Regulation In Offspring Research Articles

PSV-3 Effects of maternal early gestational weight gain on multigenerational skeletal muscle gene regulation in offspring

Abstract Maternal nutrition during the periconceptional period may have multigenerational effects on the gene regulation of fetal skeletal muscle. This study aimed to investigate the impact of maternal rate of body weight gain (F0) during early gestation on the differential gene expression in the skeletal muscle of newborn (F1) and second-generation fetuses (F2) female offspring. To this end, crossbred Angus heifers (F0) were assigned to either a low gain (LG; 0.28 kg/d; n = 8) or moderate gain (MG; 0.79 kg/d; n = 8) group during the first 84 d of gestation. Subsequently, heifers (F0) were managed as a single group on a forage-based diet until the weaning of the F1 offspring (8 mo). The F1 heifers were estrus synchronized and bred via AI at 15 mo, and F2 fetuses were harvested on d 84 of gestation. Longissimus dorsi muscle was collected at birth (F1) and the 84-d harvest in F1 heifers and their F2 fetuses for multigenerational RNA-Seq analysis. Differentially expressed genes (DEGs) were identified using the DESeq2 R-package. Significant genes were retrieved based on P - value ≤ 0.05 and log2 fold change|0.5|. We previously reported that F1 heifers from MG dams at birth were ~2 kg heavier (P < 0.03), and herein we report the impact on the gene regulation of skeletal muscle in the F1 and F2 generations. At birth, F1 heifers from MG cows exhibited 275 DEGs, of which 98 were downregulated, and 177 genes were upregulated, related to the immune system (TNFAIP3, TLR5), cellular signaling and transduction (RASGRP2, NFE2), and extracellular matrix (TGM3, MMP17). Changes in gene expression persisted in F1 heifers through development, breeding, and until the evaluation at d 84 of gestation. At this time point, we identified 75 upregulated genes out of 177 DEGs. These genes were underlying cellular functions (USP43, PASK), hematopoiesis (THPO), metabolism, and enzymatic activity (SMOX, OAT) as possible metabolic adaptations. Similarly, 102 genes were downregulated, mainly associated with immune and inflammatory response (CHI3L1, LDAF1). Regarding the F2 fetuses, 151 DEGs were differentially expressed. Among them, 63 were upregulated in the MG group and involved with biological functions such as ion channels and transport (KCNAB1, SLC9A3), transcriptional regulation, and signaling (ZNF75D, TMEM106B, DPP6), enzymatic activity, and metabolism (B3GNT4, FAM20A, ALDH5A1, and PRSS23). Likewise, 88 downregulated genes were associated with the cell cycle and proliferation (APOOL, CIR1, and STIL). In conclusion, periconceptional maternal nutrition aimed at moderate weight gains can have multigenerational effects on the gene regulation of fetal muscle tissue.

Impact of Mid and Late-gestation Toll-like Receptor 7 Stimulation on Development and Anxiety-like Behavior in Offspring

Maternal immune activation (MIA) can occur during pregnancy due to exposure to infectious diseases or other inflammatory conditions. MIA is a risk factor for various psychiatric disorders, such as major depressive disorder, as well as cardiac disorders in the offspring. Resiquimod (R-848), a toll-like receptor (TLR) 7 agonist, induces systemic inflammatory responses and mimics responses to viral infections. Previous studies have shown that MIA with a TLR 4 agonist lipopolysaccharide or the viral mimic, TLR 3 agonist polyinosinic:polycytidylic acid produces neuropsychiatric effects in the offspring. The current project investigates the degree to which mid and late-gestation MIA with R-848 impacts offspring development and anxiety-like behavior. Pregnant rat dams received vehicle (phosphate-buffered saline) or R-848 (1 mg/kg, s.c.) injections on gestation day (GD) 14 (mid-gestation) or GD18 (late gestation). Maternal body weight as well as offspring body weight, developmental milestones, and anxiety-like behavior were assessed. Although all dams gained weight throughout pregnancy, the R-848 dams from both injection days displayed pronounced weight fluctuations post-injection, with a trend toward attenuated weight gain in dams injected in late gestation. On postnatal day 21 (PND21), the R-848 dams injected on GD14 had significantly lower body weights (p=0.007) compared to the vehicle dams, whereas the body weights of the R-848 dams injected on GD18 did not differ significantly from the vehicles. Litter size, male-to-female ratio, and birth weight were also not affected by R-848. Semi-weekly offspring weights were not statistically different between any experimental groups by sex during any measured week in the mid-gestation-exposed cohort, but both male and female R-848-exposed offspring in the late-gestation exposure cohort displayed significantly decreased body weights at week 7 (males, p=0.0282 and females, p=0.0009). Eye opening, an important developmental milestone, was not different between the vehicle and R-848 pups regardless of the timing of exposure. Open field testing in the mid-gestation-exposed adult offspring revealed no significant locomotion differences or differences in time spent in the center zone. Open field testing in the late-gestation-exposed adult offspring also revealed no locomotion differences, however, the R-848-exposed female offspring spent markedly less time in the center zone than all other groups. These findings suggest that late gestation R-848 exposure results in attenuated maternal weight gain as well as increased anxiety-like behaviors in female offspring. Future exploration of pre-pubertal stages and assessments of autonomic regulation in offspring exposed to R-848 in late gestation will provide further insight into the long-term consequences of immune activation during pregnancy. NIH U54 MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Discussion around SSRIs and pregnancy still leans toward treatment

