Dysfunction In Offspring Research Articles

Pregnancy in obese women and mechanisms of increased cardiovascular risk in offspring

Abstract Pregnancy complicated by maternal obesity contributes to an increased cardiovascular risk in offspring, which is increasingly concerning as the rates of obesity and cardiovascular disease are higher than ever before and still growing. There has been much research in humans and preclinical animal models to understand the impact of maternal obesity on offspring health. This review summarizes what is known about the offspring cardiovascular phenotype, describing a mechanistic role for oxidative stress, metabolic inflexibility, and mitochondrial dysfunction in mediating these impairments. It also discusses the impact of secondary postnatal insults, which may reveal latent cardiovascular deficits that originated in utero. Finally, current interventional efforts and gaps of knowledge to limit the developmental origins of cardiovascular dysfunction in offspring of obese pregnancy are highlighted.

Pre-pregnancy and gestational interventions to prevent childhood obesity.

Childhood obesity is a significant global health issue with complex and multifactorial origins, often beginning before conception and influenced by both maternal and paternal health. The increased prevalence of pre-pregnancy obesity and gestational diabetes mellitus in women of reproductive age contributes to a heightened risk of metabolic dysfunction in offspring. Current clinical practices often implement lifestyle interventions after the first trimester, and have limited success, implying that they miss a critical window for effective metabolic adjustments. This review examines the limitations of lifestyle interventions during pregnancy in improving perinatal outcomes and highlights the importance of initiating such interventions before conception to positively impact parental health and fetal development. A re-evaluation of strategies is needed to enhance the metabolic health of prospective parents as a preventive measure against childhood obesity.

The High Estradiol Environment after IVF Causes the Increased Risk of Glucose Metabolic Dysfunction in Offspring.

Assisted reproductive technology (ART) is associated with increased metabolic risks in offspring. The effect of high maternal estradiol (E2) levels during early pregnancy on the glucose metabolism of offspring remains unclear. To evaluate glucose metabolism in in vitro fertilization (IVF)-conceived children and assess whether high E2 exposure during early pregnancy is associated with metabolic alterations. This retrospective analysis included 500 singletons aged 3-10 years born after fresh embryo transfer (ET) (n=200), frozen ET (n=100), and natural conception (NC) (n=200) from a university hospital. Children underwent anthropometric measurements and examinations for fasting glucose, insulin, and lipid levels. A mouse model of high E2 exposure during early pregnancy was established to study glucose and insulin tolerance, and insulin secretion. Compared with NC, children born after fresh ET showed higher fasting glucose/insulin levels, increased insulin resistance, and higher incidence of impaired fasting glucose, which might be associated with a higher maternal E2 levels. Frozen ET showed intermediate results. In mice, offspring exposed to high E2 levels during gestation exhibited impaired glucose/insulin tolerance and defects in insulin secretion. High maternal E2 levels in early pregnancy are associated with altered glucose metabolism and increased metabolic risks in IVF-conceived children. Further studies are needed to elucidate the underlying mechanisms.

CHANGES IN THE CONTENT AND ACTIVITY OF MUSCLE PROTEINS AS A MARKER IN THE CASE OF EXPOSURE TO IONIZING RADIATION IN ANIMALS

Objective. To find out the specifics of muscle tissue contraction under the conditions of exposure to low doses of ionizing radiation in parents and their irradiated offspring by evaluating changes in the content of contractile proteins and ATPase activity of skeletal and cardiac muscles. Methods. Experimental studies were conducted on 50 rats. Animals were randomized as follows: group 1 — intact sexually mature rats; 2 — sexually mature animals irradiated with a dose of 1.0 Gy; group 3 — monthold rats obtained from intact individuals; group 4 — month-old rat pups obtained from parents irradiated with a dose of 1.0 Gy; group 5 — month-old rats obtained from animals irradiated with a dose of 1.0 Gy, which were irradiated at the same dose. The results. Muscle dysfunction in irradiated offspring and parents is manifested by a decrease in the content of contractile proteins, functional dysfunction of the actomyosin bridge, and a decrease in the ATPase activity of contractile proteins. Marked muscle dysfunctions during the post-radiation time period may be the reason for the formation of orthopedic pathology in a significant contingent of irradiated persons. Conclusions. The expression of muscle dysfunction in the offspring of irradiated animals, which were also exposed to ionizing radiation, is greater than the corresponding processes in their irradiated parents, which indicates the mediation of muscle dysfunction in the second generation of irradiated animals by epigenetic mechanisms. Marked muscle dysfunctions during the post-radiation time period may be the reason for the formation of orthopedic pathology in a significant contingent of irradiated persons

