Maternal preconception glucose intolerance and fatty acid intake from conception to weaning: impact on offspring energy homeostasis in both male and female.

Environmental factors in the early life stages can lead the descendant to adaptations in gene expression, permanently impacting several structures and organs. The amount and quality of fatty acids in the maternal diet in pregnancy and lactation were found to impact offspring metabolism. So, maternal diet and insulin resistance can affect the male and female descendants through distinct pathways and at different time points. We hypothesized that maternal high-fat diet (HFD) intake before conception and an adequate amount of different fatty acids intake during pregnancy and lactation could influence the energy homeostasis system of 21-day-old offspring. Female rats received control diet (C) or HFD (HF) for 8 weeks before pregnancy. During pregnancy and lactation C group remained with same diet (C-C), HF group were distributed into 4 groups and received C diet (HF-C), normolipidic diet based on saturated fatty acids (HF-S) or based on polyunsaturated fatty acids n-3 (HF-P) or remained in same diet (HF-HF). Maternal HFD in preconception, pregnancy, and lactation (HF-HF) led to lower glucagon-like peptide-1 levels in male (HF-HF21) compared to other groups (C-C21, HF-C21, and HF-P21) and compared to HF-HF21 females. Neuropeptide YY levels were higher in the HF-HF21, HF-C21, and HF-S21 male offspring compared to HF-P21. HF-P21 was similar to C-C21. Positive correlations were found among the energy homeostasis markers genes expressed in the offspring hypothalamus. Maternal diet changes to adequate quantities of fatty acids during pregnancy and lactation showed less impaired results but was not entirely avoided. A maternal diet based on PUFA n-3 during pregnancy and lactation seems to reverse the damage of an HFD in preconception. These results of homeostasis energy system disturbance in the offspring at weaning give us clues about changes that precede the onset of the disease in adult life - adding notes to the knowledge for future investigations of prevention and treatment of chronic diseases.

The Effects of Maternal Nutrient Restriction during Mid to Late Gestation with Realimentation on Fetal Metabolic Profiles in the Liver, Skeletal Muscle, and Blood in Sheep.

Poor maternal nutrition during gestation negatively affects offspring growth and metabolism. To evaluate the impact of maternal nutrient restriction and realimentation on metabolism in the fetal liver, skeletal muscle, and circulation, on day 50 of gestation, ewes (n = 48) pregnant with singletons were fed 100% (CON) or 60% (RES) of requirements until day 90 of gestation, when a subset of ewes (n = 7/treatment) were euthanized, and fetal samples were collected. The remaining ewes were maintained on a current diet (CON-CON, n = 6; RES-RES, n = 7) or switched to an alternative diet (CON-RES, RES-CON; n = 7/treatment). On day 130 of gestation, the remaining ewes were euthanized, and fetal samples were collected. Fetal liver, longissimus dorsi (LD), and blood metabolites were analyzed using LC-MS/MS, and pathway enrichment analysis was conducted using MetaboAnalyst. Then, 600, 518, and 524 metabolites were identified in the liver, LD, and blood, respectively, including 345 metabolites that were present in all three. Nutrient restriction was associated with changes in amino acid, carbohydrate, lipid, and transulfuration/methionine metabolic pathways, some of which were alleviated by realimentation. Fetal age also affected metabolite abundance. The differential abundance of metabolites involved in amino acid, methionine, betaine, and bile acid metabolism could impact fetal epigenetic regulation, protein synthesis, lipid metabolism, and signaling associated with glucose and lipid metabolism.

Pre-existing maternal cardiovascular disease and the risk of offspring cardiovascular disease from infancy to early adulthood.