Last year a seminal study, “Prenatal antidepressant exposure and offspring brain morphologic trajectory” by Dojukan Koc, M.D., and colleagues was published in JAMA Psychiatry. The cohort study results suggested that there may be an association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and changed brain regions involved in emotional regulation in offspring; however, in some brain regions such as the amygdala, the changes disappeared by age 15. The Koc study included a total of 2,198 mother‐child dyads; compared to nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter, and a steeper increase in amygdala volume and gyrus from 7 to 15 years of age. Changes in the amygdala and fusiform gyrus did not persist until early adolescence. Postnatal depression in the mother was associated with a reduced fusiform gyrus in the offspring; prenatal depression was aassociated with a smaller volume of the rostral anterior cingulate gyrus in the child. There was no association of SSRI use before pregnancy with brain outcomes in offspring. The Koc study was notable for its long follow‐up of brain growth, allowing for a focus on trajectory and not just a single image.

Pembinaan Masyarakat Awam dalam Penggunaan Alat Kontrasepsi di Desa Samiran

The use of a computerized system to determine the number of children and the severity of their illness is called a family plan. Allowed family planning is an effort to regulate or thin out births or an effort to prevent pregnancy temporarily with the agreement of husband and wife due to certain situations and conditions for the benefit of the family, society, and the state, thus family planning here has the same meaning as regulation of offspring. The goal after a brief coaching is expected to increase knowledge and understanding in choosing contraceptives according to needs and as an effort to make the government's program to have 2 children better. The activities carried out in the form of coaching and brief socialization using Manikin and leaflets. The results of fostering family planning acceptors are able to increase mother's knowledge in choosing types of contraception and understand the advantages and disadvantages of each contraceptive. The conclusion in this community service is that the mother's knowledge of contraceptives increases so that she can choose the right contraceptive.

31.2 Objectively Assessed Sleep, Physical Activity, and Circadian Rhythmicity and Their Association With Mood Regulation in Offspring of Parents With Mood Disorders

31.2 Objectively Assessed Sleep, Physical Activity, and Circadian Rhythmicity and Their Association With Mood Regulation in Offspring of Parents With Mood Disorders

