothers and babies is assumed to be "normal" (a paradigm) but actually puts newborns at increased risk for morbidity and mortality. The author presents arguments and ethical perspectives for a new perspective on what is "normal," keeping newborns with their mothers is the infant's physiological expectation and critical requirement for healthy development. The author reviews the scientific rationale for changing the paradigm, based on synchronous interactions of oxytocin on both mother and infant. This follows a critique of the new policies that highlights the role of immediate SSC.

This critique strengthens the case for implementing the WHO guidelines on KMC for small and sick babies. System changes will be necessary in both obstetric and neonatal settings to ensure seamless perinatal care. Based on the role of oxytocin, the author identifies that many current routine care practices may actually contribute to stress and increased vulnerability to the newborn. WHO has actionable recommendations about family involvement and presence in newborn intensive care units.

The concepts of resilience and vulnerability have specific definitions well known in perinatal care: the key outcome of care should be resilience rather than merely the absence of vulnerability. Newborns in all settings and contexts need us to re-evaluate our paradigms and adopt and implement the new WHO guidelines on KMC in perinatal care.

This study aimed to evaluate the unexplored relationship between BDNF methylation, long-term outcomes, and its interaction with suicidal ideation (SI), which is closely associated with both BDNF expression and stroke outcomes.

A total of 278 stroke patients were assessed for BDNF methylation status and SI using suicide-related item in the Montgomery-Åsberg Depression Rating Scale at 2 weeks post-stroke. We investigated the incidence of composite cerebro-cardiovascular events (CCVEs) during an 8-14-year period after the initial stroke as long-term stroke outcome. We conducted Cox regression models adjusted for covariates to evaluate the association between BDNF methylation status and CCVEs, as well as its interaction with post-stroke SI at 2 weeks.

Higher methylation status of CpG 1, 3, and 5, but not the average value, predicted a greater number of composite CCVEs during 8-14 years following the stroke. The associations between a higher methylation status of CpGs 1, 3, 5, and 8, as well as the average BDNF methylation value, and a greater number of composite CCVEs, were prominent in patients who had post-stroke SI at 2 weeks. Notably, a significant interaction between methylation status and SI on composite CCVEs was observed only for CpG 8.

The significant association between BDNF methylation and poor long-term stroke outcomes, particularly amplified in individuals who had post-stroke SI at 2 weeks, suggested that evaluating the biological marker status of BDNF methylation along with assessing SI during the acute phase of stroke can help predict long-term outcomes.

Historically, a lower incidence of cardiovascular diseases (CVD) and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous bone marrow stem cell (BMSC) clinical trials for cardiac cell therapy overwhelmingly included male patients. However, meta-analysis data from these trials suggest a better functional outcome in postmenopausal women as compared with aged-matched men. Mechanisms governing sex-specific cardiac reparative activity in BMSCs, with and without the influence of sex hormones, remain unexplored. To discover these mechanisms, Male (M), female (F), and ovariectomized female (OVX) mice-derived EPCs were subjected to a series of molecular and epigenetic analyses followed by in vivo functional assessments of cardiac repair. F-EPCs and OVX EPCs show a lower inflammatory profile and promote enhanced cardiac reparative activity after intra-cardiac injections in a male mouse model of myocardial infarction (MI). Epigenetic sequencing revealed a marked difference in the occupancy of the gene repressive H3K9me3 mark, particularly at transcription start sites of key angiogenic and proinflammatory genes in M-EPCs compared with F-EPCs and OVX-EPCs. Our study unveiled that functional sex differences in EPCs are, in part, mediated by differential epigenetic regulation of the proinflammatory and anti-angiogenic gene CCL3, orchestrated by the control of H3K9me3 by histone methyltransferase, G9a/Ehmt2. Our research highlights the importance of considering the sex of donor cells for progenitor-based tissue repair.

Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Animal studies support a link between developmental dieldrin exposure and increased neuronal susceptibility in the α-synuclein preformed fibril (α-syn PFF) and MPTP models in adult male C57BL/6 mice. In a previous study, we showed that developmental dieldrin exposure was associated with sex-specific changes in DNA modifications within genes related to dopaminergic neuron development and maintenance at 12 weeks of age. Here, we used capture hybridization-sequencing with custom baits to interrogate DNA modifications across the entire genetic loci of the previously identified genes at multiple time points - birth, 6 weeks, 12 weeks, and 36 weeks old. We identified largely sex-specific dieldrin-induced changes in DNA modifications at each time point that annotated to pathways important for neurodevelopment, potentially related to critical steps in early neurodevelopment, dopaminergic neuron differentiation, synaptogenesis, synaptic plasticity, and glial-neuron interactions. Despite large numbers of age-specific DNA modifications, longitudinal analysis identified a small number of DMCs with dieldrin-induced deflection of epigenetic aging. The sex-specificity of these results adds to evidence that sex-specific responses to PD-related exposures may underly sex-specific differences in disease. Overall, these data support the idea that developmental dieldrin exposure leads to changes in epigenetic patterns that persist after the exposure period and disrupt critical neurodevelopmental pathways, thereby impacting risk of late life diseases, including PD.

Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber-DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha (Ppara) and low-density lipoprotein receptor (Ldlr), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.

Epidemiological data provide varying degrees of evidence for associations between prenatal exposure to ambient air pollutants and adverse birth outcomes (suboptimal measures of fetal growth, preterm birth and stillbirth). To assess further certainty of effects, this review examines the experimental literature base to identify mechanisms by which air pollution (particulate matter, nitrogen dioxide and ozone) could cause adverse effects on the developing fetus. It likely that this environmental insult impacts multiple biological pathways important for sustaining a healthy pregnancy, depending upon the composition of the pollutant mixture and the exposure window owing to changes in physiologic maturity of the placenta, its circulations and the fetus as pregnancy ensues. The current body of evidence indicates that the placenta is a target tissue, impacted by a variety of critical processes including nitrosative/oxidative stress, inflammation, endocrine disruption, epigenetic changes, as well as vascular dysregulation of the maternal-fetal unit. All of the above can disturb placental function and, as a consequence, could contribute to compromised fetal growth as well increasing the risk of stillbirth. Furthermore, given that there is often an increased inflammatory response associated with preterm labour, inflammation is a plausible mechanism mediating the effects of air pollution on premature delivery. In the light of increased urbanisation and an ever-changing climate, both of which increase ambient air pollution and negatively affect vulnerable populations such as pregnant individuals, it is hoped that the collective evidence may contribute to decisions taken to strengthen air quality policies, reductions in exposure to air pollution and subsequent improvements in the health of those not yet born.

Epidemiologic research has increasingly acknowledged the importance of developmental origins of health and disease (DOHaD) and suggests that prior exposures can be transferred across generations. Multigenerational cohorts are crucial to verify the intergenerational inheritance among human subjects. We carried out this scoping review aims to summarize multigenerational cohort studies' characteristics, issues, and implications and hence provide evidence to the DOHaD and intergenerational inheritance. We adopted a comprehensive search strategy to identify multigenerational cohorts, searching PubMed, EMBASE, and Web of Science databases from the inception of each dataset to June 20th, 2022, to retrieve relevant articles. After screening, 28 unique multigenerational cohort studies were identified. We classified all studies into four types: population-based cohort extended three-generation cohort, birth cohort extended three-generation cohort, three-generation cohort, and integrated birth and three-generation cohort. Most cohorts (n = 15, 53%) were categorized as birth cohort extended three-generation studies. The sample size of included cohorts varied from 41 to 167,729. The study duration ranged from two years to 31 years. Most cohorts had common exposures, including socioeconomic factors, lifestyle, and grandparents' and parents' health and risk behaviors over the life course. These studies usually investigated intergenerational inheritance of diseases as the outcomes, most frequently, obesity, child health, and cardiovascular diseases. We also found that most multigenerational studies aim to disentangle genetic, lifestyle, and environmental contributions to the DOHaD across generations. We call for more research on large multigenerational well-characterized cohorts, up to four or even more generations, and more studies from low- and middle-income countries.

Human life history schedules vary, partly, because of adaptive, plastic responses to early-life conditions. Little is known about how prenatal conditions relate to puberty timing. We hypothesized that fetal exposure to adversity may induce an adaptive response in offspring maturational tempo. In a longitudinal study of 253 mother-child dyads followed for 15 years, we investigated if fetal exposure to maternal psychological distress related to children's adrenarche and gonadarche schedules, assessed by maternal and child report and by dehydroepiandrosterone sulfate (DHEA-S), testosterone, and estradiol levels. We found fetal exposure to elevated maternal prenatal psychological distress predicted earlier adrenarche and higher DHEA-S levels in girls, especially first-born girls, and that associations remained after covarying indices of postnatal adversity. No associations were observed for boys or for gonadarche in girls. Adrenarche orchestrates the social-behavioral transition from juvenility to adulthood; therefore, significant findings for adrenarche, but not gonadarche, suggest that prenatal maternal distress instigates an adaptive strategy in which daughters have earlier social-behavioral maturation. The stronger effect in first-borns suggests that, in adverse conditions, it is in the mother's adaptive interest for her daughter to hasten social maturation, but not necessarily sexual maturation, because it would prolong the duration of the daughter allomothering younger siblings. We postulate a novel evolutionary framework that human mothers may calibrate the timing of first-born daughters' maturation in a way that optimizes their own reproductive success.

