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Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman's reports of social adversity during the third trimester were associated with their infant's resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants' cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

This review evaluates in-vitro models for studying how maternal influences during pregnancy impact the development of offspring microglia, the immune cells of the central nervous system. The models examined include primary microglia cultures, microglia cell lines, iPSC-derived microglia, PBMC-induced microglia-like cells, 3D brain organoids derived from iPSCs, and Hofbauer cells. Each model is assessed for its ability to replicate the in-vivo environment of the developing brain, with a focus on their strengths, limitations, and practical challenges. Key factors such as scalability, genetic and epigenetic fidelity, and physiological relevance are highlighted. Microglia cell lines are highly scalable but lack genetic and epigenetic fidelity. iPSC-derived microglia provide moderate physiological relevance and patient-specific genetic insights but face operational and epigenetic challenges inherent to reprogramming. 3D brain organoids, derived from iPSCs, offer an advanced platform for studying complex neurodevelopmental processes but require extensive resources and technical expertise. Hofbauer cells, which are fetal macrophages located in the placenta and share a common developmental origin with microglia, are uniquely exposed to prenatal maternal factors and, depending on fetal barrier maturation, exhibit variable epigenetic fidelity. This makes them particularly useful for exploring the impact of maternal influences on fetal programming of microglial development. The review concludes that no single model comprehensively captures all aspects of maternal influences on microglial development, but it offers guidance on selecting the most appropriate model based on specific research objectives and experimental constraints. [ABSTRACT FROM AUTHOR]

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 childrens 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 mothers 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.

ABSTRACT: The performance of an adult dairy cow may be influenced by heat stress that occurs during her gestation. The present study investigated potential effects of temperature-humidity index (THI) experienced by a cow during pregnancy on the gestated daughter's performance on her first lactation, for the French Holstein and Montbéliarde dairy cattle populations. We analyzed 14 traits, all measured on genotyped cows: 305-d milk, fat, and protein yields; 305-d SCS; clinical mastitis (both occurrence and number of events); body conformation traits; and heifer and cow conception rate. To study the effect of heat stress, we considered the THI experienced by the gestating cow, averaged for each month of her pregnancy and then categorized in 7 classes (≤40, [40,45], [45,50], [50,55], [55,60], [60,65], and >65). These average THI classes were then fitted as categorical covariates in the regression models used for this study, which included other fixed effects, and the GEBV as a covariate, both specific to each trait, the latter being previously obtained from the official French evaluations. The THI effect was therefore estimated as the deviation between the observed and predicted performances. In general, the estimated heat stress effects were small, presenting limited practical impact on the studied traits, and particularly for fertility and udder health, the estimated heat stress effects were not statistically significant. For the production traits (i.e., milk, fat, and protein yields), the estimated effect associated with high THI experienced at the beginning of the gestation was negative, and slightly positive when associated with high THI experienced by the dam at the end of her pregnancy. Finally, our results suggest that under the current French climate conditions, heat stress experienced by cows during any stage of their pregnancy has limited impact on the future performance of their gestated daughters; however, we cannot exclude that a significant in utero heat stress effect may be present in climate conditions warmer than the French.

Fetal growth restriction (FGR) is a risk factor for obesity in adult life. Importantly, growth‐restricted females are more prone to obesity than males. The mechanisms involved in this sexually dimorphic programming are not known. Previously, we have demonstrated that ambient hyperthermia (40°C) led to placental insufficiency and significant FGR, and the perirenal adipose tissue undergoes sexually dimorphic gene expression. We demonstrated that males undergo significant changes in gene expression with growth restriction. This was not the case in females. We have also demonstrated that the isolated preadipocytes from male FGR (MFGR) have reduced differentiation potential compared to control males & females and female FGR (FFGR). Thus, we hypothesized that growth restriction differentially programs gene expression and genetic pathways in perirenal preadipocytes, which reduces their differentiation potential in male fetuses in a sexually dimorphic manner. We created FGR by exposing pregnant sheep to ambient hyperthermia. After isolating preadipocytes from perirenal adipose tissue, we differentiated them following published protocols. We examined the gene expression before and after differentiation from control male, control female, MFGR, and FFGR female. We also compared our data with other published studies in mouse and human preadipocytes. Our results demonstrate that a set of 21 genes altered with preadipocyte differentiation to mature adipocytes is common in adipose tissue from both sexes, humans, mice, and sheep, at different organismal ages (embryonic, fetal, and adult) and different sites (subcutaneous inguinal, pancreatic, perirenal). We also demonstrate that female FFGR fetuses demonstrate all these 21 genes altered similar to control males and females; however, MFGR fetuses have six genes (Dgat2, Fabp4, Lipe, Lrrfip1, Spred3, and Thrsp) that are not changed with preadipocyte differentiation to mature adipocyte. These genes may be responsible for reduced differentiation potential and obesity in FGR males compared to FGR females. Another important finding of the present study is that Lrrfip1, known to be associated with obesity, was upregulated with FGR and requires further investigation. Overall, our studies provide several target genes that may play a crucial role in reducing the risk of MFGR for obesity. [ABSTRACT FROM AUTHOR]

A prenatal low-protein (LP) diet disrupts glucose homeostasis in adult offspring. Skeletal muscles are one of the main sites of glucose clearance, and mitochondria residing in the muscle fibers are central to glucose homeostasis. Our previous studies indicated that impaired mitochondrial health is central to dysregulated glucose metabolism in the gastrocnemius muscle of the LP-programmed female rats. In addition, dysfunctional mitochondria are often an indicator of underlying irregularities in energy metabolism and metabolic inflexibility. Therefore, this study examined the mitochondrial function and metabolic flexibility in the skeletal muscles of prenatal LP-programmed adult male rats. Pregnant Wistar rats were randomly allotted to a control diet (20% protein) or an isocaloric LP diet (6% protein). Standard laboratory rat chow was given to the dams and the pups after delivery and weaning. Gene and protein expressions, mtDNA copy number, and electron microscopy were assessed in gastrocnemius (GS) muscle, and the mitochondrial oxygen consumption rate was determined using isolated flexor digitorum brevis muscle fibers. The genes associated with mitochondrial outer membrane fusion, mitofusin1 and 2 (Mfn1 and Mfn2), fission (Fis1), and biogenesis (Pgc1B, Nrf1, and Esrra) were lower in the LP group. Further, our functional studies showed that the ATP-linked oxygen consumption rate (OCR), maximal, spare respiratory, and non-mitochondrial respiration-associated OCRs were lower in the LP rats. Further, the mRNA and protein expressions of Ndufb8, a key factor involved in the complex-I catalytic activity, were downregulated in the LP group. In addition, the expression of genes linked to mitochondrial pyruvate transport (Mpc1) and metabolism (Pdha1) was lower in the LP group. In contrast, the expression of mitochondrial fatty acid transporters (Cpt1a and Cpt2) was higher in the LP when compared to the control group. However, electron microscopic analysis exhibited no difference in the mitochondrial ultrastructure in the LP muscle compared to the control. Altogether, our results indicate that the LP diet affects the mitochondrial complex-I integrity and dynamics and leads to altered expression of genes associated with substrate oxidation and mitochondrial dysfunction in the skeletal muscle of the male LP offspring. [ABSTRACT FROM AUTHOR]