Prenatal Antidepressant Exposure and Offspring Brain Morphologic Trajectory

Clinical decision-making on antidepressant treatment during pregnancy, particularly selective serotonin reuptake inhibitors (SSRIs), is challenging, as both prenatal SSRI exposure and maternal depressive symptoms may be associated with negative outcomes in offspring. To investigate the association between intrauterine SSRI exposure and maternal depressive symptoms and structural brain development in offspring from mid-childhood to early puberty. This prospective, population-based cohort study was embedded in the Generation R Study in Rotterdam, the Netherlands. All pregnant individuals with an expected delivery date between April 1, 2002, and January 31, 2006, were invited to participate. Data were analyzed from February 1 to September 30, 2022. Maternal-reported SSRI use verified by pharmacy records. In mid-pregnancy and 2 and 6 months after delivery, participants reported depressive symptoms using the Brief Symptom Inventory and were divided into 5 groups: SSRI use during pregnancy (n = 41; 80 scans), SSRI use only before pregnancy (n = 77; 126 scans), prenatal depressive symptoms without prenatal SSRI use (n = 257; 477 scans), postnatal depressive symptoms only (n = 74; 128 scans), and nonexposed control individuals (n = 2749; 4813 scans). The main outcome was brain morphometry in offspring, including global and cortical brain volumes, measured at 3 magnetic resonance imaging assessments from 7 to 15 years of age. The study included 3198 mother-child dyads. A total of 3198 mothers (100%) identified as women; mean (SD) age at intake was 31.1 (4.7) years. Children (1670 [52.2%] female) underwent brain imaging assessment from 7 to 15 years of age with 5624 total scans. Most brain gray matter volumes showed an inverted U-shaped trajectory. Compared with nonexposed controls, children prenatally exposed to SSRIs had less cerebral gray matter (β [SE], -20 212.2 [7285.6] mm3; P = .006), particularly within the corticolimbic circuit, which persisted up to 15 years of age. Children exposed to SSRIs prenatally showed a steeper increase in volumes of the amygdala (age interaction: β [SE], 43.3 [13.4] mm3; P = .006) and fusiform gyrus (age interaction: β [SE], 168.3 [51.4] mm3; P = .003) from 7 to 15 years of age. These volumetric differences in the amygdala and fusiform observed in childhood did not persist until early adolescence. Prenatal depression was associated with a smaller volume in the rostral anterior cingulate gyrus (β [SE], -166.3 [65.1] mm3; P = .006), and postnatal depression was associated with a reduced fusiform gyrus (β [SE], -480.5 [189.2] mm3; P = .002). No association of SSRI use before pregnancy with brain outcomes was observed. The results of this cohort study suggest that prenatal SSRI exposure may be associated with altered developmental trajectories of brain regions involved in emotional regulation in offspring. Further research on the functional implications of these findings is needed.

Effect of maternal periconceptional undernutrition in sheep on cortisol regulation in offspring from mid-late gestation, through to adulthood.

Maternal periconceptional undernutrition (PCUN) alters fetal hypothalamic-pituitary-adrenal axis (HPAA) function and placental glucocorticoid metabolism in sheep. The effects of PCUN on HPAA function in adult life are not known. We investigated the effects of PCUN on fetal adrenal development across gestation and on cortisol regulation in adult offspring. Ewes were undernourished from 61 days before to 30 days after conception ('PCUN') or fed ad libitum ('N'). mRNA expression in the fetal adrenal gland of ACTH receptor (ACTHR), steroidogenic acute regulatory protein (STAR), cytochrome P450 17A1 (CYP17A1), 11beta-hydroxysteroid-dehydrogenase type 2 (11βHSD2), insulin-like growth factor-2 (IGF2), and in the fetal hippocampus of 11βHSD1, 11βHSD2, mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) was determined at 50 (adrenal only), 85, 120 and 131 days of gestation (term=148 days). In adult offspring (≥ 3 years, N; 10 female, 5 male, PCUN; 10 female, 10 male) a combined arginine vasopressin (AVP, 0.1 μg/kg) and corticotropin-releasing hormone (CRH, 0.5 μg/kg) challenge and a metyrapone (40 mg/kg) challenge were undertaken. mRNA expression of ACTHR, STAR and CYP17A1 were determined in adult adrenals. Fetal adrenal STAR, CYP17A1 and IGF2 mRNA expression were not different between groups in early gestation but were higher in PCUN than N at 131 days' gestation (all p<0.01). PCUN reduced fetal hippocampal MR and GR mRNA expression by 50% at 85 day, but not in later gestation. Adult offspring plasma cortisol responses to AVP+CRH or metyrapone were not different between groups. Plasma ACTH response to AVP+CRH was lower in PCUN males but ACTH response to metyrapone was not different between groups. Adult adrenal ACTHR, STAR, and CYP17A1 mRNA expression were not affected by PCUN. We conclude that the effects of PCUN on fetal HPAA function that became apparent in late gestation, are not reflected in adrenal cortisol secretion in mid-adulthood.

The Endocrine–Metabolic Axis Regulation in Offspring Exposed to Maternal Obesity—Cause or Consequence in Metabolic Disease Programming?