Emotion regulation (ER) is critical for children's healthy socio-emotional development, in part through its modulation of negative emotions that might otherwise place children at risk for psychopathology. The cognitive ER strategy of reappraisal appears to be particularly protective against the development of symptoms of anxiety and depression during childhood. Despite widespread acceptance of the benefits of reappraisal for children's long-term affective function, little is known about the developmental mechanisms that support emerging reappraisal in young children. Proximal mechanisms supporting reappraisal include biological processes; the modulation of reactivity to negative emotional stimuli is visible at the neural level through the Late Positive Potential (LPP). Influences on the developmental course of mechanisms like the LPP almost certainly include contextual factors, including quality of the environment, which have been largely ignored in work to date. The present study included a test of early (age 3-4) socioeconomic status (SES) as a moderator of children's reappraisal, evidenced by differences in the LPP to passive view and reappraisal conditions, at age 5. Results supported the presence of moderation. Reappraisal was visible as differences in LPP across conditions at high, but not low, levels of SES. Findings offer a foundation for delineating the development of reappraisal and understanding contexts that may promote preschoolers' reappraisal. Results also contribute to the delineation of the role of early psychophysiological markers in affective function and early risk for psychopathology.

Maternal high-fat diet (HFD) is related to an increased risk of glucose metabolism disorders throughout the whole life of offspring. The pancreas is a glucose homeostasis regulator. Accumulating evidence has revealed that maternal HFD affects offspring pancreas structure and function. However, the potential mechanism remains unclear. In this study, the mouse dam was fed with HFD or control diet (CD) during prepregnancy, pregnancy and lactation. The pancreatic insulin secretion function and islet genome methylome of offspring were analyzed. Pancreatic islet specific gene methylation was detected by using MeDIP qPCR. The results showed that body weight, blood glucose after oral glucose loads, fasting serum insulin, and HOMA-IR index values were significantly higher in male 12-week-old offspring from HFD dams than in the offspring from CD dams. Maternal HFD induced insulin secretion defects in male offspring. Compared with that in maternal CD group, methylation of the Abcc8 and Kcnj11 genes was increased in maternal HFD group in male offspring pancreatic islets. Furthermore, the expression levels of Abcc8 and Kcnj11 were downregulated by intrauterine exposure to a maternal HFD. In summary, maternal HFD results in a long-term functional disorder of the pancreas that is involved in insulin secretion-related gene DNA hypermethylation.

Methylation profile scores (MPSs) index biological aging and aging-related disease in adults and are cross-sectionally associated with social determinants of health in childhood. MPSs thus provide an opportunity to trace how aging-related biology responds to environmental changes in early life. Information regarding the stability of MPSs in early life is currently lacking.

We use longitudinal data from children and adolescents ages 8-18 (N = 428, M age = 12.15 years) from the Texas Twin Project. Participants contributed two waves of salivary DNA-methylation data (mean lag = 3.94 years), which were used to construct four MPSs reflecting multi-system physiological decline and mortality risk (PhenoAgeAccel and GrimAgeAccel), pace of biological aging (DunedinPACE), and cognitive function (Epigenetic-g). Furthermore, we exploit variation among participants in whether they were exposed to the COVID-19 pandemic during the course of study participation, in order to test how a historical period characterized by environmental disruption might affect children's aging-related MPSs.

All MPSs showed moderate longitudinal stability (test-retest rs = 0.42, 0.44, 0.46, 0.51 for PhenoAgeAccel, GrimAgeAccel, and Epigenetic-g, and DunedinPACE, respectively). No differences in the stability of MPSs were apparent between those whose second assessment took place after the onset of the COVID-19 pandemic vs. those for whom both assessments took place prior to the pandemic.

Aging-related DNA-methylation patterns are less stable in childhood than has been previously observed in adulthood. Further developmental research on the methylome is necessary to understand which environmental perturbations in childhood impact trajectories of biological aging and when children are most sensitive to those impacts.