BACKGROUND AND AIMS: A variety of maternal heart conditions are associated with abnormal placentation and reduced foetal growth. However, their impact on offspring's long-term cardiovascular health is poorly studied. This study aims to investigate the association between intrauterine exposure to pre-existing maternal cardiovascular disease (CVD) and offspring CVD occurring from infancy to early adulthood, using paternal CVD as a negative control. METHODS: This nationwide cohort study used register data of live singletons without major malformations or congenital heart disease born between 1992 and 2019 in Sweden. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for essential maternal characteristics. Paternal CVD served as a negative control for assessment of unmeasured genetic and environmental confounding. RESULTS: Of the 2 597 786 offspring analysed (49.1% female), 26 471 (1.0%) were born to mothers with pre-existing CVD. During a median follow-up of 14 years (range 1-29 years), 17 382 offspring were diagnosed with CVD. Offspring of mothers with CVD had 2.09 times higher adjusted HR of CVD (95% CI 1.83, 2.39) compared with offspring of mothers without CVD. Compared with maternal CVD, paternal CVD showed an association of smaller magnitude (HR 1.49, 95% CI 1.32, 1.68). Increased hazards of offspring CVD were also found when stratifying maternal CVD into maternal arrhythmia (HR 2.94, 95% CI 2.41, 3.58), vascular (HR 1.59, 95% CI 1.21, 2.10), and structural heart diseases (HR 1.48, 95% CI 1.08, 2.02). CONCLUSIONS: Maternal CVD was associated with an increased risk of CVD in offspring during childhood and young adulthood. Paternal comparison suggests that genetic or shared familial factors may not fully explain this association.

Pregnancy vitamin D supplementation and offspring bone mineral density in childhood follow-up of a randomized controlled trial.

BACKGROUND: Findings from the MAVIDOS trial demonstrated a positive effect of gestational cholecalciferol supplementation on offspring bone mineral density (BMD) at age 4 y. Demonstrating the persistence of this effect is important to understanding whether maternal vitamin D supplementation could be a useful public health strategy to improving bone health. OBJECTIVES: We investigated whether gestational vitamin D supplementation increases offspring BMD at ages 6-7 y in an exploratory post-hoc analysis of an existing trial. METHODS: In the MAVIDOS randomized controlled trial, pregnant females <14 wk' gestation with a singleton pregnancy and serum 25-hydroxyvitamin D 25-100nmol/l at 3 United Kingdom hospitals (Southampton, Sheffield, and Oxford) were randomly assigned to either 1000 IU/d cholecalciferol or placebo from 14 to 17-wk gestation until delivery. Offspring born at term to participants recruited in Southampton were invited to the childhood follow-up at ages 4 and 6-7 y. The children had a dual-energy X-ray absorptiometry (DXA, Hologic discovery) scan of whole-body-less-head (WBLH) and lumbar spine, from which bone area, bone mineral content (BMC), BMD, and bone mineral apparent density (BMAD) were derived. Linear regression was used to compare the 2 groups adjusting for age, sex, height, weight, duration of consumption of human milk, and vitamin D use at 6-7 y. RESULTS: A total of 454 children were followed up at ages 6-7 y, of whom 447 had a usable DXA scan. Gestational cholecalciferol supplementation resulted in higher WBLH BMC [0.15 SD, 95% confidence interval (CI): 0.04, 0.26], BMD (0.18 SD, 95% CI: 0.06, 0.31), BMAD (0.18 SD, 95% CI: 0.04, 0.32), and lean mass (0.09 SD, 95% CI: 0.00, 0.17) compared with placebo. The effect of pregnancy cholecalciferol on bone outcomes was similar at ages 4 and 6-7 y. CONCLUSIONS: Supplementation with cholecalciferol 1000 IU/d during pregnancy resulted in greater offspring BMD and lean mass in mid-childhood compared with placebo in this exploratory post-hoc analysis. These findings suggest that pregnancy vitamin D supplementation may be an important population health strategy to improve bone health. TRIAL REGISTRATION NUMBER: This trial was registered at the ISRCTN (https://doi.org/10.1186/ISRCTN82927713) as 82927713 and EUDRACT (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001716-23/results) as 2007-001716-23.

Intestinal gluconeogenesis controls the neonatal development of hypothalamic feeding circuits.

OBJECTIVE: Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. METHODS: We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. RESULTS: Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. CONCLUSION: These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood.

Maternal high-fat high-sugar diet impairs bone quality and strength but not cartilage in aging mice.