Background/Objectives: Childhood obesity is a global health problem that affects at least 41 million children under the age of five. Increased BMI in children is associated with serious long-term health consequences, such as type 2 diabetes, cardiovascular disease, and psychological problems, including depression and low self-esteem. Although the etiology of obesity is complex, research suggests that the diet and lifestyle of pregnant women play a key role in shaping metabolic and epigenetic changes that can increase the risk of obesity in their children. Excessive gestational weight gain, unhealthy dietary patterns (including the Western diet), and pregnancy complications (such as gestational diabetes) are some of the modifiable factors that contribute to childhood obesity. The purpose of this narrative review is to summarize the most important and recent information on the impact of the diet and lifestyle of pregnant women on the risk of childhood obesity. Methods: This article is a narrative review that aims to summarize the available literature on the impact of pregnant women's diet and lifestyle on the risk of obesity in their offspring, with a focus on metabolic and epigenetic mechanisms. Results/Conclusions: Current evidence suggests that a pregnant woman's lifestyle and diet can significantly contribute to lowering the risk of obesity in their offspring. However, further high-quality research is needed to understand better the metabolic and epigenetic relationships concerning maternal factors that predispose offspring to obesity. [ABSTRACT FROM AUTHOR]

Background: The term "fetal programming" refers to the effects of endogenous and exogenous corticosteroids, whether received from the mother or the fetus, on brain development and the hypothalamic–pituitary–adrenal axis reset. The authors of this narrative review examine the WHO's guidelines for prenatal corticosteroids in pregnant women who are at high risk of premature delivery. These guidelines are regarded as the best available for preventing late-life problems resulting from preterm. Methods: In order to find full-text publications published in peer-reviewed journals between 1990 and 2023 that were written in English, the authors searched PubMed, Scopus, Cochrane Library, and Web of Science. Results: The authors highlight the possible adverse long-term effects of prenatal corticosteroid medication on human brain development and function. This pharmacological feature is therapeutically significant because there is less evidence in the scientific literature regarding the potential role that the timing, mode, and dosage of exogenous steroid treatment may have in neurological illnesses down the road. Conclusions: The authors expect that these studies will shed light on the relationship between specially designed prenatal corticosteroid therapy and the molecular mechanisms underlying the prenatal programming of neurodevelopment in childhood and adulthood. [ABSTRACT FROM AUTHOR]

Pregnancy is distinguished by a multitude of intricate interactions between the mother and the new individual, commencing at implantation and persisting until the maturation and integration of the fetal apparatus and systems. The physiological increase in fat mass during pregnancy and the association of maternal obesity with adverse neonatal outcomes have directed attention to the study of maternal adipokines as participants in fetal development. Interestingly, maternal concentrations of certain adipokines such as adiponectin, leptin, tumor necrosis factor-alpha, and interleukin-6 have been found to be associated with offspring anthropometry and adiposity at birth and at three months of age, even with neurodevelopmental alterations later in life. This is partly explained by the functions of these adipokines in the regulation of maternal metabolism and placental nutrient transport. This review compiles, organizes, and analyzes the most relevant studies on the association between maternal adipokines with anthropometry, adiposity, and neurodevelopmental outcomes of the offspring. Furthermore, it proposes the underlying mechanisms involved in this association. [ABSTRACT FROM AUTHOR]

The role of long intergenic noncoding RNAs (lincRNAs) in fetal development has emerged as a significant area of study, challenging the traditional protein-centric view of gene expression. While messenger RNAs (mRNAs) have long been recognized for their role in encoding proteins, recent advances have illuminated the critical functions of lincRNAs in various biological processes. Initially identified through high-throughput sequencing technologies, lincRNAs are transcribed from intergenic regions between protein-coding genes and exhibit unique regulatory functions. Unlike mRNAs, lincRNAs are involved in complex interactions with chromatin and chromatin-modifying complexes, influencing gene expression and chromatin structure. LincRNAs are pivotal in regulating tissue-specific development and embryogenesis. For example, they are crucial for proper cardiac, neural, and reproductive system development, with specific lincRNAs being associated with organogenesis and differentiation processes. Their roles in embryonic development include regulating transcription factors and modulating chromatin states, which are essential for maintaining developmental programs and cellular identity. Studies using RNA sequencing and genetic knockout models have highlighted the importance of lincRNAs in processes such as cell differentiation, tissue patterning, and organ development. Despite their functional significance, the comprehensive annotation and understanding of lincRNAs remain limited. Ongoing research aims to elucidate their mechanisms of action and potential applications in disease diagnostics and therapeutics. This review summarizes current knowledge on the functional roles of lincRNAs in fetal development, emphasizing their contributions to tissue-specific gene regulation and developmental processes. [ABSTRACT FROM AUTHOR]

Extending the voluntary waiting period (VWP) for insemination in dairy cows is of interest as a strategy to reduce the frequency of calving events and inseminate at a moment with fewer fertility problems. Little is known about the calves born from dams with a different VWP followed by a different calving interval (CInt). The objective of the current study was to identify the effect of dam's CInt on body condition, metabolic status, and milk production of their offspring from birth until 100 DIM of the offspring's first lactation. Holstein-Friesian dairy cows (n = 154, 41 primiparous, 113 multiparous) were blocked according to parity, milk yield, and SCC and randomly assigned to a VWP of 50, 125, or 200 d. Female calves (n = 62) from cows with different CInt were monitored from birth until their first calving event as heifer. Certain dams were not successfully inseminated soon after the planned VWP, resulting in differences between the intended VWP and the actual CInt. Calves were regrouped according to their dam's actual CInt (CInt_1: 324–408 d; CInt_2: 409–468 d; CInt_3: 469–586 d). The dam's CInt did not affect calf birth weight. From birth to weaning, the calves born to dams in CInt_1 had a higher plasma nonesterified fatty acids (NEFA) concentration (0.34 mmol/L; CI: 0.30, 0.37) than CInt_2 (0.28 mmol/L; CI: 0.26, 0.31) and CInt_3 (0.26 mmol/L; CI: 0.24, 0.29) calves. Calves born to dams with a shorter CInt (CInt_1) had greater IgG and IgM against keyhole limpet hemocyanin (KLH) than CInt_3 (IgG: 6.05 ± 0.30 vs. 4.64 ± 0.30; IgM: 6.45 ± 0.17 vs. 5.89 ± 0.16, respectively; mean ± SE) before weaning. After weaning till calving, CInt_1 calves tended to have greater plasma NEFA concentration than CInt_3-calves. During the first 100 DIM, a longer CInt of the dams resulted in lower plasma IGF_1 (CInt_2), lower milk lactose (CInt_3), and lower fat- and protein-corrected milk (FPCM; CInt_2) in offspring, compared with shorter CInt of the dams (CInt_1). Collectively, a longer CInt in dams did not affect birth weight of their calves or BW during the weaning or rearing phase. From birth till weaning, a longer CInt in dams resulted in less anti-KLH IgG and lower plasma NEFA concentration in plasma of the calves. During the first lactation of their offspring, a longer CInt in dams can result in a lower plasma IGF_1 and FPCM during the first 100 DIM, although effects were not present in all CInt categories. The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. [ABSTRACT FROM AUTHOR]