Obesity incidence is rising worldwide, including women of reproductive age, contributing to increased gestations in which Maternal Obesity (MO) occurs. Offspring born to obese mothers present an increased predisposition to develop metabolic (e.g., obesity, diabetes) and cardiovascular disease (CVD). The developmental programming of the metabolic dysfunction in MO offspring can initiate in utero. The different availability of metabolic substrates, namely glucose, can modulate cellular growth, proliferation, and differentiation, resulting in different levels of tissue maturation and function. We defined the remodelling of these early processes as the first hit of metabolic disease programming. Among these, adipocyte early differentiation and gut dysbiosis are initial repercussions occurring in MO offspring, contributing to -tissue-specific dysfunction. The second hit of disease programming can be related to the endocrine–metabolic axis dysregulation. The endocrine–metabolic axis consists of multi-organ communication through the release of factors that are able to regulate the metabolic fate of cells of organs involved in physiological metabolic homeostasis. Upon adipose tissue and gut early dysregulation, these organs’ endocrine function can be programmed to the disrupted release of multiple factors (e.g., adiponectin, leptin, glucagon-like peptide). This can be perceived as a natural mechanism to overcome metabolic frailty in an attempt to prevent or postpone organ-specific disease. However, the action of these hormones on other tissues may potentiate metabolic dysfunction or even trigger disease in organs (liver, pancreas, heart) that were also programmed in utero for early disease. A second phase of the endocrine–metabolic dysregulation happens when the affected organs (e.g., liver and pancreas) self-produce an endocrine response, affecting all of the involved tissues and resulting in a new balance of the endocrine–metabolic axis. Altogether, the second hit exacerbates the organ-specific susceptibility to disease due to the new metabolic environment. The developmental programming of the endocrine–metabolic axis can start a vicious cycle of metabolic adaptations due to the release of factors, leading to an endocrine response that can jeopardize the organism’s function. Diseases programmed by MO can be boosted by endocrine dysregulation, namely Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Pancreas Disease, and the aggravation of the adipose tissue and gut dysfunction. Chronic metabolic dysregulation can also predispose MO offspring to CVD through the modulation of the endocrine environment and/or the metabolic status. To cease the vicious cycle of MO disease transmission among generations and-provide preventive and specialized prenatal and postnatal care to MO offspring, it is necessary to understand the molecular mechanisms underlying the MO-related disease development. In this review, we summarize most of the developmental programming molecular events of the endocrine–metabolic axis described on the offspring exposed to MO, providing a brief overview of the potential mechanisms that predispose MO offspring to metabolic disease, and discuss the programming of the endocrine–metabolic axis as a plausible mechanism for metabolic disease predisposition in MO offspring.

119 Randel Lectureship: The Role of Maternal Nutrition in Developmental Programming Using a Sheep Model

Abstract Appropriate nutrition during gestation is critical for optimal fetal development and life-long health. Poor nutrition during gestation, defined as excess or restricted nutrition, can lead to altered growth and metabolic dysregulation in the offspring. Using a sheep model, we have demonstrated that both restricted- and over-feeding alter offspring growth, impair muscle growth, increase fat accumulation, alter circulating growth and metabolic hormones, and alter mRNA expression of genes involved in myogenesis, lipogenesis, inflammation, and glycogen metabolism. More importantly, these negative impacts of poor maternal nutrition persist through adulthood, and can be passed to subsequent generations. Using omics approaches, we have begun to elucidate the mechanisms by which maternal diet impacts developmental programming and contributes to these persistent effects. In offspring from restricted-fed mothers, fetal liver and muscle morphology demonstrated impaired growth and alterations in key metabolites in methionine, betaine, and bile salt pathways. In offspring from both restricted- and over-fed mothers, global metabolomics demonstrated altered lipid and protein metabolism profiles. These changes in metabolites likely contribute to maternal programming of offspring growth and metabolism including efficiency of energy utilization. In addition to changes in key genes involved in growth, lipid accretion, and protein synthesis, preliminary studies suggest these persistent effects may be due to changes epigenetic regulation in offspring. Using the sheep model of both restricted- and over-feeding we, and others, have demonstrated that the negative effects of poor maternal nutrition affect multiple key metabolic tissues during fetal development and that these changes persist into maturity. Therefore, the focus of our current studies is to determine the multigenerational impacts of poor maternal nutrition on offspring growth and health and elucidate the mechanisms that contribute to these persistent changes.