Intergenerational neurotoxicity of polystyrene nanoplastics in offspring mice is mediated by dysfunctional microbe-gut-brain axis

Nanoplastics (NPs) are ubiquitous in daily life, posing potential risks to the environment and human. While their negative effects on parental organisms have been extensively studied, intergenerational effects are still in the early stages of investigation. Here, we aimed to investigate the impact of maternal exposure to an environmentally relevant level of polystyrene NPs (PSNPs, 100 nm) during gestation and lactation (∼32 days, 50 μg/mouse/day) on neurotoxicity mediated by the microbe-gut-brain axis in offspring mice. Maternal PSNPs exposure significantly increased brain TNF-α level and microglia by 1.43 and 1.48 folds respectively, compared to control, accompanied by nuclear pyknosis and cell vacuolization in cortex and hippocampus. Targeted neurotransmitter metabolomics analysis revealed dysregulation in dopamine and serotonin metabolism. Specifically, dopamine levels increased significantly from 0.007 ng/L to 0.015 ng/L, while N-acetylseroton and 3,4-dihydroxyphenylacetic acid decreased significantly from 0.002 and 0.929 ng/L to 0.001 and 0.680 ng/L, respectively. Through a combination of 16S rRNA sequencing and biochemical analysis, we discovered that maternal PSNPs exposure led to a depletion of anti-inflammatory bacteria and an enrichment of pro-inflammatory bacteria resulting in intestinal barrier damage, elevated levels of lipopolysaccharide in blood, and subsequent activation of neuroinflammation. Meanwhile, gut bacteria dysbiosis interfered with communication between gut and brain by dysregulating neurotransmitter synthesis, as evidenced by significant associations between neurotransmitter-related bacteria (Akkermansia, Family_XIII_AD3011_group, Lachnoclostridium) and dopamine/serotonin related metabolites. Furthermore, transcriptional alterations in dopamine and serotonin related pathways were observed in the enteric nervous system, suggesting abnormal signal transduction from gut to brain contributes to neurotoxicity. This study provides new insights into NPs-induced neurotoxicity within the context of microbe-gut-brain axis and highlights the risk of cerebral dysfunction in offspring with maternal NPs exposure.

Glucose intolerance as a consequence of hematopoietic stem cell dysfunction in offspring of obese mice

ObjectiveMaternal obesity is increasingly common and negatively impacts offspring health. Children of mothers with obesity are at higher risk of developing diseases linked to hematopoietic system abnormalities and metabolism such as type 2 diabetes. Interestingly, disease risks are often dependent on the offspring's sex, suggesting sex-specific reprogramming effect of maternal obesity on offspring hematopoietic stem and progenitor cell (HSPC) function. However, the impact of maternal obesity exposure on offspring HSPC function, and the capability of HSPC to regulate offspring metabolic health is largely understudied. This study aims to test the hypothesis that offspring of obese mice exhibit sex-differences in HSPC function that affect offspring's metabolic health. MethodsWe first assessed bone marrow hematopoietic stem and progenitor cell phenotype using postnatal day 21 (P21) and 8-week-old C57BL/6J mice born to control and diet-induced obese dams. We also sorted HSPC (Lineage-, Sca1+, cKit + cells) from P21 mice for competitive primary and secondary transplant, as well as transcriptomic analysis. Body weight, adiposity, insulin tolerance test and glucose tolerance tests were performed in primary and secondary transplant recipient animals. ResultsWe discovered sex-differences in offspring HSPC function in response to maternal obesity exposure, where male offspring of obese dams (MatOb) showed decreased HSPC numbers and engraftment, while female MatOb offspring remained largely unaffected. RNA-seq revealed immune stimulatory pathways in female MatOb offspring. Finally, only recipients of male MatOb offspring HSPC exhibited glucose intolerance. ConclusionsThis study demonstrated the lasting effect of maternal obesity exposure on offspring HSPC function and implicates HSPC in metabolic regulation.

Acetylcholinesterase Inhibitor Ameliorates Early Cardiometabolic Disorders in Fructose-Overloaded Rat Offspring.