The growing prevalence of hypertension, heart disease, diabetes, and obesity along with an aging population is leading to a higher incidence of renal diseases in society. Chronic kidney disease (CKD) is characterized mainly by persistent inflammation, fibrosis, and gradual loss of renal function leading to renal failure. Sex is a known contributor to the differences in incidence and progression of CKD. Epigenetic programming is an essential regulator of renal physiology and is critically involved in the pathophysiology of renal injury and fibrosis. Epigenetic signaling integrates intrinsic and extrinsic signals onto the genome, and various environmental and hormonal stimuli, including sex hormones, which regulate gene expression and downstream cellular responses. The most extensively studied epigenetic alterations that play a critical role in renal damage include histone modifications and DNA methylation. Notably, these epigenetic alterations are reversible, making them candidates for potential therapeutic targets for the treatment of renal diseases. Here, we will summarize the current knowledge on sex differences in epigenetic modulation of renal fibrosis and inflammation and highlight some possible epigenetic therapeutic strategies for CKD treatment.

Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups (n = 119) were allocated to four groups and gavaged with either 10 mL·kg-1 body mass 0.5% dimethyl sulfoxide, 100 mg·kg-1 body mass fenofibrate, fructose (20%, w / v), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect (p > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations (p < 0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats.

The impact of infection on infant nutritional status, body size, and growth is well documented. However, research into the impact of infection on infant body composition is limited. Greater understanding is, therefore, needed on the effects of infection in early life.

Associations between a composite morbidity index consisting of the sum of the cumulative tallies for a range of symptoms representing infection and morbidity in the infants and nutritional status (height-for-age (HAZ), and weight-for-height (WHZ)), and body composition (fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), and fat mass index (FMI)) at 6 months of age were investigated using hierarchical regression analysis.

The sample comprised data between birth and 6 months postnatally, of 156 infants who were a priori born healthy in Soweto, South Africa. Morbidity, over the cumulative period of birth to 6 months, was associated with lower FMI (β = -1.77) and lower FM (β = -0.61), and conversely with higher FFM (β = 0.94), in infants at 6 months. No associations were found between the morbidity index and FFMI, HAZ, and WHZ. Increased birthweight was associated with a higher FFM (β = 0.66), HAZ (β = 1.14), and WHZ (β = 0.87). Finally, safely managed sanitation facilities, representative of reduced environmental exposure to fecal-oral transmission pathways were associated with a higher HAZ (β = 1.21).

Reduction in FMI and FM and exposure to inflammatory cytokines associated with mounting an immune response could alter phenotypic trajectories during to this period of plasticity. From a public health perspective, these results imply that it is important to intensify efforts to prevent infection in infants in the first 6 months postnatally, and that these efforts should concentrate on access to safely managed sanitation facilities.

It is known that dietary factors within the gestational and nursing period affect early life and stably affect later life traits in animals. However, there is very little understanding of whether dietary factors within the early life period from post-nursing to adulthood affect traits in adulthood. To address this, we conducted studies on male C57Bl/6J mice fed from 3 weeks (immediately post-nursing) until 12 weeks (full maturity) using nine different diets varying in all three major macronutrients to parse out the effects of individual macronutrients. Early life macronutrient balance affected body composition and glucose homeostasis in early adulthood, with dietary protein and fat showing major effects. Despite this, mice showed rapid reversal of the effects on body composition and glucose homeostasis of early life diet feeding, upon standard diet feeding in adulthood. However, some traits were persistent, with early life low dietary protein levels stably affecting lean and muscle mass, and early life dietary fat levels stably affecting serum and liver triglyceride levels. In summary, macronutrient balance in the post-nursing early life period does not stably affect adiposity or glucose homeostasis but does impact muscle mass and lipid homeostasis in adulthood, with prominent effects of both protein and fat levels. KEY POINTS: Early life dietary low protein and high fat levels lowered and heightened body mass, respectively. These effects did not substantially persist into adulthood with rapid catch-up growth on a normal diet. Early life protein (negative) and fat (positive) levels affected fat mass. Early life low protein levels negatively affected lean mass. Low protein effects on lower lean and muscle mass persisted into adulthood. Early life macronutrient balance effects did not affect later life glucose homeostasis but early life high fat level affected later life dyslipidaemia. Effects of dietary carbohydrate levels in early and later life were minor.