Osteoarthritis (OA) is a prevalent aging disorder of synovial joints and recent work suggests that a parental high-fat diet increases OA severity following joint injury in offspring. We hypothesized that a maternal high-fat high-sugar (HFHS) diet would promote spontaneous osteoarthritis-related cartilage and bone changes in 1-year-old offspring. Female C57BL/6 J mice were placed on either a chow control or HFHS diet for 6 weeks before mating to a chow-fed C57BL/6 J male and maintained on their assigned diets throughout pregnancy and lactation. Male and female offspring were weaned onto a chow diet, raised to 1 year of age, and evaluated for cartilage and bone changes indicative of OA. However, offspring did not show early signs of OA as measured by histological Mankin scoring, mechanical testing of the pericellular matrix, histological synovitis scoring, or subchondral bone thickening as measured by microcomputed Tomography. On the other hand, male offspring from HFHS-fed dams had reduced trabecular bone quality in the tibial metaphysis and decreased cortical thickness. Although maternal HFHS diet did not impact trabecular or cortical bone quality in tibias of female offspring, the radii of these animals had decreased cortical thickness, increased medullary area, and impaired breaking strength compared to those of control-fed dams. Finally, we evaluated bone quality and strength in male and female F2 offspring and found that the grandmaternal diet modestly impacted radial bone geometry but not strength. Together these results suggest that maternal HFHS diet impairs F1 offspring skeletal integrity in a sex and bone site-specific manner.

Through a teratological lens: A narrative review of exposure to stress and drugs of abuse during pregnancy on neurodevelopment.

Teratological research shows that both prenatal stress and prenatal substance exposure have a significant impact on neurodevelopmental outcomes in children. Using human research, the purpose of this narrative review is to explore the degree to which these exposures may represent complex prenatal and postnatal risks for the development of cognition and behavior in children. An understanding of the HPA axis and its function during pregnancy as well as the types and operationalization of prenatal stress provide a context for understanding the direct and indirect mechanisms by which prenatal stress affects brain and behavior development. In turn, prenatal substance exposure studies are evaluated for their importance in understanding variables that indicate a potential interaction with prenatal stress including reactivity to novelty, arousal, and stress reactivity during early childhood. The similarities and differences between prenatal stress exposure and prenatal substance exposure on neurodevelopmental outcomes including arousal and emotion regulation, cognition, behavior, stress reactivity, and risk for psychopathology are summarized. Further considerations for teratological studies of prenatal stress and/or substance exposure include identifying and addressing methodological challenges, embracing the complexity of pre-and postnatal environments in the research, and the importance of incorporating parenting and resilience into future studies.

Early life stress and iron metabolism in developmental psychoneuroimmunology.

An estimated 250 million children face adverse health outcomes from early life exposure to severe or chronic social, economic, and nutritional adversity, highlighting/emphasizing the pressing concern about the link between ELS and long-term implications on mental and physical health. There is significant overlap between populations experiencing high levels of chronic stress and those experiencing iron deficiency, spotlighting the potential role of iron as a key mediator in this association. Iron, an essential micronutrient for brain development and immune function, is often depleted in stress conditions. Iron deficiency among the most common nutrient deficiencies in the world. Fetal and infant iron status may thus serve as a crucial intermediary between early chronic psychological stress and subsequent immune system changes to impact neurodevelopment. The review presents a hypothesized pathway between early life stress (ELS), iron deficiency, and neurodevelopment through the hypothalamic-pituitary-adrenocortical (HPA) axis and the IL-6-hepcidin axis. This hypothesis is derived from (1) evidence that stress impacts iron status (2) long-term neurodevelopmental outcomes that are shared by ELS and iron deficiency exposure, and (3) possible mechanisms for how iron may mediate the relation between ELS and iron deficiency through alterations in the developing immune system. The article concludes by proposing future research directions, emphasizing the need for rigorous studies to elucidate how stress and iron metabolism interact to modify the developing immune system. Understanding these mechanisms could open new avenues for improving human health and neurodevelopment for women and children globally, making it a timely and vital area of study in psychoneuroimmunology research.

Dissecting the Impact of Maternal Androgen Exposure on Developmental Programming through Targeting the Androgen Receptor.

Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation in circulating androgens during pregnancy, an independent risk factor linked to pregnancy complications and adverse outcomes in offspring. Yet, further studies are required to understand the effects of elevated androgens on cell type-specific placental dysfunction and fetal development. Therefore, a PCOS-like mouse model induced by continuous androgen exposure is examined. The PCOS-mice exhibited impaired placental and embryonic development, resulting in mid-gestation lethality. Co-treatment with the androgen receptor blocker, flutamide, prevents these phenotypes including germ cell specification. Comprehensive profiling of the placenta by whole-genome bisulfite and RNA sequencing shows a reduced proportion of trophoblast precursors, possibly due to the downregulation of Cdx2 expression. Reduced expression of Gcm1, Synb, and Prl3b1 is associated with reduced syncytiotrophoblasts and sinusoidal trophoblast giant cells, impairs placental labyrinth formation. Importantly, human trophoblast organoids exposed to androgens exhibit analogous changes, showing impaired trophoblast differentiation as a key feature in PCOS-related pregnancy complications. These findings provide new insights into the potential cellular targets for future treatments.