Background: In utero exposure to maternal hyperglycemia and obesity can trigger detrimental effects in the newborn through epigenetic programming. We aimed to assess the DNA methylation levels in the promoters of MC4R and LPL genes from maternal blood, placenta, and buccal swab samples collected in children born to mothers with and without obesity and Gestational Diabetes Mellitus (GDM). Methods: A total of 101 Caucasian mother–infant pairs were included in this study. Sociodemographic characteristics, clinical parameters, physical activity, and adherence to the Mediterranean diet were evaluated in the third trimester of pregnancy. Clinical parameters of the newborns were recorded at birth. Results: A negative relationship between MC4R DNA methylation on the fetal side of the GDM placenta and birth weight (r = −0.630, p = 0.011) of newborns was found. MC4R DNA methylation level was lower in newborns of GDM women (CpG1: 2.8% ± 3.0%, CpG2: 3.8% ± 3.3%) as compared to those of mothers without GDM (CpG1: 6.9% ± 6.2%, CpG2: 6.8% ± 5.6%; p < 0.001 and p = 0.0033, respectively), and it was negatively correlated with weight (r = −0.229; p = 0.035), head circumference (r = −0.236; p = 0.030), and length (r = −0.240; p = 0.027) at birth. LPL DNA methylation was higher on the fetal side of the placenta in obese patients as compared to normal-weight patients (66.0% ± 14.4% vs. 55.7% ± 15.2%, p = 0.037), and it was associated with maternal total cholesterol (r = 0.770, p = 0.015) and LDL-c (r = 0.783, p = 0.012). Conclusions: These results support the role of maternal MC4R and LPL methylation in fetal programming and in the future metabolic health of children. [ABSTRACT FROM AUTHOR]

BACKGROUND: Season of birth has been associated with age at menarche. Maternal vitamin D levels in pregnancy may explain this effect. We investigated whether the season of first trimester or maternal 25-hydroxyvitamin D3 [25(OH)D3] levels were associated with pubertal timing in children. METHODS: We conducted a follow-up study of 15 819 children born in 2000-03 from the Puberty Cohort, nested in the Danish National Birth Cohort (DNBC). Mean differences in attaining numerous pubertal markers, including a combined estimate for the average age at attaining all pubertal markers, were estimated for low (November-April) relative to high (May-October) sunshine exposure season in the first trimester using multivariable interval-censored regression models. Moreover, we conducted a two-sample instrumental variable analysis using season as an instrument for maternal first-trimester 25(OH)D3 plasma levels obtained from a non-overlapping subset (n = 827) in the DNBC. RESULTS: For the combined estimate, girls and boys of mothers who had their first trimester during November-April had earlier pubertal timing than girls and boys of mothers whose first trimester occurred during May-October: -1.0 months (95% CI: -1.7 to -0.3) and -0.7 months (95% CI: -1.4 to -0.1), respectively. In the instrumental variable analysis, girls and boys also had earlier pubertal timing: respectively, -1.3 months (95% CI: -2.1 to -0.4) and -1.0 months (95% CI: -1.8 to -0.2) per SD (22 nmol/L) decrease in 25(OH)D3. CONCLUSIONS: Both first pregnancy trimester during November-April and lower 25(OH)D3 were associated with earlier pubertal timing in girls and boys.

Maternal obesity is a major global health problem with serious implications for maternal and fetal well-being. It creates a lipotoxic environment in the placenta, characterised by increased inflammation, oxidative stress and disturbances in mitochondrial dynamics and biogenesis. The aim of this review is to explore the intricate interactions between mitochondrial dynamics, biogenesis and mitophagy in the context of gestational obesity. Adverse mitochondrial adaptations associated with maternal obesity contribute to placental dysfunction, impairing its ability to support healthy fetal development and increasing the risk of metabolic, cardiovascular and neurodegenerative diseases in the offspring. In addition, mitochondrial dysfunction exacerbates oxidative stress, creating a vicious cycle that further impairs cellular processes. The findings highlight the urgent need for targeted interventions to improve mitochondrial function and placental health, ultimately reducing long-term health risks for both mother and child.

Abstract Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28–45 kg/m2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM.

Accidental exposure to high-dose radiation while pregnant has shown significant negative effects on the developing fetus. One fetal organ which has been studied is the placenta. The placenta performs all essential functions for fetal development, including nutrition, respiration, waste excretion, endocrine communication, and immunological functions. Improper placental development can lead to complications during pregnancy, as well as the occurrence of intrauterine growth-restricted (IUGR) offspring. IUGR is one of the leading indicators of fetal programming, classified as an improper uterine environment leading to the predisposition of diseases within the offspring. With numerous studies examining fetal programming, there remains a significant gap in understanding the placenta's role in irradiation-induced fetal programming. This review aims to synthesize current knowledge on how irradiation affects placental function to guide future research directions. This review provides a comprehensive overview of placental biology, including its development, structure, and function, and summarizes the placenta's role in fetal programming, with a focus on the impact of radiation on placental biology. Taken together, this review demonstrates that fetal radiation exposure causes placental degradation and immune function dysregulation. Given the placenta's crucial role in fetal development, understanding its impact on irradiation-induced IUGR is essential. [ABSTRACT FROM AUTHOR]

The role of fructose consumption in the development of obesity, MetS, and CVD epidemic has been widely documented. Notably, among other effects, fructose consumption has been demonstrated to induce cardiac hypertrophy. Moreover, fructose intake during pregnancy can cause hypertrophy of the maternal heart. Our previous research has demonstrated that maternal fructose intake has detrimental effects on fetuses, which persist into adulthood and are exacerbated upon re-exposure to fructose. Additionally, we found that maternal fructose consumption produces changes in female progeny that alter their own pregnancy. Despite these findings, fructose intake during pregnancy is not currently discouraged. Given that cardiac hypertrophy is a prognostic marker for heart disease and heart failure, this study aimed to determine whether metabolic changes occurring during pregnancy in the female progeny of fructose-fed mothers could provoke a hypertrophic heart. To test this hypothesis, pregnant rats from fructose-fed mothers, with (FF) and without (FC) fructose supplementation, were studied and compared to pregnant control rats (CC). Maternal hearts were analyzed. Although both FF and FC mothers exhibited heart hypertrophy compared to CC rats, cardiac DNA content was more diminished in the hearts of FF dams than in those of FC rats, suggesting a lower number of heart cells. Accordingly, changes associated with cardiac hypertrophy, such as HIF1α activation and hyperosmolality, were observed in both the FC and FF dams. However, FF dams also exhibited higher oxidative stress, lower autophagy, and decreased glutamine protection against hypertrophy than CC dams. In conclusion, maternal fructose intake induces changes in female progeny that alter their own pregnancy, leading to cardiac hypertrophy, which is further exacerbated by subsequent fructose intake. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) adversely affects offspring glucose homeostasis and risk of developing obesity. Here, we examined the association between glycemia in pregnant women with overweight or obesity without GDM and offspring metabolic health. Maternal fasting glucose concentrations and glucose 2-h after an oral glucose tolerance test (OGTT) were measured in 208 women with a pre-pregnancy body mass index (BMI) of 28–45 kg/m2 without GDM. Offspring outcomes were collected at birth, 3, and 5 years of age. Linear mixed models with time as fixed factor and subject ID as random effects were used for analysis. No associations were found between maternal fasting or 2-h glucose concentrations with offspring glucose and insulin concentrations from birth to 5 years of age. However, maternal fasting glucose in GW 28 and 36, and 2-h OGTT glucose in GW 28 were positively associated with C-peptide concentration at birth. Maternal fasting glucose concentrations in GW 28 and 36 were positively associated with weight-for-length, and maternal fasting glucose in GW 36 was associated with BMI z-score at birth. In summary, blood glucose in pregnant women with overweight or obesity is positively associated with offspring C-peptide concentration, weight-for-length, and BMI z-score at birth, even in the absence of GDM. [ABSTRACT FROM AUTHOR]