Worldwide, fetal growth restriction (FGR) affects 7%-10% of pregnancies, or roughly 20.5 million infants, each year. FGR increases not only neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR "programs" an obese phenotype are not well understood. Studies demonstrate that FGR females are more prone to obesity compared to males; however, the molecular mechanisms that lead to the sexually dimorphic programming of FGR are not known. Thus, we hypothesized that FGR leads to the sexually dimorphic programming of preadipocytes and reduces their ability to differentiate into mature adipocytes. To test the hypothesis, we utilized a maternal hyperthermia-induced placental insufficiency to restrict fetal growth in sheep. We collected perirenal adipose tissue from near-term (∼140 days gestation) male and female FGR and normal-weight fetal lambs (N = 4 to 5 in each group), examined the preadipocytes' differentiation potential, and identified differential mRNA transcript expression in perirenal adipose tissue. Male FGR fetuses have a lower cellular density (nuclei number/unit area) compared to control male fetuses. However, no difference was observed in female FGR fetuses compared to control female fetuses. In addition, the ability of preadipocytes to differentiate into mature adipocytes with fat accumulation was impaired in male FGR fetuses, but this was not observed in female FGR fetuses. Finally, we examined the genes and pathways involved in the sexually dimorphic programming of obesity by FGR. On enrichment of differentially expressed genes in males compared to females, the Thermogenesis KEGG Pathway was downregulated, and the Metabolic and Steroid Biosynthesis KEGG pathways were upregulated. On enrichment of differentially expressed genes in male FGR compared to male control, the Steroid Biosynthesis KEGG Pathway was downregulated, and the PPAR Signaling KEGG pathway was upregulated. No pathways were altered in females in response to growth restriction in perirenal adipose tissue. Thus, the present study demonstrates a sexually dimorphic program in response to growth restriction in sheep fetal perirenal adipose tissue.

This study investigated whether changes in DNA methylation (DNAm) at TXNIP are associated with glycemic changes and whether such an association differs with early-life adiposity changes.

A total of 594 Bogalusa Heart Study participants who had blood DNAm measurements at two time points in midlife were included. Of them, 353 participants had at least four BMI measurements during childhood and adolescence. The incremental area under the curve was calculated as a measure of long-term trends of BMI during childhood and adolescence.

Increase in DNAm at TXNIP was significantly associated with decrease in fasting plasma glucose (FPG) independent of covariates (p < 0.001). The study found that the strength of this relationship was significantly modified by a trend of increasing BMI during childhood and adolescence (p-interaction = 0.003). Each 1% increase in DNAm at TXNIP was associated with a 2.90- (0.77) mg/dL decrease in FPG among participants with the highest tertile of BMI incremental area under the curve and a 0.96- (0.38) mg/dL decrease among those with the middle tertile, whereas no association was observed among participants with the lowest tertile.

These results indicate that changes in blood DNAm at TXNIP are significantly associated with changes in FPG in midlife, and this association was modified by BMI trends during childhood and adolescence.

Personalised and precision nutrition uses information on individual characteristics and responses to nutrients, foods and dietary patterns to develop targeted nutritional advice that is more effective in improving the diet and health of each individual. Moving away from the conventional 'one size fits all', such targeted intervention approaches may pave the way to better population health, including lower burden of non-communicable diseases. To date, most personalised and precision nutrition approaches have been focussed on tackling obesity and cardiometabolic diseases with limited efforts directed to cancer prevention and for cancer survivors. Advances in understanding the biological basis of cancer and of the role played by diet in cancer prevention and in survival after cancer diagnosis, mean that it is timely to test and to apply such personalised and precision nutrition approaches in the cancer area. This endeavour can take advantage of the enhanced understanding of interactions between dietary factors, individual genotype and the gut microbiome that impact on risk of, and survival after, cancer diagnosis. Translation of these basic research into public health action should include real-time acquisition of nutrigenomic and related data and use of AI-based data integration methods in systems approaches that can be scaled up using mobile devices.

Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i.e., were switched on or switched off) in the experiment vs. the control. Our data indicated that NLI triggers the long-term animal growth retardation, cardiomyocyte hyperpolyploidy, and extensive transcriptomic rearrangements. Many of these rearrangements are known as manifestations of heart pathologies, including DNA and telomere instability, inflammation, fibrosis, and reactivation of fetal gene program. Moreover, bioinformatic analysis identified possible causes of these pathologic traits, including the impaired signaling via thyroid hormone, calcium, and glutathione. We also found transcriptomic manifestations of increased cardiomyocyte polyploidy, such as the induction of gene modules related to open chromatin, e.g., "negative regulation of chromosome organization", "transcription" and "ribosome biogenesis". These findings suggest that ploidy-related epigenetic alterations acquired in the neonatal period permanently rewire gene regulatory networks and alter cardiomyocyte transcriptome. Here we provided first evidence indicating that NLI can be an important trigger of developmental programming of adult cardiovascular disease. The obtained results can help to develop preventive strategies for reducing the NLI-associated adverse effects of inflammation on the developing cardiovascular system.

Despite the intergenerational effects of metabolic disorders, evidence is greatly lacking on early pregnancy metabolic syndrome (MetS) and its effects on pregnancy outcomes from low- and middle-income countries. Thus, this prospective cohort of South Asian pregnant women aimed to evaluate how early pregnancy MetS would affect pregnancy outcomes.