We investigate the role of galantamine on autonomic dysfunction associated with early cardiometabolic dysfunction in the offspring of fructose-overloaded rats. Wistar rats received fructose diluted in drinking water (10%) or water for 60 days prior to mating. Fructose overload was maintained until the end of lactation. The offspring (21 days after birth) of control and fructose-overloaded animals were divided into three groups: control (C), fructose (F) and fructose + galantamine (GAL). GAL (5 mg/kg) was administered orally until the offspring were 51 days old. Metabolic, hemodynamic and cardiovascular autonomic modulation were evaluated. The F group showed decreased insulin tolerance (KITT) compared to the C and GAL groups. The F group, in comparison to the C group, had increased arterial blood pressure, heart rate and sympathovagal balance (LF/HF ratio) and a low-frequency band of systolic arterial pressure (LF-SAP). The GAL group, in comparison to the F group, showed increased vagally mediated RMSSD index, a high-frequency band (HF-PI) and decreased LF/HF ratio and variance in SAP (VAR-SAP) and LF-SAP. Correlations were found between HF-PI and KITT (r = 0.60), heart rate (r = -0.65) and MAP (r = -0.71). GAL treatment significantly improved cardiovascular autonomic modulation, which was associated with the amelioration of cardiometabolic dysfunction in offspring of parents exposed to chronic fructose consumption.

Influence of gestational window on offspring vascular health in rodents with in utero exposure to electronic cigarettes.

Studies have shown cerebrovascular dysfunction in offspring with full-gestational electronic cigarette (Ecig) exposure, but little is known about how individual trimester exposure impacts offspring health. This study aimed to determine if there is a critical window during gestation that contributes to vascular and anxiety-like behavioural changes seen with full-term exposure. To test this, rats were time-mated, and the pregnant dams were randomly assigned to Ecig exposure during first trimester (gestational day, GD2-7), second trimester (GD8-14), third trimester (GD15-21) or full-term gestation (GD2-21). We also assessed the effect of maternal preconception exposure. Both male and female offspring from all maternal exposure conditions were compared to offspring from dams under ambient air (control) conditions. Ecig exposure consisted of 60-puffs/day (5days/week) using either 5 or 30watts for each respective exposure group. We found that maternal exposure to Ecig in the second and third trimesters resulted in a decrease (23-38%) in vascular reactivity of the middle cerebral artery (MCA) reactivity in 3- and 6-month-old offspring compared to Air offspring. Further, the severity of impairment was comparable to the full-term exposure (31-46%). Offspring also displayed changes in body composition, body mass, anxiety-like behaviour and locomotor activity, indicating that Ecigs influence neurodevelopment and metabolism. Maternal preconception exposure showed no impact on offspring body mass, anxiety-like behaviour, or vascular function. Thus, the critical exposure window where Ecig affects vascular development in offspring occurs during mid- to late-gestation in pregnancy, and both 5W and 30W exposure produce significant vascular dysfunction compared to Air. KEY POINTS: Exposure to electronic cigarettes (Ecigs) is known to increase risk factors for cardiovascular disease in both animals and humans. Maternal Ecig use during pregnancy in rodents is found to impair the vascular health of adolescent and adult offspring, but the critical gestation window for Ecig-induced vascular impairment is not known. This study demonstrates Ecig exposure during mid- and late-gestation (i.e. second or third trimester) results in impaired endothelial cell-mediated dilatation (i.e. middle cerebral artery reactivity) and alters anxiety-like behaviour in offspring. Maternal exposure prior to conception did not impact offspring's vascular or anxiety-like behavioural outcomes. Rodent models have been a reliable and useful predictor of inhalation-induced harm to humans. These data indicate maternal use of Ecigs during pregnancy should not be considered safe, and begin to inform clinicians and women about potential long-term harm to their offspring.

Parental Alcohol Exposures Associate with Lasting Mitochondrial Dysfunction and Accelerated Aging in a Mouse Model.