Numerous studies indicate that intrauterine growth restriction (IUGR) can predispose individuals to metabolic syndrome (MetS) in adulthood. Several reports have demonstrated that pharmacological concentrations of biotin have therapeutic effects on MetS. The present study investigated the beneficial effects of prenatal biotin supplementation in a rat model of intrauterine caloric restriction to prevent cardiometabolic risk in adult female offspring fed fructose after weaning. Female rats were exposed to a control (C) diet or global caloric restriction (20%) (GCR), with biotin (GCRB) supplementation (2 mg/kg) during pregnancy. Female offspring were exposed to 20% fructose (F) in drinking water for 16 weeks after weaning (C, C/F, GCR/F, and GCRB/F). The study assessed various metabolic parameters including Lee's index, body weight, feed conversion ratio, caloric intake, glucose tolerance, insulin resistance, lipid profile, hepatic triglycerides, blood pressure, and arterial vasoconstriction. Results showed that GCR and GCRB dams had reduced weights compared to C dams. Offspring of GCRB/F and GCR/F dams had lower body weight and Lee's index than C/F offspring. Maternal biotin supplementation in the GCRB/F group significantly mitigated the adverse effects of fructose intake, including hypertriglyceridemia, hypercholesterolemia, hepatic steatosis, glucose and insulin resistance, hypertension, and arterial hyperresponsiveness. This study concludes that prenatal biotin supplementation can protect against cardiometabolic risk in adult female offspring exposed to postnatal fructose, highlighting its potential therapeutic benefits. [ABSTRACT FROM AUTHOR]

Introduction: Prenatal exposure to supraphysiological glucocorticoid (GC) levels may lead to long‐lasting developmental changes in numerous biological systems. Our prior study identified an association between prenatal GC prophylaxis and reduced cognitive performance, electrocortical changes, and altered autonomic nervous system (ANS) activity in children aged 8–9 years. This follow‐up study aimed to examine whether these findings persisted into adolescence. Material and Methods: Prospective observational follow‐up study involving twenty‐one 14‐ to 15‐year‐old adolescents born to mothers who received betamethasone for induction of fetal lung maturation in threatened preterm birth, but who were born with a normal weight appropriate for their gestational age (median 37+4 gestational weeks). Thirty‐five children not exposed to betamethasone served as the reference group (median 37+6 gestational weeks). The primary endpoint was cognitive performance, measured by intelligence quotient (IQ). Key secondary endpoints included symptoms of attention‐deficit/hyperactivity disorder (ADHD) and metabolic markers. Additionally, we determined electrocortical (electroencephalogram), hypothalamus–pituitary–adrenal axis (HPAA), and ANS activity in response to a standardized stress paradigm. Results: No statistically significant group difference was observed in global IQ (adjusted mean: betamethasone 103.9 vs references 105.9, mean difference −2.0, 95% confidence interval [CI]: −7.12 to 3.12, p = 0.44). Similarly, ADHD symptoms, metabolic markers, the overall and stress‐induced activity of the HPAA and the ANS did not differ significantly between groups. However, the betamethasone group exhibited reduced electrocortical activity in the frontal brain region (spectral edge frequency–adjusted means: 16.0 Hz vs 17.8 Hz, mean difference −1.83 Hz, 95% CI: −3.21 to −0.45, p = 0.01). Conclusions: In 14‐ to 15‐year‐old adolescents, prenatal GC exposure was not associated with differences in IQ scores or ANS activity compared to unexposed controls. However, decelerated electrocortical activity in the frontal region potentially reflects disturbances in the maturation of cortical and/or subcortical brain structures. The clinical significance of these changes remains unknown. Given the small sample size, selective participation/loss of follow‐up and potential residual confounding, these findings should be interpreted cautiously. Further research is required to replicate these results in larger cohorts before drawing firm clinical conclusions. [ABSTRACT FROM AUTHOR]

AbstractExposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman’s reports of social adversity during the third trimester were associated with their infant’s resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants’ cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.

AbstractObjectives The purpose of this study was to determine the relationship between fetal exposure to maternal prenatal stressors and infant parasympathetic (PNS) and sympathetic (SNS) nervous function at 3 timepoints across the first year of life.Background Autonomic nervous system impairments may mediate associations between gestational exposure to stressors and later infant health problems. Heart rate variability (HRV) provides a sensitive index of PNS and SNS function. However, no studies have assessed longitudinal associations between prenatal stressors and infant HRV measures of both PNS and SNS over the first year of life.Methods During the third trimester of pregnancy, 233 women completed measures of life stressors and depression. At 1, 6 and 12 months of age, a stressor protocol was administered while infant electrocardiographic (ECG) data were collected from a baseline through a post-stressor period. HRV measures of PNS and SNS activity (HF, LF, LF/HF ratio) were generated from ECG data. We used multilevel regression to examine the aims, adjusting for maternal depression and neonatal morbidity.Results There were no associations between prenatal stressors and any baseline or reactivity HRV metric over the infant’s first year of life. However, exposure to more stressors was associated with lower post-stressor LF HRV at both 6 (β = −.44, p = .001) and 12 (β = −.37, p = .005) months of age.Conclusions Findings suggest potential alterations in development of the vagally mediated baroreflex function as a result of exposure to prenatal stressors, with implications for the infants’ ability to generate a resilient recovery in response to stressors.