Developmental programming of production and reproduction in dairy cows: V. Association of the main and interactive effects of maternal level of milk production and milk fat to protein ratio with offspring's birth weight, survival, and productive and reproductive performance from birth to the first lactation period.

Level of dam milk production (DMP) and dam milk fat to protein ratio (DFPR), as an indicator of metabolic status in dairy cows, have been identified to be associated with productive and reproductive performance of the offspring. Yet whether the interaction of DMP by DFPR can be associated with performance of the offspring have not been studied to our knowledge. Therefore, the present study was conducted to investigate the association of the main and interactive effects of DMP and DFPR with offspring's birth weight, survival, milk yield and fertility. To this end, data of birth weight, culling rate, milk yield and reproductive variables of offspring born to lactating dams (n = 14,582) and data associated with DMP and DFPR during 305-day lactation were retrieved. Afterwards, offspring were classified in three categories of DMP, including DMP1 (dams with <10.00 × 103 kg of 305-day milk production), DMP2 (dams with ≥10.00 × 103 kg and <14.00 × 103 kg of 305-day milk production), DMP3 (dams with ≥14.00 × 103 kg of 305-day milk production), and three categories of DFPR, including DFPR1 (offspring born to dams with <1.00 FPR), DFPR2 (offspring born to dams with ≥1.00 and < 1.40 FPR) and DFPR3 (offspring born to dams with ≥1.40 FPR). Statistical analysis revealed no association of the interaction effect of DMP by DFPR with investigated variables in the offspring (P > 0.05). However, the main effect of DMP was positively associated with milk yield, but negatively associated with survival, age at first insemination and conception during nulliparity, and transgenerational improvement in milk yield in the offspring (P < 0.05). Moreover, the main effect of DFPR was positively associated with birth weight, survival and first service conception rate during nulliparity, but negatively associated with metabolic status and reproductive performance during primiparity in the offspring (P < 0.05). In conclusion, the present study did not find any interaction effect of DMP by DFPR on productive and reproductive variables in the offspring. This finding implicates the association of DMP with milk production in the offspring was regardless of DFPR. Moreover, this finding implies the association of DFPR with postpartum metabolic status and reproductive performance in the offspring was regardless of DMP.

Cord blood methylation at TNFRSF17 is associated with early allergic phenotypes.

Food allergy and eczema are the earliest allergic phenotypes in childhood. These diseases could be related to either IgE-mediated or non-IgE-mediated reactions to the allergen. TNFRSF17 is a key molecule in B cell maturation and is important in both types of responses.We conducted a study comparing the relative expression and the methylation status at the TNFRSF17 in regard to the child's early atopic sensitisation and allergic phenotypes.In the recruited population of 200 women and 174 children with available clinical data (physical examination by allergist and antigen-specific IgE measurements), 78 cord blood samples were included in the gene expression analysis (relative gene expression with GAPDH as reference by RT-PCR) and 96 samples with microarray DNA methylation data (whole genome methylation profile Infinium MethylationEPIC).The altered TNFRSF17 methylation pattern in the cord blood at both single cg04453550 and mean methylation at upstream of TNFRSF17 was observed in children who developed food allergy and/or eczema in early childhood. The change in methylation profile was mirrored by the relative expression. The profile of IgE sensitisation to food and/or inhalant allergens was not significantly associated with either methylation or expression of TNFRSF17.In conclusion, methylation at the upstream sites at TNFRSF17 in the cord blood at birth is associated with food allergy and eczema early in childhood.

Epigenetic regulation by hypoxia, N-acetylcysteine and hydrogen sulphide of the fetal vasculature in growth restricted offspring: A study in humans and chicken embryos.