Although detrimental changes in mitochondrial morphology and function are widely described symptoms of fetal alcohol exposure, no studies have followed these mitochondrial deficits into adult life or determined if they predispose individuals with fetal alcohol spectrum disorders (FASDs) to accelerated biological aging. Here, we used a multiplex preclinical mouse model to compare markers of cellular senescence and age-related outcomes induced by maternal, paternal, and dual-parental alcohol exposures. We find that even in middle life (postnatal day 300), the adult offspring of alcohol-exposed parents exhibited significant increases in markers of stress-induced premature cellular senescence in the brain and liver, including an upregulation of cell cycle inhibitory proteins and increased senescence-associated β-galactosidase activity. Strikingly, in the male offspring, we observe an interaction between maternal and paternal alcohol use, with histological indicators of accelerated age-related liver disease in the dual-parental offspring exceeding those induced by either maternal or paternal alcohol use alone. Our studies indicate that chronic parental alcohol use causes enduring mitochondrial dysfunction in offspring, resulting in a reduced NAD+/NAHD ratio and altered expression of the NAD+-dependent deacetylases SIRT1 and SIRT3. These observations suggest that some aspects of FASDs may be linked to accelerated aging due to programmed changes in the regulation of mitochondrial function and cellular bioenergetics.

Feasibility and efficacy of pemafibrate for prevention of maternal high-fat intake-induced glucose metabolic dysfunction in offspring

Given the significance of the intrauterine lipid environment in glucose metabolic homeostasis in offspring, the present study was undertaken to investigate the feasibility and efficacy of pemafibrate, a triglyceride-lowering peroxisome proliferator-activated agent, for maternal high-fat diet (HFD) intake-induced glucose metabolic dysfunction in offspring. A mouse model of HFD-induced gestational obesity was employed, and pemafibrate was orally administered from day 10 of gestation until delivery. The influences of maternal pemafibrate treatment on biological processes and toxicity were evaluated in both newborns and 12-week-old offspring. The findings of a dose-dependent decrease of β cell islet mass and of impairment of glucose tolerance and insulin sensitivity in offspring suggest that maternal pemafibrate intervention can prevent maternal HFD-intake-induced diabetes in offspring. Of particular interest in the prevention of future glucose metabolic dysfunction in offspring, low-dose maternal pemafibrate treatment (0.02 mg/kg/day) had sufficient efficacy and appeared to be safe in offspring. Therefore, pemafibrate may be a potential agent for the prevention of maternal high-fat exposure-induced diabetes in offspring.Abbreviations: CD, control diet; DEG, differentially expressed genes; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; MC, 0.5w/v% methyl cellulose 400 solution; PPAR, triglyceride-lowering peroxisome proliferator-activated receptor; RNA-seq, RNA sequencing; TC, total cholesterol; TG, triglycerides.

Intrauterine hyperglycaemia during late gestation caused mitochondrial dysfunction in skeletal muscle of male offspring through CREB/PGC1A signaling

BackgroundMaternal diabetes mellitus can influence the development of offspring. Gestational diabetes mellitus (GDM) creates a short-term intrauterine hyperglycaemic environment in offspring, leading to glucose intolerance in later life, but the long-term effects and specific mechanism involved in skeletal muscle dysfunction in offspring remain to be clarified.MethodsPregnant mice were divided into two groups: The GDM group was intraperitoneally injected with 100 mg/kg streptozotocin on gestational days (GDs) 6.5 and 12.5, while the control (CTR) group was treated with vehicle buffer. Only pregnant mice whose random blood glucose level was higher than 16.8 mmol/L beginning on GD13.5 were regarded as the GDM group. The growth of the offspring was monitored, and the glucose tolerance test was performed at different time points. Body composition analysis and immunohistochemical methods were used to evaluate the development of lean mass at 8 weeks. The exercise capacity and grip strength of the male mouse offspring were assessed at the same period. Transmission electron microscopy was used to observe the morphology inside skeletal muscle at 8 weeks and as a foetus. The genes and proteins associated with mitochondrial biogenesis and oxidative metabolism were investigated. We also coanalyzed RNA sequencing and proteomics data to explore the underlying mechanism. Chromatin immunoprecipitation and bisulfite-converted DNA methylation detection were performed to evaluate this phenomenon.ResultsShort-term intrauterine hyperglycaemia inhibited the growth and reduced the lean mass of male offspring, leading to decreased endurance exercise capacity. The myofiber composition of the tibialis anterior muscle of GDM male offspring became more glycolytic and less oxidative. The morphology and function of mitochondria in the skeletal muscle of GDM male offspring were destroyed, and coanalysis of RNA sequencing and proteomics of foetal skeletal muscle showed that mitochondrial elements and lipid oxidation were consistently impaired. In vivo and in vitro myoblast experiments also demonstrated that high glucose concentrations impeded mitochondrial organisation and function. Importantly, the transcription of genes associated with mitochondrial biogenesis and oxidative metabolism decreased at 8 weeks and during the foetal period. We predicted Ppargc1α as a key upstream regulator with the help of IPA software. The proteins and mRNA levels of Ppargc1α in the skeletal muscle of GDM male offspring were decreased as a foetus (CTR vs. GDM, 1.004 vs. 0.665, p = 0.002), at 6 weeks (1.018 vs. 0.511, p = 0.023) and 8 weeks (1.006 vs. 0.596, p = 0.018). In addition, CREB phosphorylation was inhibited in GDM group, with fewer activated pCREB proteins binding to the CRE element of Ppargc1α (1.042 vs. 0.681, p = 0.037), Pck1 (1.091 vs. 0.432, p = 0.014) and G6pc (1.118 vs. 0.472, p = 0.027), resulting in their decreased transcription. Interestingly, we found that sarcopenia and mitochondrial dysfunction could even be inherited by the next generation.ConclusionsShort-term intrauterine hyperglycaemia significantly reduced lean mass in male offspring at 8 weeks, resulting in decreased exercise endurance and metabolic disorders. Disrupted organisation and function of the mitochondria in skeletal muscle were also observed among them. Foetal exposure to hyperglycaemia decreased the ratio of phosphorylated CREB and reduced the transcription of Ppargc1α, which inhibited the transcription of downstream genes involving in mitochondrial biogenesis and oxidative metabolism. Abnormal mitochondria, which might be transmitted through aberrant gametes, were also observed in the F2 generation.