Choline and Folic Acid Balance in Diets During Pregnancy Programs Food Intake Regulation in Wistar Rat Offspring (FS08-05-19)

ObjectivesHigh gestational folic acid (FA) induces an obesogenic phenotype in male Wistar rat offspring. Imbalances between FA and other methyl-nutrients (i.e., choline) leading to perturbations in the 1-carbon cycle may account for the effects of high FA diets. Canadian women consume high (2–7-fold) intakes of FA, but most are not meeting recommended adequate intakes for choline. Choline is also absent from Canadian prenatal supplements. The objective of this study is to evaluate the effects of the interaction between choline and FA in maternal diets of rats on the 1-carbon cycle, and the programming of food intake, body weight gain and biomarkers of obesity in the offspring later in life. MethodsPregnant Wistar rat dams were fed the AIN-93 G diet with recommended (1X) choline and FA (RCRF, control), or a 5X FA diet with either 0.5X choline (LCHF), 1X choline (RCHF), or 2.5X choline (HCHF). Brain and blood were collected at birth. At weaning one male pup/dam from all groups was maintained on the control diet for 20 weeks then terminated. Dependent measures include weekly body weight-gain and food intake, plasma glucoregulatory hormones and 1-carbon metabolites at birth and post-weaning. ResultsIncreasing choline content to 2.5-fold in a high (5-fold) gestational FA diet (HCHF) led to lower plasma insulin and leptin levels at birth compared to the LCHF and RCHF diets, respectively (P < 0.05). It also led to lower (25%, P = 0.03) plasma 5-methyltetrahydrofolate concentrations at birth compared to the RCHF diet, suggesting more efficient utilization of FA. Offspring born to dams maintained on a high folic acid diet with either low or recommended choline had higher weekly food intake (6%, P < 0.05) and body weight-gain (9%, P < 0.01). In contrast, offspring from dams fed the HCHF gestational diet were not different from those born to dams fed the RCRF (control) diet, highlighting the mitigating effects of a balanced choline and FA gestational diet. ConclusionsIncreased intakes of choline mitigate the effects of high FA diets. Maternal dietary choline interacts with FA on the long-term programming of food intake regulation in the offspring; emphasizing a need for more attention to improving choline intakes by women of child-bearing age. Funding SourcesThis research was funded by the Canadian Institute of Health Research, Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD).

Modulation of neural regulators of energy homeostasis, and of inflammation, in the pups of mice exposed to e-cigarettes

BackgroundMaternal smoking can lead to perturbations in central metabolic regulators such as neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) signalling components in offspring. With the growing interest in e-cigarettes as a tobacco replacement, this short report assessed central metabolic regulation in offspring of mouse dams exposed to e-cigarettes. We examined the impact of continuous use of e-cigarettes, and e-cigarette replacement of tobacco cigarettes during pregnancy. Supplementation of an antioxidant l-carnitine was also co-used with tobacco cigarette in the mother to determine whether the impact of maternal tobacco smoking was oxidative stress driven. MethodsBalb/c mice were exposed to either nicotine-containing (E-cig18) or nicotine-free (E-cig0) e-cigarette aerosols or tobacco smoke (SE) prior to mating and until their pups were weaned. After mating, two SE sub-groups were changed to E-cig18 exposure (Replacement), or supplementation l-carnitine while SE was continued. Male offspring were studied at weaning age. ResultsThe offspring of E-cig0 dams were the heaviest with the most body fat. Replacing SE with E-cig18 during pregnancy resulted in offspring with significantly less body fat. E-cig0 offspring had significantly increased mRNA expression of brain NPY and iNOS. Maternal SE upregulated mRNA expression of NPY, NPY Y1 receptor, POMC downstream components, and iNOS expression, which were normalised in Replacement offspring, but only partially normalised with maternal L-carnitine supplementation during gestation and lactation. ConclusionsMaternal exposure to either tobacco and nicotine-free e-cigarettes lead to disturbances in the level of central homeostatic control markers in offspring, suggesting that maternal exposure to e-cigarettes is not without risks.

Maternal emotion dysregulation and the functional organization of preschoolers’ emotional expressions and regulatory behaviors.