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and functional studies to determine whether N-acetylcysteine (NAC) and hydrogen sulphide (H2S) protect cardiovascular function in growth-restricted unborn offspring. In human umbilical and placental arteries from control or FGR pregnancy and in vessels from near-term chicken embryos incubated under normoxic or hypoxic conditions, we determined the expression of the H2S gene CTH (i.e. cystathionine γ-lyase) (via quantitative PCR), the production of H2S (enzymatic activity), the DNA methylation profile (pyrosequencing) and vasodilator reactivity (wire myography) in the presence and absence of NAC treatment. The data show that FGR and hypoxia increased CTH expression in the embryonic/fetal vasculature in both species. NAC treatment increased aortic CTH expression and H2S production and enhanced third-order femoral artery dilator responses to the H2S donor sodium hydrosulphide in chicken embryos. NAC treatment also restored impaired endothelial relaxation in human third-to-fourth order chorionic arteries from FGR pregnancies and in third-order femoral arteries from hypoxic chicken embryos. This NAC-induced protection against endothelial dysfunction in hypoxic chicken embryos was mediated via nitric oxide independent mechanisms. Both developmental hypoxia and NAC promoted vascular changes in CTH DNA and NOS3 methylation patterns in chicken embryos. Combined, therefore, the data support that the effects of NAC and H2S offer a powerful mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy. KEY POINTS: Gestation complicated by chronic fetal hypoxia and fetal growth restriction (FGR) increases a prenatal origin of cardiovascular disease in offspring, increasing interest in antenatal therapy to prevent against a fetal origin of cardiovascular dysfunction. We investigated the effects between N-acetylcysteine (NAC) and hydrogen sulphide (H2S) in the vasculature in FGR human pregnancy and in chronically hypoxic chicken embryos. Combining cellular, molecular, epigenetic and functional studies, we show that the vascular expression and synthesis of H2S is enhanced in hypoxic and FGR unborn offspring in both species and this acts to protect their vasculature. Therefore, the NAC/H2S pathway offers a powerful therapeutic mechanism of human translational potential against fetal cardiovascular dysfunction in complicated pregnancy.

High-Fat Diets Fed during Pregnancy Cause Changes to Pancreatic Tissue DNA Methylation and Protein Expression in the Offspring: A Multi-Omics Approach.

Maternal obesity, caused by diets rich in fats and sugars during pregnancy, can predispose offspring to metabolic diseases such as diabetes. We hypothesized that obesity during pregnancy leads to increased DNA methylation and reduced protein expression in factors regulating ß-cell function and apoptosis. Female C57BL/6J mice were fed a high-fat diet (HFD; 42% fat content; n = 3) or a control diet (CON; 16% fat content; n = 3) for fourteen weeks before and during pregnancy. Offspring were euthanized at 8 weeks and pancreatic tissue was collected. Isolated DNA was analyzed using whole-genome bisulfite sequencing. Protein expression was quantified using LC-MS. No significant differences in body weight were observed between HFD and control pups (p = 0.10). Whole-genome bisulfite sequencing identified 91,703 and 88,415 differentially methylated regions (DMRs) in CON vs. HFD male and female offspring. A total of 34 and 4 proteins were determined to have changes in expression that correlated with changes in DNA methylation in CON vs. HFD males and females, respectively. The majority of these factors were grouped into the metabolic function category via pathway analyses. This study illustrates the complex relationship between epigenetics, diet, and sex-specific responses, therefore offering insights into potential therapeutic targets and areas for further research.

Influence of leptin administration to pregnant mice on fetal gene expression and adaptation to sweet and fatty food in adult offspring of different sexes.

Elevated leptin in pregnant mice improves metabolism in offspring fed high-calorie diet and its influence may be sex-specific. Molecular mechanisms mediating leptin programming action are unknown. We aimed to investigate programming actions of maternal leptin on the signaling function of the placenta and fetal liver and on adaptation to high-calorie diet in male and female offspring. Female C57BL/6J mice received leptin injections in mid-pregnancy. Gene expression was assessed in placentas and in the fetal brain and liver at the end of pregnancy. Metabolic parameters and gene expression in the liver, brown fat and hypothalamus were assessed in adult male and female offspring that had consumed sweet and fatty diet (SFD: chow, lard, sweet biscuits) for 2 weeks. Females had lower blood levels of leptin, glucose, triglycerides and cholesterol than males. Consuming SFD, females had increased Ucp1 expression in brown fat, while males had accumulated fat, decreased blood triglycerides and liver Fasn expression. Leptin administration to mothers increased Igf1 and Dnmt3b expression in fetal liver, decreased post-weaning growth rate, and increased hypothalamic Crh expression in response to SFD in both sexes. Only in male offspring this administration decreased expression of Fasn and Gck in the mature liver, increased fat mass, blood levels of glucose, triglycerides and cholesterol and Dmnt3a expression in the fetal liver. The results suggest that the influence of maternal leptin on the expression of genes encoding growth factors and DNA methyltransferases in the fetal liver may mediate its programming effect on offspring metabolic phenotypes.