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 NOS3methylation 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.

P-627 Does artificial hormonal therapy increase the TSH levels in frozen embryo transfer?

Abstract Study question Does administration of estradiol valerate for frozen embryo transfer (FET) increase the TSH value and the risk of miscarriage? Summary answer TSH is increased at the time of endometrial thickness and pregnancy test in HRT cycles. Women with higher TSH have an increased risk of miscarriage. What is known already Several studies describe the correlation between estradiol and TSH levels during menstrual cycles. The circulated TSH is upregulated by estradiol, in fact, TSH increases in the periovulatory phase and in women taking oral contraceptive therapy. A higher estradiol in the first trimester is correlated with an increased risk of thyroid dysfunction in offspring. TSH is also correlated to beta-Human Chorionic Gonadotropin (b-HCG) levels, many studies reported an increase of TSH values at b-HCG peak during 10-12 weeks of gestation. Study design, size, duration This is a retrospective, single-center, observational study enrolling 607 patients at IVI Roma from April 2022 to June 2023.Patients with 30-47 years old with single blastocyst transfer were included in the study. Both euploid frozen embryo transfer (FET) from autologous oocyte ICSI-PGT-A cycles and FET from ICSI cycles using donated oocytes were considered. FET performed under artificial endometrial preparation with HRT using exogenous estradiol and progesterone (vaginal, subcutaneous and intramuscular) were included in the study. Participants/materials, setting, methods TSH was evaluated before estradiol valerate administration (T0), at the control for endometrial thickness (T1), the day of embryo transfer (T2), and the day of b-HCG evaluation (T3). Accordingly, the patients were divided into two groups based on their TSH levels (low-normal group, ≤ 2.5 mIU/L; high group, > 2.5 mIU/L). The primary outcome was TSH values at different times. The secondary outcome evaluated the miscarriage rate (MR) calculated for FET. Main results and the role of chance TSH mean at T0 was 1.65 ± 0.87. The mean value of TSH after estradiol valerate administration was 1.97 ± 1.28. TSH value increased during the estradiol valerate administration with a mean increase of 0.29 mIU/L reaching statistical significance (p < 0.0001). No statistical differences were reported between T0-T2 (p = 0.64) while the statistical difference was reported in time T0-T3 with a mean increase of 0.40 mIU/L (p < 0.0001). Women with T1-TSH value > 2.5 mIU/L were 18.95%. The miscarriage rate in the group with TSH value >2.5 mIU/L was 17.81%. The univariate analysis showed that T1-TSH values >2.5 mIU/L did not affect the miscarriage rate OR 0.79 (95 CI% 0.37-1.67), p = 0.54. The multivariate analysis considering age, BMI and source of oocytes showed no statistical significance on the miscarriage rate OR 0.82 (95 CI% 0.39-1.72), p = 0.62. T2-TSH values did not affect the miscarriage rate in the univariate and multivariate analyses. Regarding T3-TSH, the univariate analysis showed that THS >2.5 mIU/L affects the miscarriage rate OR 1.97(95 CI% 1.07-3.65), p = 0.03. Multivariate analysis considering possible confounders showed that women with THS >2.5 mIU/L have a higher risk of miscarriage OR 1.96 (95 CI% 1.02-3.78), p = 0.04. Limitations, reasons for caution The retrospective design and patients with different female infertility factors for IVF were included in the study, leading to a possible biased population. The T1-TSH assessment was not scheduled at the same time for each patient. Women with TSH >2.5 mIU/L at the T1-TSH value were treated with levothyroxine. Wider implications of the findings This study emphasizes the correlation between estradiol valerate administration and TSH values and the possible relation with increasing risk of miscarriage in women with higher TSH. Patients undergoing FET with HRT should consider thyroid supplementation or increasing dosage to reduce the risk of miscarriage. Trial registration number not applicable