A prospective cohort study was conducted among first-trimester (T1) pregnant women of Anuradhapura district, Sri Lanka recruited to the Rajarata Pregnancy Cohort in 2019. MetS was diagnosed by the Joint Interim Statement criteria before 13 weeks of gestational age (GA). Participants were followed up until their delivery, and the major outcomes measured were large for gestational age (LGA), small for gestational age (SGA), preterm birth (PTB) and miscarriage (MC). Gestational weight gain, gestational age at delivery and neonatal birth weight were used as measurements to define the outcomes. Additionally, outcome measures were re-assessed with adjusting fasting plasma glucose (FPG) thresholds of MetS to be compatible with hyperglycemia in pregnancy (Revised MetS).

2326 T1 pregnant women with a mean age of 28.1 years (SD-5.4), and a median GA of 8.0 weeks (IQR-2) were included. Baseline MetS prevalence was 5.9% (n = 137, 95%CI-5.0-6.9). Only 2027 (87.1%) women from baseline, had a live singleton birth, while 221(9.5%) had MC and 14(0.6%) had other pregnancy losses. Additionally, 64(2.8%) were lost to follow-up. A higher cumulative incidence of LGA, PTB, and MC was noted among the T1-MetS women. T1-MetS carried significant risk (RR-2.59, 95%CI-1.65-3.93) for LGA, but reduced the risk for SGA (RR-0.41, 95%CI-0.29-0.78). Revised MetS moderately increased the risk for PTB (RR-1.54, 95%CI-1.04-2.21). T1-MetS was not associated (p = 0.48) with MC. Lowered FPG thresholds were significantly associated with risk for all major pregnancy outcomes. After adjusting for sociodemographic and anthropometric confounders, revised MetS remained the only significant risk predictor for LGA.

Pregnant women with T1 MetS in this population are at an increased risk for LGA and PTB and a reduced risk for SGA. We observed that a revised MetS definition with lower threshold for FPG compatible with GDM would provide a better estimation of MetS in pregnancy in relation to predicting LGA.

Low birth weight (LBW), biological vulnerability that includes preterm birth (PTB) and small for gestational age (SGA), is associated with reduced maternal sensitivity ("making accurate inferences about an infant's physical and emotional needs and responding appropriately") and impaired infant cognitive development. However, research does not examine if preterm birth, SGA, or both drive these associations. This study separated these measures of biological vulnerability to examine associations of LBW, PTB, and SGA with maternal sensitivity and infant cognitive development (controlling for maternal depression, breastfeeding, and demographic covariates).

The sample included 6900 9-month-old infants from the Early Childhood Longitudinal Study-Birth Cohort and used birth certificate data, maternal interviews, assessments of maternal sensitivity and infant cognitive development. Multiple linear regressions examined LBW, PTB, and SGA associations with concurrent measures of maternal sensitivity and infant cognition.

Of the biological vulnerabilities, preterm birth had the strongest negative association with maternal sensitivity (F_1,6450 = 29.48 versus 15.33 and 5.51, ps < .001) and infant cognitive development (F_1,6450) = 390.65 versus 248.02 and 14.43, ps < .001). In the final regression model, preterm birth and maternal sensitivity were uniquely associated with infant cognitive development (R² = .05, p < .001), after controlling for maternal depression, breastfeeding, and demographics.

In this nationally representative infant sample infants, PTB had a stronger negative association with both maternal sensitivity and infant cognitive development in comparison to SGA or LBW. The LBW designation combines infants born preterm with SGA infants, potentially minimizing differences in developmental outcomes of PTB and SGA infants.

Hypovitaminosis D currently represents a public health problem and is related to the emergence of chronic diseases. Furthermore, this vitamin deficiency has been associated with pregnancy complications, and it can also influence newborn's growth and development. The purpose of this review is to understand the effects of vitamin D nutritional status on women during pregnancy, as well as its impact on newborn's health.

Review of observational studies, published between 2020 and 2021. The research was carried out in the following databases: Pubmed and SciELO. The search terms used to select the articles were: vitamin D, 25(OH)D, serum levels, pregnancy, lactation, gene expression, maternal results, complications, pre-eclampsia, obesity, gestational diabetes, and children. As inclusion criteria, were considered observational studies that addressed the topic and answered the review aims.

52 articles were identified and at the end of the selection process, 19 articles were considered, in which they met all the established eligibility criteria. According to the findings in this review, hypovitaminosis D is related to gestational diabetes, pre-eclampsia and gestational weight gain, changes in laboratory parameters as well as outcomes in newborns.