Provision of choline chloride to the bovine preimplantation embryo alters postnatal body size and DNA methylation†.

Choline is a vital micronutrient. In this study, we aimed to confirm, and expand on previous findings, how choline impacts embryos from the first 7 days of development to affect postnatal phenotype. Bos indicus embryos were cultured in a choline-free medium (termed vehicle) or medium supplemented with 1.8 mM choline. Blastocyst-stage embryos were transferred into crossbred recipients. Once born, calves were evaluated at birth, 94 days, 178 days, and at weaning (average age = 239 days). Following weaning, all calves were enrolled into a feed efficiency trial before being separated by sex, with males being slaughtered at ~580 days of age. Results confirm that exposure of 1.8 mM choline chloride during the first 7 days of development alters postnatal characteristics of the resultant calves. Calves of both sexes from choline-treated embryos were consistently heavier through weaning and males had heavier testes at 3 months of age. There were sex-dependent alterations in DNA methylation in whole blood caused by choline treatment. After weaning, feed efficiency was affected by an interaction with sex, with choline calves being more efficient for females and less efficient for males. Calves from choline-treated embryos were heavier, or tended to be heavier, than calves from vehicle embryos at all observations after weaning. Carcass weight was heavier for choline calves and the cross-sectional area of the longissimus thoracis muscle was increased by choline.

Transcriptomic analysis of sheep hypothalamus discloses regulatory genes potentially involved in sex-dependent differences in body weight of progeny born to dams supplemented with omega-3 fatty acids or methionine during late-gestation.

Fetal programming research conducted in sheep has reported sexually dimorphic responses on growth of the progeny born to in-utero methionine or omega-3 fatty acids supplementation. However, the biological mechanism behind the nutrient by sex interaction as a source of variation in offspring body weight is still unknown. A high-throughput RNA sequencing data of hypothalamus samples from 17 lambs were used in the current study to identify differentially expressed genes (DEGs) between males and females born to dams supplemented with different nutrients during late-gestation. Ewes received a basal diet without omega-3 fatty acids or methionine supplementation as the control (CONT); omega-3 fatty acids supplementation (FAS), or methionine supplementation (METS). A list of regulated genes was generated. Data were compared as CONT vs. FAS and CONT vs. METS. For CONT vs. METS, a treatment by sex interaction was found (adjusted P-value < 0.05) on 121 DEGs (112 upregulated and 9 downregulated) on female lambs born to METS compared with METS males. Importantly, with the sex interaction term, more than 100 genes were upregulated in female lamb's hypothalamuses born to METS. Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA) were performed using the DEGs from female lambs. Terms under biological process (related to morphogenesis, organism, and tissue development), cellular component (related to chromatin, extracellular components), and molecular function (involved in chromatin structure and transcription and factors linked to binding DNA) were presented (adjusted P-value < 0.05) for GO. For the IPA, the top-scoring network was developmental disorder, endocrine system development and function, and organ morphology. Only a few differences were observed in the comparison between the interaction of sex and treatment for the CONT vs. FAS comparison. The markedly increased number of DEGs substantially involved in developmental and growth processes indicates the extent to which maternal methionine supplementation causes the sexually dimorphic effects observed in the offspring.

Feeding dams during gestation affects the development of the offspring for their entire life. The objective of the current experiment was to evaluate the changes of the transcriptome in the hypothalamus of the offspring lambs born from dams supplemented with (i) a control diet (without lipids or methionine supplementation), (ii) an omega-3 fatty acid supplementation, or (iii) a methionine supplementation. The supplementation took place in the last third of gestation and the hypothalamus of male and female offspring was collected after being on a fattening diet for 54 d. Hypothalamus samples were used to extract RNA and analyzed using RNA sequencing. There was an interaction due to sex and methionine supplementation. The pathways that were modified were chromatin structure, developmental processes, and organ morphology. The modification observed on these pathways could explain the sex by treatment interaction differences previously observed in growth. There were few sex by omega-3 fatty acid interactions on the hypothalamus transcriptome. Therefore, the sexual dimorphism observed by methionine supplementation may be regulated by the hypothalamus.