Effect of maternal cigarette smoke exposure on COPD progression in offspring mice

ObjectiveTo investigate the impact of maternal smoking on chronic obstructive pulmonary disease (COPD) progression in offspring. MethodsUsing female C57BL/6 J mice, a maternal cigarette smoke exposure (CSE) model was established. Mice were exposed to cigarette smoke for 2 hours/day, 7 days/week, with a minimum 4-hour interval between exposures. Experimental groups included control (Con), pregnancy exposure (AS), pre-pregnancy exposure (SA), and pre-pregnancy + pregnancy exposure (SS). Lung function tests (Penh, PAU, TVb, EF50, Tr) were conducted on male offspring at 7 weeks. Histopathology, electron microscopy, and protein level changes were examined. ResultsLung function tests revealed significant impairments in Penh, PAU, TVb, EF50, and Tr in offspring across all exposure scenarios. Specifically, AS experienced significant lung function impairment and mitochondrial dysfunction in offspring, with noticeable pulmonary lesions and increased apoptosis. SA showed similar or even more severe lung function impairment and cellular apoptosis. SS exhibited the most pronounced effects, with the highest levels of lung dysfunction, mitochondrial damage, and apoptosis. Histopathological analysis showed pulmonary lesions in offspring exposed to maternal CSE. Flow cytometry revealed increased apoptosis and reduced mitochondrial membrane potential in offspring lung cells. Electron microscopy confirmed mitochondrial dysfunction. Upregulation of apoptotic proteins and downregulation of anti-apoptotic protein Bcl-2 were found in offspring lung tissue exposed to maternal CSE. ConclusionMaternal smoking induces impaired lung function, pulmonary lesions, and mitochondrial dysfunction in offspring, regardless of exposure timing and duration. Additionally, it alters expression of apoptosis-related proteins in offspring lung tissue, potentially contributing to COPD susceptibility.

HDAC1/2/3-mediated downregulation of neurogranin is involved in cognitive impairment in offspring exposed to maternal subclinical hypothyroidism.

Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.

Maternal Injection with Dexamethasone Results in Female-Biased Autonomic Dysregulation in Rat Offspring