Although psychopathology in mothers is known to be a significant risk factor for child outcomes, less is known about how emotion dysregulation, a transdiagnostic feature that cuts across many diagnoses, shapes emotion-related parenting practices and the development of emotion regulation in offspring. Building upon previous research that examined the functional relations between emotions and regulatory actions in children, we sought to examine the association of maternal emotion dysregulation and emotion socialization with these functional links in an at-risk community sample of mother-preschooler (children ages 36-60 months) dyads that oversampled for mothers with elevated symptoms of borderline personality disorder (n = 68). We found that maternal emotion dysregulation was associated with children displaying more sadness and engaging in less problem solving during the Locked Box Task, which is designed to elicit anger. Maternal emotion dysregulation was also associated with children being more distracted and talking less in the context of sadness. Maternal nonsupportive emotion socialization responses were associated with children engaging in more defiant behaviors throughout the task and using less problem solving in the context of happiness, whereas maternal supportive emotion socialization responses were associated with more play throughout the task and less talking in the context of sadness, above and beyond the effect of maternal emotion dysregulation. These findings indicate that maternal emotion dysregulation and nonsupportive emotion socialization practices are both meaningfully associated with the development of aberrant patterns of emotional and behavioral responding during the preschool years. (PsycINFO Database Record

Mapping Alterations to the Endogenous Elemental Distribution within the Lateral Ventricles and Choroid Plexus in Brain Disorders Using X-Ray Fluorescence Imaging.

The choroid plexus and cerebral ventricles are critical structures for the production of cerebral spinal fluid (CSF) and play an important role in regulating ion and metal transport in the brain, however many aspects of its roles in normal physiology and disease states, such as psychiatric illness, remain unknown. The choroid plexus is difficult to examine in vivo, and in situ ex vivo, and as such has typically been examined indirectly with radiolabeled tracers or ex vivo stains, making measurements of the endogenous K+, Cl−, and Ca+ distributions unreliable. In the present study, we directly examined the distribution of endogenous ions and biologically relevant transition metals in the choroid plexus and regions surrounding the ventricles (ventricle wall, cortex, corpus callosum, striatum) using X-ray fluorescence imaging (XFI). We find that the choroid plexus was rich in Cl− and Fe while K+ levels increase further from the ventricle as Cl− levels decrease, consistent with the known role of ion transporters in the choroid plexus CSF production. A polyI:C offspring displayed enlarged ventricles, elevated Cl− surrounding the ventricles, and intraventricular calcifications. These observations fit with clinical findings in patients with schizophrenia and suggest maternal treatment with polyI:C may lead to dysfunctional ion regulation in offspring. This study demonstrates the power of XFI for examining the endogenous elemental distributions of the ventricular system in healthy brain tissue as well as disease models.

Let-7 miRNA profiles are associated with the reversal of left ventricular hypertrophy and hypertension in adult male offspring from mothers undernourished during pregnancy after preweaning growth hormone treatment.

Maternal undernutrition (UN) is known to cause cardiac hypertrophy, elevated blood pressure, and endothelial dysfunction in adult offspring. Maternal UN may also lead to disturbances in GH regulation in offspring. Because GH plays a key role in cardiac development, we used a model of maternal UN to examine the effects of neonatal GH treatment on cardiac hypertrophy, cardiac micro RNA (miRNA) profiles, and associated gene regulation in adult offspring. Female Sprague-Dawley rats were fed either a standard control diet (CON) or 50% of CON intake throughout pregnancy (UN). From neonatal day 3 until weaning (d 21), CON and UN pups received either saline (S) (CON-S, UN-S) or GH (2.5 μg/g·d) (CON-GH, UN-GH). Heart structure was determined by hematoxylin and eosin staining, and miRNA was isolated from cardiac tissue and miRNA expression analyzed using Cardiovascular miRNA gene Arrays (SABiosciences Ltd). Maternal UN caused marked increases in cardiac hypertrophy and left ventricular cardiomyocyte area, which were reversed by preweaning GH treatment. Systolic blood pressure was increased in UN-S groups and normalized in UN-GH groups (CON-S 121 ± 2 mmHg, CON-GH 115 ± 3 mm Hg, UN-S 146 ± 3 mmHg, and UN-GH 127 ± 2 mmHg). GH treatment during early development facilitated a reversal of pathological changes in offspring hearts caused by UN during pregnancy. Specific cardiac miRNA profiles were exhibited in response to maternal UN, accompanied by up-regulation of the lethal-7 (LET-7) miRNA family in GH-treated offspring. miRNA target analysis revealed a number of genes associated with inflammation and cardiovascular development, which may be involved in the altered cardiac function of these offspring. Up-regulation of the LET-7 family of miRNAs observed in GH groups may mediate the reversal of cardiac hypertrophy observed in adult offspring males of UN mothers.