Hypovitaminosis D can adversely influence pregnancy and newborn's health, evidencing the need to assess the nutritional status of vitamin D, as well as the existence, or not, of a clinic during pregnancy. It is important that new scientific evidence is published to support this hypothesis.

Worldwide increase in life expectancy has boosted research on aging. Overcoming the concept of chronological age, higher attention has been addressed to biological age, which reflects a person's real health state, and which may be the resulting combination of both intrinsic and environmental factors. As epigenetics may exert a pivotal role in the biological aging, epigenetic clocks were developed. They are based on mathematical models aimed at identifying DNA methylation patterns that can define the biological age and that can be adopted for different clinical scopes (i.e., estimation of the risks of developing age-related disorders or predicting lifespan). Recently, epigenetic clocks have gained a peculiar attention in the fertility research field, in particular in the female counterpart. The insight into the possible relations between epigenetic aging and women's infertility might glean additional information about certain conditions that are still not completely understood. Moreover, they could disclose significant implications for health promotion programs in infertile women. Of relevance here is that the impact of biological age and epigenetics may not be limited to fertility status but could translate into pregnancy issues. Indeed, epigenetic alterations of the mother may transfer into the offspring, and pregnancy itself as well as related complications could contribute to epigenetic modifications in both the mother and newborn. However, even if the growing interest has culminated in the conspicuous production of studies on these topics, a global overview and the availability of validated instruments for diagnosis is still missing. The present narrative review aims to explore the possible bonds between epigenetic aging and fertility timeline. In the "infertility" section, we will discuss the advances on epigenetic clocks focusing on the different tissues examined (endometrium, peripheral blood, ovaries). In the "pregnancy" section, we will discuss the results obtained from placenta, umbilical cord and peripheral blood. The possible role of epigenetic aging on infertility mechanisms and pregnancy outcomes represents a question that may configure epigenetic clock as a bond between two apparently opposite worlds: infertility and pregnancy.

How organisms capture and ultimately use metabolic energy-a limiting resource of life-has profound implications for understanding evolutionary legacies and current patterns of phenotypic variation, adaptation, and health. Energetics research among humans has a rich history in biological anthropology and beyond. The energetics of childhood, however, remains relatively underexplored. This shortcoming is notable given the accepted importance of childhood in the evolution of the unique human life history pattern as well as the known sensitivity of childhood development to local environments and lived experiences. In this review, I have three objectives: (1) To overview current knowledge regarding how children acquire and use energy, highlighting work among diverse human populations and pointing to recent advances and remaining areas of uncertainty; (2) To discuss key applications of this knowledge for understanding human variation, evolution, and health; (3) To recommend future avenues for research. A growing body of evidence supports a model of trade-offs and constraint in childhood energy expenditure. This model, combined with advancements on topics such as the energetics of immune activity, the brain, and the gut, provides insights into the evolution of extended human subadulthood and the nature of variation in childhood development, lifetime phenotype, and health.

Studies on maternal microRNA expression have emerged to better understand regulatory mechanisms during the gestational period, since microRNA expression has been associated with pregnancy disorders.

This study aims to investigate the association between the expression of the maternal microRNAs miR-let-7d-3p and miR-451a during the second gestational trimester and neuropsychomotor development at 90 days of life of infants.

This is a case-control study nested within a cohort, with the groups being divided into dyads in which pregnant women presented Major Depressive Episode (MDE) (n = 64), these being the cases, and their respective controls (no MDE; n = 64). The Bayley Scale III was used to assess the outcome of child development, and MDE was assessed through the Mini International Neuropsychiatric Interview Plus. The analysis of miR-let-7d-3p and miR-451a was done via serum from the pregnant women, utilizing the qRT-PCR (n = 128).

The results indicated a negative association between expression levels of miR-451a (β -3.3 CI95% -6.4;-0.3) and a positive associated of the miR-let-7d-3p with the cognitive development domain (β 1.7 CI95% 0.1; 3.0), and a positive association between expression of miR-let-7d-3p with motor development of the infants (β 1.6 CI95% 0.3; 2.9).

This is a pioneering study on the topic that indicates a biological interrelationship between the miRNAs miR-let-7d-3p and miR-451a evaluated during the pregnancy and the motor and cognitive domains of infant development at 90 days postpartum.

We examine multi-generational impacts of positive in utero health interventions using a new research design that exploits sharp increases in prenatal Medicaid eligibility that occurred in some states. Our analyses are based on U.S. Vital Statistics Natality files, which enables linkages between individuals' early life Medicaid exposure and the next generation's health at birth. We find evidence that the health benefits associated with treated generations' early life program exposure extend to later offspring. Our results suggest that the returns on early life health investments may be substantively underestimated.