BackgroundAn extensive body of animal literature supports the premise that maternal obesity during pregnancy can alter the development of the fetal hypothalamus (HTH, a critical regulator of energy balance) with implications for offspring obesity risk (i.e., long-term energy imbalance). Yet, the relationship in humans between maternal overweight/obesity during pregnancy and fetal hypothalamic development remains largely unknown. Here, using an international (Finland and California, USA) multi-site diffusion tensor imaging (DTI) dataset, we test the hypothesis that maternal pre-pregnancy BMI is associated with newborn offspring HTH mean diffusivity (HTH MD, a replicable neural correlate of BMI in adults).MethodsHTH MD was independently quantified in two separate BMI-matched cohorts (up to class II obesity; BMIRange = 17-35) using a high-resolution atlas-based definition of HTH. A total of n = 231 mother-child dyads were available for this analysis (nSite,1 = 152, age at MRI = 26.7 ± 8.1 days, gestational age at birth = 39.9 ± 1.2 weeks, nM/F = 82/70, BMI = 24.2 ± 3.8; nSite,2 = 79, age at MRI = 25.6 ± 12.5 days, gestational age at birth = 39.3 ± 1.5 weeks, nM/F = 45/34, BMI = 25.1 ± 4.0). The association between maternal pre-pregnancy BMI and newborn offspring HTH MD was examined separately in each cohort using linear regression adjusting for gestational age at birth, postnatal age at scan, sex, whole white matter mean diffusivity, and DTI quality control criteria. In post hoc analyses, additional potentially confounding factors including socioeconomic status, ethnicity, and obstetric risk were adjusted where appropriate.ResultsThe distribution of maternal pre-pregnancy BMI was comparable across sites but differed by ethnicity and socioeconomic status. A positive linear association between maternal pre-pregnancy BMI and newborn offspring HTH MD was observed at both sites ([Formula: see text]Site,1 = 0.17, pSite,1 = 0.01; [Formula: see text]Site,2 = 0.22, pSite,2 = 0.03) and remained significant after adjusting for cohort-relevant covariates.ConclusionsThese findings translate the preclinically established association between maternal obesity during pregnancy and offspring hypothalamic microstructure to the human context. In addition to further replication/generalization, future efforts to identify biological mediators of the association between maternal obesity and fetal HTH development are warranted to develop targeted strategies for the primary prevention of childhood obesity.

Administration of antenatal corticosteroids (AC) is the standard of care during pregnancy for women who are at risk of early delivery. Evidence indicates that AC improve survival and reduce morbidity for preterm infants. However, research suggests that infants whose mothers receive AC have an altered hypothalamic-pituitary-axis (HPA) response to stressors in early life. Results are mixed regarding the nature of these effects, with studies showing both suppressed and augmented HPA activity. In addition, research is very limited beyond the 4th month of life. The purpose of this study was to determine if AC exposure was associated with infant cortisol levels in a resting state or in response to a stressor at 1, 6 and 12 months postnatal. We also evaluated the moderating role of preterm birth in this association. 181 women and their infants participated in the study. Women were recruited during the 3rd trimester of pregnancy; at this time, they completed the Perceived Stress Scale and provided 8 salivary samples over a 2-day period for cortisol assay. They provided these data again at 6 and 12 months postnatal. At 1, 6, and 12 months postnatal, salivary samples were collected from infants to examine their cortisol levels before and after participation in a 'stressor protocol'. Data were extracted from the medical record on AC exposure, gestational age, maternal obstetric risk, and neonatal morbidity. Mixed effects multilevel regression modeling was used to examine the aims. Infants whose mothers received AC had significantly lower resting state (B = -2.47, CI: -3.691, -0.0484) and post-stressor (B = -2.51, CI: -4.283, -0.4276) cortisol levels across the first year of life than infants whose mothers did not receive AC. There was no moderating effect of preterm birth on the relationship between AC exposure and cortisol. Results indicate a state of dampened HPA activation and cortisol hypo-arousal that persists across the first year of life among infants who were exposed to corticosteroids in utero. Further research is needed to examine mechanisms responsible for any alterations that occur during development of the fetal HPA axis, including epigenetic and biochemical factors that control hormonal secretion, negative feedback, and glucocorticoid receptor function throughout the HPA axis. Findings warrant careful consideration by obstetric clinicians of the benefits and risks of prescribing AC.

The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.

While advancements in early detection and improved access to care have significantly enhanced breast cancer survival rates, the disease remains a significant global malignancy, constituting approximately 12.5% of all new cancer cases and claiming nearly 700,000 lives in 2020. As a result, there is widespread consensus that the most sustainable solution lies in prevention. Indeed, preventive strategies, including lifestyle modifications and research into risk-reducing interventions, offer the potential to address the root causes of noncommunicable diseases such as breast cancer. While conventional wisdom has long attributed established risk factors for breast cancer to age, lifestyle, familial history, and reproductive factors, evidence highlights the maternal environment as a pivotal stage for fetal programming of disease risk, as elucidated in the developmental origins of health and disease (DOHaD) framework. Consequently, a growing body of research has been focused on elucidating epigenomic signatures that influence fetal development while shaping health outcomes and susceptibility to diseases later in life. This review aims to identify fetal mammary developmental genes that have been implicated in breast cancer etiology and the potential interplay of maternal environment in epigenetic programming of breast cancer risk in adulthood.

BackgroundMitochondria are multifunctional energy-producing and signaling organelles that support life and contribute to stress adaptation. There is a growing understanding of the dynamic relationship between stress exposure and mitochondrial biology; however, the influence of stress on key domains of mitochondrial biology during early-life, particularly the earliest phases of intra-uterine/prenatal period remains largely unknown. Thus, the goal of this study was to examine the impact of fetal exposure to stress (modeled as the biological construct allostatic load) upon mitochondrial biology in early childhood.MethodsIn n = 30 children (range: 3.5-6 years, 53% male), we quantified mitochondrial content via citrate synthase (CS) activity and mtDNA copy number (mtDNAcn), and measured mitochondrial bioenergetic capacity via respiratory chain enzyme activities (complexes I (CI), II (CII), and IV (CIV)) in platelet-depleted peripheral blood mononuclear cells (PBMCs). In a cohort of healthy pregnant women, maternal allostatic load was operationalized as a latent variable (sum of z-scores) representing an aggregation of early-, mid- and late-gestation measures of neuroendocrine (cortisol), immune (interleukin-6, C-reactive protein), metabolic (homeostasis model assessment of insulin resistance, free fatty acids), and cardiovascular (aggregate systolic and diastolic blood pressure) systems, as well as an anthropometric indicator (pre-pregnancy body mass index [BMI]).ResultsAn interquartile increase in maternal allostatic load during pregnancy was associated with higher mitochondrial content (24% and 15% higher CS and mtDNAcn), and a higher mitochondrial bioenergetic capacity (16%, 23%, and 25% higher CI, CII and CIV enzymatic activities) in child leukocytes. The positive association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity remained significant after accounting for the effects of key pre- and post-natal maternal and child covariates (p's

Children exposed to prenatal maternal psychological distress are at elevated risk for a range of adverse outcomes; however, it remains poorly understood whether postnatal influences can ameliorate impairments related to prenatal distress. The current study evaluated if sensitivematernal care during the first postnatal year could mitigate child cognitive and emotional impairments associated with prenatal psychological distress. Prenatal maternal psychological distress was assessed via self-reports of anxiety, depression, and perceived stress for 136 mothers at five prenatal and four postpartum time points. Quality of maternal care (sensitivity to nondistress, positive regard, and intrusiveness reverse-scored) were assessed during a mother-child play interaction at 6 and 12 months. Child cognitive function and negative emotionality were assessed at 2 years, using The Bayley Scales and the Early Childhood Behavior Questionnaire. Elevated prenatal distress was associated with poorer child cognitive function and elevated negative emotionality. Children exposed to elevated prenatal maternal distress did not, however, display these outcomes if they received high-quality caregiving. Specifically, maternal care moderated the relation between prenatal psychological distress and child cognitive function and negative emotionality. This association remained after consideration of postnatal maternal psychological distress and relevant covariates. Sensitive maternal care was associated with altered offspring developmental trajectories, supporting child resilience following prenatal distress exposure.