Maternal high fat diet programming of the endocrine system

Maternal high fat diet programming of the endocrine system

Maternal Immunization Affects In Utero Programming of Insulin Resistance and Type 2 Diabetes

Maternal immunization with oxidized lipoproteins prior to pregnancy protects against atherogenic in utero programming by gestational hypercholesterolemia and enhances beneficial lymphocyte-dependent immune responses in offspring. To determine whether in utero programming and immunomodulation also affect insulin resistance (IR) and type 2 diabetes, we investigated the effects of immunization on glucose and insulin responses in LDL receptor-deficient mice fed regular or 60% sucrose diets, as well as in offspring fed 0.5% cholesterol or 60% sucrose diets. IR was assessed by fasting glucose and insulin levels, oral glucose tolerance tests, glucose clamps, pancreatic immunohistochemistry and plasma free fatty acid concentrations. Immunizations improved glucose responses in both genders and protected both immunized mice and their offspring against IR and type 2 diabetes. Protection occurred even under euglycemic conditions, but was greatest in obese males exposed to very obesogenic/diabetogenic conditions. Hyperinsulinemic euglycemic clamps confirmed that maternal immunization protected mainly by reducing IR, but pancreatic immunocytochemistry also indicated some protection against beta cell damage. Maternal immunization was associated with marked regulation in offspring of 4 genes relevant to diabetes and 19 genes of importance for oxidative stress, as well as increased hepatic activities of key antioxidant enzymes. These findings establish that targeted immunomodulation may be used to protect immunized subjects and their offspring against IR and type 2 diabetes, and thus to reduce cardiovascular risk. They also support the notion that in utero programming influences offspring disease not by a single mechanism, but by multiple systemic effects.

High multivitamin intakes during pregnancy and postweaning obesogenic diets interact to affect the relationship between expression of PPAR genes and glucose regulation in the offspring

High multivitamin intake (HV) during pregnancy increases body fat and weight and alters glucose and fatty acid metabolism in Wistar rat offspring. This study investigated the expression of peroxisome-proliferator activated receptors (PPARs) genes involved in regulation of glucose and fatty acid metabolism in their tissues. Dams received the AIN-93G diet with either the regular (RV) or 10-fold multivitamins (HV) during pregnancy. Male offspring were weaned to either the RV diet (RV-RV and HV-RV) or an obesogenic diet (RV-Ob and HV-Ob). Gene expression of PPARs in tissues was analyzed by real-time reverse transcriptase polymerase chain reaction. Gestational diet (GD) did not affect PPARs gene expression in offspring at either birth or weaning. In liver, at 14 weeks postweaning, PPAR-γ was 30% lower in the HV-RV and 30% higher in HV-Ob than in the RV-RV group [GD P=.76, postweaning diet (PD) P=.19, interaction P=.02, by two-way analysis of variance]. In muscle, PPAR-α expression was affected by GD and PD (GD P=.05, PD P<.01, interaction P=.07). In adipose tissue, PPAR-α expression was higher in all groups compared to RV-RV (GD P=.25, PD P=.85, interaction P=.03). PPAR-γ mRNA levels correlated with abdominal fat (r=0.45, P<.05) and insulin resistance index (r=0.39, P<.05). In liver, PPAR-γ expression correlated with insulin resistance index in offspring from RV (r=−0.62, P<.05), but not in those from HV dams (r=0.13, P>.05). In conclusion, the HV diet during pregnancy interacts with postweaning diets in determining the expression of PPARs genes in a tissue- and age-dependent manner and uncouples the relationship between these genes and glucose regulation and fat mass in the rat offspring.