Life history theory emphasises plasticity in developmental and biological programming where conditions in early life, lead to long-term consequences for health and wellbeing. Studies linking water, sanitation, and hygiene, nutrition, and child growth and development have emphasised the optimisation of linear growth as a key metric for the evaluation of intervention efficacy. Life history characteristics pertaining to human growth and phenotypic plasticity, suggest that different developmental outcomes in early childhood may be responsive to different stimuli at different ages. Energy utilisation by the human brain, from birth through childhood, accounts for a disproportionate percentage of the resting metabolic rate. Undernutrition in early life, and its relative resultant energy deficiency, may trigger adaptive physiological mechanisms prioritising brain growth at the expense of body growth. Emphasis placed on linear growth may have impeded the significance of WASH due to excluding aspects of child development beyond height/weight. We propose that incorporating evolutionary public health and life history theory perspectives, allows for the identification of age-appropriate biological outcomes and WASH indicators, while anticipating the timing and life-course suitability of the interventions being operationalised. Finally, integrating reflections regarding context allows for the development of transformative WASH interventions.

The worldwide epidemic of obesity is associated with numerous comorbid conditions, including metabolic diseases such as insulin resistance and diabetes, in particular. The situation is likely to worsen, as the increase in obesity rates among children will probably lead to an earlier onset and more severe course for metabolic diseases. The origin of this earlier development of obesity may lie in both behavior (changes in nutrition, physical activity, etc.) and in children's history, as it appears to be at least partly programmed by the fetal/neonatal environment. The concept of the developmental origin of health and diseases (DOHaD), involving both organogenesis and epigenetic mechanisms, encompasses such programming. Epigenetic mechanisms include the action of microRNAs, which seem to play an important role in adipocyte functions. Interestingly, microRNAs seem to play a particular role in propagating local insulin resistance to other key organs, thereby inducing global insulin resistance and type 2 diabetes. This propagation involves the active secretion of exosomes containing microRNAs by adipocytes and adipose tissue-resident macrophages, as well as long-distance communication targeting the muscles and liver, for example. Circulating microRNAs may also be useful as biomarkers for the identification of populations at risk of subsequently developing obesity and metabolic diseases.

Resource trade-off theory suggests that increased performance on a given trait comes at the cost of decreased performance on other traits.

Growth data from 1889 subjects (996 girls) were used from the GrowUp1974 Gothenburg study. Energy Trade-Off (ETO) between height and weight for individuals with extreme body types was characterized using a novel ETO-Score (ETOS). Four extreme body types were defined based on height and ETOI at early adulthood: tall-slender, short-stout, short-slender, and tall-stout; their growth trajectories assessed from ages 0.5-17.5 years.A GWAS using UK BioBank data was conducted to identify gene variants associated with height, BMI, and for the first time with ETOS.

Height and ETOS trajectories show a two-hit pattern with profound changes during early infancy and at puberty for tall-slender and short-stout body types.Several loci (including FTO, ADCY3, GDF5, ) and pathways were identified by GWAS as being highly associated with ETOS. The most strongly associated pathways were related to 'extracellular matrix', 'signal transduction', 'chromatin organization', and 'energy metabolism'.

ETOS represents a novel anthropometric trait with utility in describing body types. We discovered the multiple genomic loci and pathways probably involved in energy trade-off.

Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease.

Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013.

Exploratory sub-study using data from the nationwide EPICOM study.

Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code.

This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples.

We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM. Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX).

These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.

The developmental origin of hypertension and renal disease is a concept highly supported by strong evidence coming from both human and animal studies. During development there are periods in which the organs are more vulnerable to stressors. Such periods of susceptibility are also called 'sensitive windows of exposure'. It was shown that as earlier an adverse event occurs; the greater are the consequences for health impairment. However, evidence show that the postnatal period is also quite important for hypertension and renal disease programming, especially in rodents because they complete nephrogenesis postnatally, and it is also important during preterm human birth. Considering that the developing kidney is vulnerable to early-life stressors, renal programming is a key element in the developmental programming of hypertension and renal disease. The purpose of this review is to highlight the great number of studies, most of them performed in animal models, showing the broad range of stressors involved in hypertension and renal disease programming, with a particular focus on the stressors that occur during the early postnatal period. These stressors mainly include undernutrition or specific nutritional deficits, chronic behavioral stress, exposure to environmental chemicals, and pharmacological treatments that affect some important factors involved in renal physiology. We also discuss the common molecular mechanisms that are activated by the mentioned stressors and that promote the appearance of these adult diseases, with a brief description on some reprogramming strategies, which is a relatively new and promising field to treat or to prevent these diseases.

Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.