Maternal obesity and/or Western diet (WD) is associated with an increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring, driven, in part, by the dysregulation of the early life microbiome. Here, using a mouse model of WD-induced maternal obesity, we demonstrate that exposure to a disordered microbiome from WD-fed dams suppressed circulating levels of endogenous ligands of the aryl hydrocarbon receptor (AHR; indole, indole-3-acetate) and TMAO (a product of AHR-mediated transcription), as well as hepatic expression of Il10 (an AHR target), in offspring at 3 weeks of age. This signature was recapitulated by fecal microbial transfer from WD-fed pregnant dams to chow-fed germ-free (GF) lactating dams following parturition and was associated with a reduced abundance of Lactobacillus in GF offspring. Further, the expression of Il10 was downregulated in liver myeloid cells and in LPS-stimulated bone marrow-derived macrophages (BMDM) in adult offspring, suggestive of a hypo-responsive, or tolerant, innate immune response. BMDMs from adult mice lacking AHR in macrophages exhibited a similar tolerogenic response, including diminished expression of Il10. Overall, our study shows that exposure to maternal WD alters microbial metabolites in the offspring that affect AHR signaling, potentially contributing to innate immune hypo-responsiveness and progression of MASLD, highlighting the impact of early life gut dysbiosis on offspring metabolism. Further investigations are warranted to elucidate the complex interplay between maternal diet, gut microbial function, and the development of neonatal innate immune tolerance and potential therapeutic interventions targeting these pathways. [ABSTRACT FROM AUTHOR]

The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus's growth, complicates fetal development, and risks the mother's life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis. [ABSTRACT FROM AUTHOR]

During the last decades, endocrine-disrupting chemicals (EDCs) have attracted the attention of the scientific community, as a result of a deepened understanding of their effects on human health. These compounds, which can reach populations through the food chain and a number of daily life products, are known to modify the activity of the endocrine system. Regarding vulnerable groups like pregnant mothers, the potential damage they can cause increases their importance, since it is the health of two lives that is at risk. EDCs can affect the gestation process, altering fetal development, and eventually inducing the appearance of many disorders in their childhood and/or adulthood. Because of this, several of these substances have been studied to clarify the influence of their prenatal exposure on the cognitive and psychomotor development of the newborn, together with the appearance of non-communicable diseases and other disorders. The most novel research on the subject has been gathered in this narrative review, with the aim of clarifying the current knowledge on the subject. EDCs have shown, through different studies involving both animal and human investigation, a detrimental effect on the development of children exposed to the during pregnancy, sometimes with sex-specific outcomes. However, some other studies have failed to find these associations, which highlights the need for deeper and more rigorous research, that will provide an even more solid foundation for the establishment of policies against the extended use of these chemicals. [ABSTRACT FROM AUTHOR]

Recent studies have shown that maternal vitamin D deficiency (VDD) causes long-term metabolic changes in offspring. However, little is known about the impact of maternal VDD on offspring endocrine pancreas development and insulin secretion in the adult life of male and female animals. Female rats (Wistar Hannover) were fed either control (1000 IU Vitamin D3/kg), VDD (0 IU Vitamin D3/kg), or a Ca2+-enriched VDD diet (0 IU Vitamin D3/kg + Ca2+ and P/kg) for 6 weeks and during gestation and lactation. At weaning, VDD status was confirmed based on low serum calcidiol levels in dams and pups. Next, male and female offspring were randomly separated and fed a standard diet for up to 90 days. At this age, serum calcidiol levels were restored to normal levels in all groups, but serum insulin levels were decreased in VDD males without affecting glucagon levels, glycemia, or glucose tolerance. Islets isolated from VDD males showed lower insulin secretion in response to different glucose concentrations, but this effect was not observed in VDD females. Furthermore, VDD males, but not females, showed a smaller total pancreatic islet area and lower β cell mass, an effect that was accompanied by reduced gene expression of Ins1, Ins2, Pdx1, and SLC2A2. The decrease in Pdx1 expression was not related to the methylation profile of the promoter region of this gene. Most of these effects were observed in the male VDD+Ca2+ group, indicating that the effects were not due to alterations in Ca2+ metabolism. These data show that maternal VDD selectively impairs the morphology and function of β cells in adult male offspring rats and that female offspring are fully protected from these deleterious effects. [ABSTRACT FROM AUTHOR]

Fetal programming is a process initiated by intrauterine conditions, leaving a lasting impact on the offspring's health, whether they manifest immediately or later in life. It is believed that children born to mothers with gestational diabetes mellitus (GDM) and excessive gestational weight gain (EGWG) may be at an increased risk of developing type 2 diabetes mellitus (T2DM) and obesity later in their adult lives. Substance P is a neurotransmitter associated with obesity development and impairment of insulin signaling. Dysregulation of substance P could lead to several pregnancy pathologies, such as preeclampsia and preterm birth. Our study aimed to compare substance P concentrations in serum and umbilical cord blood in patients with GDM, EGWG, and healthy women with a family history of gestational weight gain. Substance P levels in umbilical cord blood were significantly higher in the GDM group compared to the EGWG and control groups. Substance P levels in serum and umbilical cord blood were positively correlated in all groups and the GDM group. A very interesting direction for future research is the relationship between the concentration of substance P in newborns of diabetic mothers and the occurrence of respiratory distress syndrome as a complication of impaired surfactant synthesis. To our knowledge, it is the first study assessing substance P concentration in GDM and EGWG patients. [ABSTRACT FROM AUTHOR]

Aim of the study: To investigate the hypothesis that the presence of prenatal maternal stress, increased level of prenatal testosterone, and low level of vitamin D3 in pregnancy is associated with the development of ADHD-like symptoms in toddlers (< 2 years old). Material and methods: The study group comprised 53 pregnant women and 53 infants of these pregnancies. The population cohort of 53 pregnant women were recruited at their 35th to 37th week of pregnancy and investigated prospectively. The participants were selected through targeted selection. Maternal experience of stressful life events was assessed by stress standardised questionnaires, prenatal testosterone was determined in the mothers' saliva by using the immune enzymatic (ELISA) method, and maternal plasma D vitamin was measured using the ECLIA method, during pregnancy. When the age of the offspring was 6 months and then less than 2 years, the mothers completed the child behaviour and temperament checklist. Results: A small but statistically significant association was found between the common symptom complex of ADHD and the level of testosterone and vitamin D3, in the presence of prenatal maternal stress. Multiple regression analysis showed that maternal stressful events during pregnancy significantly predicted ADHD behaviours in offspring. Conclusion: The study supported the hypothesis that prenatal maternal stress, increased level of prenatal testosterone, and low level of vitamin D3 during pregnancy increases the risk of development of ADHD-like symptoms in toddlers (< 2 years old). Also, the obtained results support the hypothesis that the influence of prenatal factors causes ADHD-like symptoms in offspring through a programming effect. [ABSTRACT FROM AUTHOR]