Tracing the influence of prenatal risk factors on the offspring retina: Focus on development and putative long-term consequences.

BACKGROUND: Pregnancy represents a window of vulnerability to fetal development. Disruptions in the prenatal environment during this crucial period can increase the risk of the offspring developing diseases over the course of their lifetime. The central nervous system (CNS) has been shown to be particularly susceptible to changes during crucial developmental windows. To date, research focused on disruptions in the development of the CNS has predominantly centred on the brain, revealing a correlation between exposure to prenatal risk factors and the onset of neuropsychiatric disorders. Nevertheless, some studies indicate that the retina, which is part of the CNS, is also vulnerable to in utero alterations during pregnancy. Such changes may affect neuronal, glial and vascular components of the retina, compromising retinal structure and function and possibly impairing visual function. METHODS: A search in the PubMed database was performed, and any literature concerning prenatal risk factors (drugs, diabetes, unbalanced diet, infection, glucocorticoids) affecting the offspring retina were included. RESULTS: This review collects evidence on the cellular, structural and functional changes occurring in the retina triggered by maternal risk factors during pregnancy. We highlight the adverse impact on retinal development and its long-lasting effects, providing a critical analysis of the current knowledge while underlining areas for future research. CONCLUSIONS: Appropriate recognition of the prenatal risk factors that negatively impact the developing retina may provide critical clues for the design of preventive strategies and for early therapeutic intervention that could change retinal pathology in the progeny.

Effects of late gestational nutrient restriction on uterine artery blood flow, placental size, and cotyledonary mRNA expression in primiparous beef females.

Fall-calving primiparous beef females [body weight (BW): 451 ±â€…28 (SD) kg; body condition score (BCS): 5.4 ±â€…0.7] were individually-fed either 100% (control; CON; n = 13) or 70% (nutrient restricted; NR; n = 13) of metabolizable energy and metabolizable protein requirements for maintenance, pregnancy, and growth from day 160 of gestation to parturition. Doppler ultrasonography of both uterine arteries was conducted pre-treatment and every 21 d from days 181 to 265 of gestation. Expelled placentas were collected, and ipsilateral cotyledonary tissue was sampled to assess relative messenger ribonucleic acid (mRNA) expression. Placentas were separated into ipsilateral and contralateral sides, dissected (cotyledonary vs. intercotyledonary), and dried. Data were analyzed with nutritional plane, treatment initiation date, and calf sex (when P < 0.25) as fixed effects. Uterine blood flow included day and nutritional plane × day as repeated measures. We previously reported that post-calving, NR dams weighed 64 kg less and were 2.0 BCS lower than CON, but calf birth weight was not affected. Maternal heart rate was less (P < 0.001) for NR dams than CON after nutritional planes began. Nutritional plane did not affect (P ≥ 0.20) uterine artery hemodynamics, but all variables were affected (P ≤ 0.04) by day. Contralateral cotyledonary and placental weight were less (P ≤ 0.04) and contralateral intercotyledonary weight and number of cotyledons tended to be less (P ≤ 0.10) for NR dams than CON, but ipsilateral and whole placental weights were not affected (P ≥ 0.13). Ipsilateral placental weight as a percentage of total placental weight was greater (P = 0.03) for NR dams than CON. Whole placental cotyledonary: intercotyledonary weight was less (P = 0.01) for NR dams than CON. Placental efficiency was not affected (P = 0.89) by nutritional plane. Cotyledonary relative mRNA expression of GLUT3 and SNAT2 was greater (P ≤ 0.05) and relative expression of GLUT1, GLUT4, and NOS3 tended to be greater (P ≤ 0.07) for NR dams than CON. Nutritional plane did not affect (P ≥ 0.13) relative mRNA expression of GLUT5, 4F2hc, CAT1, LAT1, LAT2, VEGFA, FLT1, KDR, GUCY1B3, and PAG2. Despite less contralateral placental growth, beef heifers experiencing late gestational nutrient restriction maintained uterine artery blood flow and total placental mass and had 4 nutrient transporters and 1 angiogenic factor upregulated in cotyledons, all of which likely contributed to conserving fetal growth.