Autonomic dysfunction is an underlying risk factor for cardiovascular disease (CVD). Maternal injection of the synthetic GC dexamethasone (DEX) during the last 4 days of gestation results in female-biased increases in stress-responsive pressor (MAP), heart rate (HR) and altered heart rate variability (HRV) in adult rat offspring, suggesting a role for GC-mediated programming of autonomic function. The present study used pharmacological antagonists for adrenergic (SYM) or cholinergic (PS) receptors to investigate the degree to which changes in SYM or PS activity underlie the autonomic dysfunction in offspring of dams injected with DEX during late gestation. Naïve breeders were injected with DEX (0.4mg/kg/day, s.c.) or vehicle (hydroxypropyl beta cyclodextrin; Veh) on gestation days 18-21. Radiotelemetry was used in adult offspring for recording HR, MAP, and HRV (root mean square of successive differences: RMSSD). At 10-11 weeks rats were randomly assigned to receive SYM antagonists, α-adrenoceptor (prazosin; 0.5mg/kg, i.p.) + β-adrenoceptor (atenolol; 1mg/kg, i.p.), a PS antagonist (homatropine methylbromide; 0.2mg/kg, i.p), or saline (SAL, i.p.). Evaluations were made over 20 min following injection and then during a 20 min restraint. Females were tested on diestrus. In utero DEX exposure resulted in significantly lower RMSSD, an index of vagal tone, in DEX-exposed females and males. PS blockade significantly reduced RMSSD in Veh-, but not DEX-exposed female offspring. SYM blockade did not influence RMSSD in females. In males, PS blockade reduced in RMSSD in both DEX- and Veh-exposed offspring. SYM blockade only reduced RMSSD in males exposed to DEX. Area under the curve (AUC) analysis revealed that in female offspring, SYM blockade resulted in a greater reduction in HR in DEX-exposed offspring, compared to Veh (DEX-SYM: −220 bpm vs. DEX-SAL; Veh-SYM: −197 bpm vs. VEH-SAL) and during restraint (DEX-SYM: −535 bpm vs. DEX-SAL; Veh-SYM: −342 bpm vs. VEH-SAL). PS blockade resulted in a greater increase in HR in Veh-exposed females both following the injection (Veh-PS: −187 bpm vs. VEH-SAL; DEX-PS: −101 bpm vs. DEX-SAL) and during restraint (Veh-PS: −161 bpm vs. VEH-SAL; DEX-PS: −61 bpm vs. DEX-SAL). AUC analysis for MAP showed similar responses to those for HR with SYM blockade having a greater impact in DEX-exposed females and PS blockade having a greater effect in Veh-exposed females. By contrast, in male offspring in utero DEX exposure did not influence HR or MAP responses to SYM or PS blockade. Overall, these findings suggest that maternal DEX injections alter autonomic development primarily in in female offspring and is characterized by a shift from PS to SYM predominance. Better understanding of the mechanisms involved in this programming are important for identifying individuals at risk for CVD and development of interventional strategies for prevention of CVD. Funding: 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.

Medical and social aspects of preeclampsia

Preeclampsia (PE) is a relevant healthcare problem and represents a high risk for the development of various diseases in both the mother and fetus. In domestic and foreign literature, the number of works on the influence of PE on the cardiovascular and nervous systems of the fetus is constantly increasing. Thus, PE is associated with an increased risk of congenital heart defects, high blood pressure (BP), increased body mass index (BMI), and systemic vascular dysfunction in off spring. In addition, PE leads to disorders of the development of the nervous system, such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). PE is one of the main causes of adverse perinatal outcomes and neonatal mortality. This review also presents the correlation between PE and the risk of developing cardiovascular diseases (CVDs), stroke, and chronic kidney disease (CKD). In recent decades, there has been increasing evidence that manifestations of PE are not limited to pregnancy but also increase the risk of long-term complications. Thus, PE is a common disease that can lead to severe consequences for the mother and fetus in later life.

Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences.

Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE.

Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia

Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes.

Exercise and insulin glargine administration in mothers with diabetes during pregnancy ameliorate function of testis in offspring: Consequences on apelin-13 and its receptor

AimsDespite the evidence exhibited that diabetes during gestation (DDG) is linked with reproductive dysfunction in offspring, the underlying cellular mechanisms involved are not precisely defined. This study was designed to assess the impact of voluntary exercise and insulin glargine on DDG-induced metabolic and reproductive disorders in male offspring. Main methodsFifty female Wistar rats (three weeks old) received a control diet (n = 10) or high-fat-high-sucrose diet (to induce DDG; n = 40) for six weeks before breeding. From the 7th day of pregnancy onwards, blood glucose over 140 mg/dL was characterized as DDG. Then, the DDG animals were randomly divided into four subgroups with/without voluntary exercise and/or insulin glargine. To evaluate insulin resistance, a glucose tolerance test was performed on the 15th day of pregnancy. After three weeks, male offspring were weaned, and fed a control diet until 12 weeks old. At the end of the experiment, the lipid profile, sex hormones, and apelin-13 in the serum, mRNA expression of apelin receptors (APJ) in the testis and sperm analysis were assessed. Key findingsOur results indicated that voluntary exercise and/or insulin glargine administration in mothers with DDG ameliorated lipid profile, and sex hormones alterations, reduced the serum level of apelin-13, as well as increased APJ expression in testis, and quality of sperm in offspring. SignificanceCombined administration of voluntary exercise and insulin glargine during pregnancy by regulating of apelinergic system and inhibiting the metabolic and reproductive complications induced by DDG, can be considered as a suitable therapeutic strategy for improving sub-or in-fertility in the male offspring.