BackgroundMaternal obesity significantly influences fetal development and health later in life; however, the molecular mechanisms behind it remain unclear. This study aims to investigate signature genes related to maternal obesity and fetal programming based on a genomic-wide transcriptional placental study using a combination of different bioinformatics tools.MethodsThe dataset (GSE128381) was obtained from Gene Expression Omnibus (GEO). The data of 100 normal body mass index (BMI) and 27 obese mothers were included in the analysis. Differentially expressed genes (DEGs) were evaluated by limma package. Thereafter, functional enrichment analysis was implemented. Then, weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) analysis were used to further screening of signature genes. Simple linear regression analysis was used to assess the correlation between signature genes and newborn birth weight. Gene set enrichment analysis (GSEA) was implemented to study signaling pathways related to signature genes. The expression of the signature genes was also explored in 48 overweight mothers in the same dataset.ResultsA total of 167 DEGs were obtained, of which 122 were up-regulated while 45 were down-regulated. The dataset was then clustered into 11 modules by WGCNA, and the MEbrown was found as the most significant module related to maternal obesity and fetal programming (cor = 0.2, p = 0.03). The LASSO analysis showed that PTX3, NCF2, HOXB5, ABCA6, and C1orf162 are signature genes related to maternal obesity and fetal programming, which were increased in the placenta of obese mothers compared to those with normal BMI. The area under the curve (AUC) of the signature genes in the receiver operating characteristic curve (ROC) was 0.709, 0.660, 0.674, 0.667, and 0.717, respectively. Simple linear regression analysis showed that HOXB5 was associated with newborn birth weight. GSEA analysis revealed that these signature genes positively participate in various signaling pathways/functions in the placenta.ConclusionPTX3, NCF2, HOXB5, ABCA6, and C1orf162 are novel signature genes related to maternal obesity and fetal programming, of which HOXB5 is implicated in newborn birth weight.

IntroductionChrononutrition studies the relation between diet, circadian rhythms and metabolism, which may alter the metabolic intrauterine environment, influencing infant fat-mass (FM) development and possibly increasing obesity risk.AimTo evaluate the association of chrononutrition in pregnancy and infant FM at 6 months.MethodsHealthy pregnant women and term-babies (n = 100pairs) from the OBESO cohort (2017–2023) were studied. Maternal registries included pregestational body-mass-index (BMI), gestational complications/medications, weight gain. Diet (three 24 h-recalls, 1 each trimester) and sleep-schedule (first and third trimesters) were evaluated computing fasting (hours from last–first meal), breakfast and dinner latencies (minutes between wake up-breakfast and dinner-sleep, respectively), number of main meals/day, meal skipping (≥1 main meal/d on three recalls) and nighttime eating (from 9:00 pm–5:59 am on three recalls). Neonatal weight, length, BMI/age were assessed. At 6 months, infant FM (kg, %; air-displacement plethysmography) was measured, and FM index (FMI—kgFM/length2) computed. Exclusive breastfeeding (EBF) was recorded. Multiple linear regression models evaluated the association between chrononutrition and 6 month infant FM.ResultsMean fasting was 11.7 ± 1.3 h; breakfast, dinner latency were 87.3 ± 75.2, 99.6 ± 65.6 min, respectively. Average meals/day were 3.0 ± 0.5. Meal skipping was reported in 3% (n = 3) of women and nighttime eating in 35% (n = 35). Most neonates had normal BMI/age (88%, n = 88). Compared to those who did not, mothers engaged in nighttime-eating had infants with higher %FM (p = 0.019). Regression models (R2 ≥ 0.308, p ≤ 0.001) showed that nighttime eating was positively associated with %FM (B: 2.7, 95%CI: 0.32–5.16). When analyzing women without complications/medications (n = 80), nighttime eating was associated with higher FM [%FM, B: 3.24 (95%CI: 0.59–5.88); kgFM, B: 0.20 (95%CI: 0.003–0.40); FMI, B: 0.54 (95%CI: 0.03–1.05)]. Infant sex and weight (6 months) were significant, while maternal obesity, pregnancy complications/medications, parity, energy intake, birth-BMI/age, and EBF were not.ConclusionMaternal nighttime eating is associated with higher adiposity in 6 month infants.

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

Abstract Background Children born to obese mothers are at increased risk of developing mood disorders and cognitive impairment. Experimental studies have reported structural changes in the brain such as the gliovascular unit as well as activation of neuroinflammatory cells as a part of neuroinflammation processing in aged offspring of obese mothers. However, the molecular mechanisms linking maternal obesity to poor neurodevelopmental outcomes are not well established. The ephrin system plays a major role in a variety of cellular processes including cell–cell interaction, synaptic plasticity, and long-term potentiation. Therefore, in this study we determined the impact of maternal obesity in pregnancy on cortical, hippocampal development, vasculature and ephrin-A3/EphA4-signaling, in the adult offspring in mice. Methods Maternal obesity was induced in mice by a high fat/high sugar Western type of diet (HF/HS). We collected brain tissue (prefrontal cortex and hippocampus) from 6-month-old offspring of obese and lean (control) dams. Hippocampal volume, cortical thickness, myelination of white matter, density of astrocytes and microglia in relation to their activity were analyzed using 3-D stereological quantification. mRNA expression of ephrin-A3, EphA4 and synaptic markers were measured by qPCR in the brain tissue. Moreover, expression of gap junction protein connexin-43, lipocalin-2, and vascular CD31/Aquaporin 4 were determined in the hippocampus by immunohistochemistry. Results Volume of hippocampus and cortical thickness were significantly smaller, and myelination impaired, while mRNA levels of hippocampal EphA4 and post-synaptic density (PSD) 95 were significantly lower in the hippocampus in the offspring of obese dams as compared to offspring of controls. Further analysis of the hippocampal gliovascular unit indicated higher coverage of capillaries by astrocytic end-feet, expression of connexin-43 and lipocalin-2 in endothelial cells in the offspring of obese dams. In addition, offspring of obese dams demonstrated activation of microglia together with higher density of cells, while astrocyte cell density was lower. Conclusion Maternal obesity affects brain size, impairs myelination, disrupts the hippocampal gliovascular unit and decreases the mRNA expression of EphA4 and PSD-95 in the hippocampus of adult offspring. These results indicate that the vasculature–glia cross-talk may be an important mediator of altered synaptic plasticity, which could be a link between maternal obesity and neurodevelopmental/neuropsychiatric disorders in the offspring. Graphical Abstract

Background: The term “fetal programming” refers to the effects of endogenous and exogenous corticosteroids, whether received from the mother or the fetus, on brain development and the hypothalamic–pituitary–adrenal axis reset. The authors of this narrative review examine the WHO’s guidelines for prenatal corticosteroids in pregnant women who are at high risk of premature delivery. These guidelines are regarded as the best available for preventing late-life problems resulting from preterm. Methods: In order to find full-text publications published in peer-reviewed journals between 1990 and 2023 that were written in English, the authors searched PubMed, Scopus, Cochrane Library, and Web of Science. Results: The authors highlight the possible adverse long-term effects of prenatal corticosteroid medication on human brain development and function. This pharmacological feature is therapeutically significant because there is less evidence in the scientific literature regarding the potential role that the timing, mode, and dosage of exogenous steroid treatment may have in neurological illnesses down the road. Conclusions: The authors expect that these studies will shed light on the relationship between specially designed prenatal corticosteroid therapy and the molecular mechanisms underlying the prenatal programming of neurodevelopment in childhood and adulthood.