Nutrient requirements increase substantially during late gestation in the beef female to support fetal, uteroplacental, and mammary growth, and in the still-growing heifer, nutrients are also needed for maternal tissue growth. During pregnancy, the placenta serves as the interface for the metabolism and transport of nutrients, gases, and wastes between maternal and fetal circulations. Inadequate gestational nutrition can result in placental insufficiency and intrauterine growth restriction of the offspring, resulting in postnatal consequences. How late gestational undernutrition in beef heifers impacts the factors involved in placental nutrient transport capacity is poorly understood. We observed that late gestational nutrient restriction in heifers decreased maternal heart rate, but total uterine artery blood flow was not affected. Additionally, total placental mass was maintained, while cotyledonary expression of 4 nutrient transporters and an angiogenic factor were upregulated in placentas of nutrient restricted dams, which collectively allowed for similar calf birth weights as adequately-fed dams.

The importance of developmental programming in the beef industry.

The beef industry relies on multiple focused segments (e.g., cow-calf, stocker/feeder, and meat packing) to supply the world with beef. Thus, the potential impact of developmental programming on the beef industry needs to be evaluated with regards to the different production traits that drive profitability within each segment. For example, when nutrient restriction of dams occurred early in gestation embryo survival was decreased and the ovarian reserve of heifer progeny was negatively affected. Restriction during mid- to late gestation negatively impacted first service conception rates and pregnancy success of daughters. Even non-nutrient stress has been reported to impact transgenerational embryo development through the male progeny. Primary and secondary muscle fibers form during months two to eight (Days 60-240) of gestation. Therefore, external stimuli (nutrition or environmental) during this window have the potential to decrease the postnatal number of muscle fibers; which has an irreversible impact on animal growth and performance. Nutrient restriction during the last third of gestation resulted in decreased weaning weights, and in some instances decreased dry mater intake, hot carcass weight, and marbling scores. Protein supplementation during late gestation; however, increased weaning weight and ADG to weaning, but progeny of dams restricted in protein in late gestation had greater ribeye area. The importance of developmental programming is recognized; however, its precise application depends on comprehension of its integrated effects across the multiple-focused segments of the beef industry.

Perinatal maternal undernutrition in baboons modulates hepatic mitochondrial function but not metabolites in aging offspring.

We previously demonstrated in baboons that maternal undernutrition (MUN), achieved by 70 % of control nutrition, impairs fetal liver function, but long-term changes associated with aging in this model remain unexplored. Here, we assessed clinical phenotypes of liver function, mitochondrial bioenergetics, and protein abundance in adult male and female baboons exposed to MUN during pregnancy and lactation and their control counterparts. Plasma liver enzymes were assessed enzymatically. Liver glycogen, choline, and lipid concentrations were quantified by magnetic resonance spectroscopy. Mitochondrial respiration in primary hepatocytes under standard culture conditions and in response to metabolic (1 mM glucose) and oxidative (100 µM H2O2) stress were assessed with Seahorse XFe96. Hepatocyte mitochondrial membrane potential (MMP) and protein abundance were determined by tetramethylrhodamine ethyl ester staining and immunoblotting, respectively. Liver enzymes and metabolite concentrations were largely unaffected by MUN, except for higher aspartate aminotransferase levels in MUN offspring when male and female data were combined. Oxygen consumption rate, extracellular acidification rate, and MMP were significantly higher in male MUN offspring relative to control animals under standard culture. However, in females, cellular respiration was similar in control and MUN offspring. In response to low glucose challenge, only control male hepatocytes were resistant to low glucose-stimulated increase in basal and ATP-linked respiration. H2O2 did not affect hepatocyte mitochondrial respiration. Protein markers of mitochondrial respiratory chain subunits, biogenesis, dynamics, and antioxidant enzymes were unchanged. Male-specific increases in mitochondrial bioenergetics in MUN offspring may be associated with increased energy demand in these animals. The similarity in systemic liver parameters suggests that changes in hepatocyte bioenergetics capacity precede detectable circulatory hepatic defects in MUN offspring and that the mitochondria may be an orchestrator of liver programming outcome.