Effect of protein source in diets fed during gestation and lactation on food intake regulation in male offspring of Wistar rats

We hypothesized that protein source in the nutritionally adequate AIN-93G diets fed during gestation, lactation, and weaning influences food intake (FI) regulation in male offspring of Wistar rats. Pregnant rats were fed the recommended casein-based (C) or soy protein-based (S) diet during gestation (experiment 1) or during gestation and lactation (experiment 2). Pups (n = 12 per group) weaned to C or S diets were followed for 9 wk (experiment 1) or 14 wk (experiment 2). At termination, body weight was 5.4% and 9.4% higher, respectively, in offspring of dams fed the S diet. Altered FI regulation was shown by failure of devazepide (a CCK-A receptor blocker) to block FI reduction after protein preloads in offspring of S diet-fed dams, whereas it had a strong effect on offspring of C diet-fed dams (P < 0.005). Similarly, naloxone (an opioid receptor blocker) blocked FI reduction more after casein than after soy protein preloads (P < 0.01). In experiment 2, offspring of dams fed the S diet had higher hypothalamic gene expression of agouti related protein at weaning (P < 0.05), and higher FI was found throughout postweaning (P < 0.0001). FI reduction after protein preloads at week 7 and after glucose preloads at week 13 was greater in offspring of C diet-fed dams (P < 0.05). Plasma insulin at weaning and insulin, ghrelin, and glucagon-like peptide-1 at week 15 were higher in offspring of S diet-fed dams (all P < 0.05). In conclusion, nutritionally complete C and S diets consumed during gestation and lactation differ in their effects on body weight and FI regulation in the offspring. Extending the diet from gestation alone to throughout gestation and lactation exaggerated the adverse effects of the S diet. However, the diet consumed postweaning had little effect on the outcome.

Effects of prenatal stress on cardiovascular regulation in offspring

Certain prenatal disorders increase risk for cardiovascular disease in adult offspring. We tested the effect of reduced uterine perfusion (RUP) during pregnancy on arterial pressure (AP), baroreflex and stress regulation in adult rat offspring.Uterine vessels were clipped (RUP) on gestational day 14. Resting AP, baroreflex control of heart rate (HR), and AP, HR and glucose and corticosterone (cort) responses to 60‐min. restraint stress were measured in conscious chronically instrumented offspring. Baroreflex control of renal sympathetic nerve activity (RSNA) was assessed in anesthetized offspring.Resting AP was ~10mmHg higher in RUP offspring from 8–12wks in males and 8–20 wks in females. Baroreflex control of HR and RSNA was similar in all groups of 8wk offspring. AP and HR at 10 and 60 min. of restraint were also similar among offspring groups. Glucose levels after 10 min. of restraint were lower in RUP male offspring, and plasma cort was lower after 60 min in this group compared with control male offspring. The cort response to stress peaked at a higher level in RUP female offspring at 10 min. and remained higher than control at 60 min (~140ug/dl).Resting AP is modestly increased in adult male and female RUP offspring. Baroreflex regulation of HR and RSNA does not appear to be adversely affected in these rats. Results suggest sex differences in metabolic and hormonal responses to stress in RUP offspring. NIH NR04184.

Concomitant Impairment in Endothelial Function and Neural Cardiovascular Regulation in Offspring of Type 2 Diabetic Subjects

Endothelial function is impaired in first-degree relatives (FDRs) of patients with type 2 diabetes. Many states characterized by endothelial dysfunction are associated with increased cardiovascular sympathetic outflow. In this study, we investigated endothelial and autonomic nervous system (ANS) functioning in FDRs and tested the hypothesis that in basal condition, impaired endothelial function is associated with impaired cardiovascular ANS regulation. Flow-mediated endothelium-dependent and -independent vasodilation of the brachial artery was measured with high-resolution ultrasound in 27 otherwise healthy FDRs (14 men and 13 women; mean age 32 years) with normal oral glucose tolerance and in 15 age- and gender-matched control subjects. Cardiovascular ANS regulation was investigated by means of spectral analysis of heart rate and systolic blood pressure (SBP) variability. Baroreflex sensitivity was assessed by the spontaneous baroreflex sequences technique. Flow-mediated endothelium-dependent vasodilation was 9.4+/-1.0% in FDRs and 17.0+/-2.3% in control subjects (P=0.001). Low-frequency oscillations in SBP variability were 8.6+/-2.8 and 2.8+/-0.6 mm Hg in FDRs and controls, respectively (P=0.04). Baroreflex sensitivity was significantly less in FDRs than controls (22.8+/-2.7 versus 37.0+/-5.8, respectively; P=0.01). Change in vessel diameter was inversely correlated with the low-frequency component of SBP variability (r=-0.40; P=0.014). In healthy FDRs of diabetic patients there is a concomitant, possibly related, impairment in endothelial and ANS functioning, which manifests, indirectly, with increase in vascular sympathetic outflow and a depressed baroreflex, vagal, control of heart rate.