Background/Objectives: Childhood obesity is a global health problem that affects at least 41 million children under the age of five. Increased BMI in children is associated with serious long-term health consequences, such as type 2 diabetes, cardiovascular disease, and psychological problems, including depression and low self-esteem. Although the etiology of obesity is complex, research suggests that the diet and lifestyle of pregnant women play a key role in shaping metabolic and epigenetic changes that can increase the risk of obesity in their children. Excessive gestational weight gain, unhealthy dietary patterns (including the Western diet), and pregnancy complications (such as gestational diabetes) are some of the modifiable factors that contribute to childhood obesity. The purpose of this narrative review is to summarize the most important and recent information on the impact of the diet and lifestyle of pregnant women on the risk of childhood obesity. Methods: This article is a narrative review that aims to summarize the available literature on the impact of pregnant women’s diet and lifestyle on the risk of obesity in their offspring, with a focus on metabolic and epigenetic mechanisms. Results/Conclusions: Current evidence suggests that a pregnant woman’s lifestyle and diet can significantly contribute to lowering the risk of obesity in their offspring. However, further high-quality research is needed to understand better the metabolic and epigenetic relationships concerning maternal factors that predispose offspring to obesity.

In this paper, we present a transdisciplinary framework and testable hypotheses regarding the process of fetal programming of energy homeostasis brain circuitry. Our model proposes that key aspects of energy homeostasis brain circuitry already are functional by the time of birth (with substantial interindividual variation); that this phenotypic variation at birth is an important determinant of subsequent susceptibility for energy imbalance and childhood obesity risk; and that this brain circuitry exhibits developmental plasticity, in that it is influenced by conditions during intrauterine life, particularly maternal-placental-fetal endocrine, immune/inflammatory, and metabolic processes and their upstream determinants. We review evidence that supports the scientific premise for each element of this formulation, identify future research directions, particularly recent advances that may facilitate a better quantification of the ontogeny of energy homeostasis brain networks, highlight animal and in vitro-based approaches that may better address the determinants of interindividual variation in energy homeostasis brain networks, and discuss the implications of this formulation for the development of strategies targeted towards the primary prevention of childhood obesity.

The early childhood period, encompassing prenatal and early stages, assumes a pivotal role in shaping cardiovascular risk factors. We conducted a narrative review, presenting a non-systematic summation and analysis of the available literature, focusing on cardiovascular risk from prenatal development to the first 1000 days of life. Elements such as maternal health, genetic predisposition, inadequate fetal nutrition, and rapid postnatal growth contribute to this risk. Specifically, maternal obesity and antibiotic use during pregnancy can influence transgenerational risk factors. Conditions at birth, such as fetal growth restriction and low birth weight, set the stage for potential cardiovascular challenges. To consider cardiovascular risk in early childhood as a dynamic process is useful when adopting a personalized prevention for future healthcare and providing recommendations for management throughout their journey from infancy to early adulthood. A comprehensive approach is paramount in addressing early childhood cardiovascular risks. By targeting critical periods and implementing preventive strategies, healthcare professionals and policymakers can pave the way for improved cardiovascular outcomes. Investing in children’s health during their early years holds the key to alleviating the burden of cardiovascular diseases for future generations.

ABSTRACT: This study aimed to evaluate the effects of differential average daily gain targets of dairy heifers throughout gestation on placental hemodynamics, uterine involution, colostrum production of the heifers, and effects on newborn calf weight and immunity transfer. Fourteen Holstein × Gyr heifers with an average body weight of 446 ± 46.7 kg and age of 25 ± 3.9 mo were randomly assigned to the following treatments: moderate body weight gain (MOD, n = 7), where heifers were fed to achieve 0.50 kg/d; and high body weight gain (HIG, n = 7), where heifers were fed to achieve 0.75 kg/d. Target average daily gains were established based on common tropical dairy production systems. The heifers received a total mixed ration feed twice daily starting at 70 d of gestation. Placentome vascularization was assessed using a color Doppler ultrasound at 180, 210, and 240 d of gestation. After calving, cotyledons were counted and sampled to analyze the mRNA expression of placental angiogenesis markers. After birth, calves were weighed and fed colostrum, and transfer of passive immunity efficiency was assessed. A significant increase in cotyledons was detected for MOD placenta soon after expulsion (81.5 ± 12.91 vs. 63.6 ± 10.52). Placentome vascularization at the final third of gestation increased for MOD heifers compared with HIG. Greater mRNA expression after membrane expulsion of VEGFB and IGFR1 in cotyledons and a greater estradiol concentration in circulation 1 d before calving was found for MOD heifers compared with HIG heifers; however, uterine involution postpartum was not different between treatment groups. Greater colostrum production was observed in HIG heifers (3.9 ± 1.05 vs. 2.2 ± 1.57 L) but with lower quality (25.2 ± 0.51 vs. 29.5 ± 0.65 Brix). No differences were observed in birth weight or transfer of passive immunity efficiency between treatments; however, HIG calves had significantly greater vitality scores than MOD calves. The results of this study indicate that a moderate feeding regimen enhances placental blood flow by increasing angiogenesis, which suggests improved nutrient transfer to the fetus without major effects on its development during the neonatal stage, colostrum production, or uterine involution in the heifers.

Background: Nutritional status and maternal feeding during the perinatal and postnatal periods can program the offspring to develop long-term health alterations. Epidemiologic studies have demonstrated an association between maternal obesity and intellectual disability/cognitive deficits like autism spectrum disorders (ASDs) in offspring. Experimental findings have consistently been indicating that maternal supplementation with methyl donors, attenuated the social alterations and repetitive behavior in offspring. Objective: This study aims to analyze the effect of maternal cafeteria diet and methyl donor-supplemented diets on social, anxiety-like, and repetitive behavior in male offspring, besides evaluating weight gain and food intake in both dams and male offspring. Design: C57BL/6 female mice were randomized into four dietary formulas: control Chow (CT), cafeteria (CAF), control + methyl donor (CT+M), and cafeteria + methyl donor (CAF+M) during the pre-gestational, gestational, and lactation period. Behavioral phenotyping in the offspring was performed by 2-month-old using Three-Chamber Test, Open Field Test, and Marble Burying Test. Results: We found that offspring prenatally exposed to CAF diet displayed less social interaction index when compared with subjects exposed to Chow diet (CT group). Notably, offspring exposed to CAF+M diet recovered social interaction when compared to the CAF group. Discussion: These findings suggest that maternal CAF diet is efficient in promoting reduced social interaction in murine models. In our study, we hypothesized that a maternal methyl donor supplementation could improve the behavioral alterations expected in maternal CAF diet offspring. Conclusions: The CAF diet also contributed to a social deficit and anxiety-like behavior in the offspring. On the other hand, a maternal methyl donor-supplemented CAF diet normalized the social interaction in the offspring although it led to an increase in anxiety-like behaviors. These findings suggest that a methyl donor supplementation could protect against aberrant social behavior probably targeting key genes related to neurotransmitter pathways.