Offspring Syndrome Research Articles

Paternal Age and the Risk of Trisomy 21

This cohort study examines whether there is an association between paternal age and Down syndrome in offspring.

Maternal Polyphenols and Offspring Cardiovascular-Kidney-Metabolic Health.

The convergence of cardiovascular, kidney, and metabolic disorders at the pathophysiological level has led to the recognition of cardiovascular-kidney-metabolic (CKM) syndrome, which represents a significant global health challenge. Polyphenols, a group of phytochemicals, have demonstrated potential health-promoting effects. This review highlights the impact of maternal polyphenol supplementation on the CKM health of offspring. Initially, we summarize the interconnections between polyphenols and each aspect of CKM syndrome. We then discuss in vivo studies that have investigated the use of polyphenols during pregnancy and breastfeeding, focusing on their role in preventing CKM syndrome in offspring. Additionally, we explore the common mechanisms underlying the protective effects of maternal polyphenol supplementation. Overall, this review underscores the potential of early-life polyphenol interventions in safeguarding against CKM syndrome in offspring. It emphasizes the importance of continued research to advance our understanding and facilitate the clinical translation of these interventions.

Maternal Dietary Strategies for Improving Offspring Cardiovascular-Kidney-Metabolic Health: A Scoping Review.

Dietary regulation has been recognized for its profound impact on human health. The convergence of cardiovascular, kidney, and metabolic disorders at the pathophysiological level has given rise to cardiovascular-kidney-metabolic (CKM) syndrome, which constitutes a significant global health burden. Maternal dietary nutrients play a crucial role in fetal development, influencing various programmed processes. This review emphasizes the effects of different types of dietary interventions on each component of CKM syndrome in both preclinical and clinical settings. We also provide an overview of potential maternal dietary strategies, including amino acid supplementation, lipid-associated diets, micronutrients, gut microbiota-targeted diets, and plant polyphenols, aimed at preventing CKM syndrome in offspring. Additionally, we discuss the mechanisms mediated by nutrient-sensing signals that contribute to CKM programming. Altogether, we underscore the interaction between maternal dietary interventions and the risk of CKM syndrome in offspring, emphasizing the need for continued research to facilitate their clinical translation.

P-584 Occupational paternal risk factors for cryptorchidism and hypospadias in the offspring: a case-control study

Abstract Study question Does paternal occupational exposures to reprotoxic chemical and physical hazards constitute risk factors to cryptorchidism and hypospadias in the offspring? Summary answer Paternal occupational reprotoxic exposures, determined through a job exposure matrix, and paternal rural lifestyle are associated with cryptorchidism, hypospadias, and other genital congenital malformations. What is known already Cryptorchidism and hypospadias are the most common congenital malformations of the male urogenital organs. Over the past century, these congenital malformations, which are associated with testicular cancer and impaired semen quality, have been included into a common disease spectrum known as the testicular dysgenesis syndrome. The association between urogenital congenital malformations and fetal exposure to many factors has been suggested, in particular to genetic and epigenetic factors and environmental factors. There is growing scientific evidence that both maternal and paternal exposure at the time of fertilization play a role after fertilization. Study design, size, duration This is a case-control study with standardized data collection of a 220 father-child cohort recruited from the consultants of our genetic counseling service at the medical university of Sfax (Tunisia), over two years. Participants/materials, setting, methods We compared 110 children diagnosed with congenital malformations to 110 children without any congenital defects. Controls did not differ from the total cohort in confounding variables. Information about paternal jobs held early in pregnancy was collected. Determined via a job exposure matrix, paternal occupational reprotoxic exposures were assessed. Logistic regression analysis was performed to assess the associations between paternal occupational exposures and the congenital testicular dysgenesis syndrome in offspring, including cryptorchidism and hypospadias. Main results and the role of chance 75.54% of children had congenital heart defects and 24.54% of them had genital malformations (n = 27). Paternal occupational exposures to pesticides were associated with the risk of developing birth defects (odds ratio = 17.568 (95% CI), 2.258-136.673). Our results indicate that paternal exposure to pesticides, phthalates, alkylphenolic compounds and other endocrine disruptors was associated with genital and cardiac birth defects. Both cryptorchidism and hypospadias in offspring were associated with paternal rural lifestyle as well as the absence of a maternal job. Limitations, reasons for caution The cohort size in this case-control study may limit the statistical power of the logistical regression to detect associations. Additionally, cases and controls may be selected in a way that does not represent the general population accurately. This can introduce bias and affect the external validity of the study. Wider implications of the findings Including paternal exposures in subsequent investigations of risk factors for cryptorchidism and hypospadias, and further exploring the connection between paternal pesticide exposure and epigenetic alterations, may offer insights into their impact on paternal spermatogenesis, sperm small RNAs, and the potential development of congenital testicular dysgenesis syndrome in future generations. Trial registration number 0400/2022

Impact of Transgenerational Nutrition on Nonalcoholic Fatty Liver Disease Development: Interplay between Gut Microbiota, Epigenetics and Immunity.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent pediatric liver disorder, primarily attributed to dietary shifts in recent years. NAFLD is characterized by the accumulation of lipid species in hepatocytes, leading to liver inflammation that can progress to steatohepatitis, fibrosis, and cirrhosis. Risk factors contributing to NAFLD encompass genetic variations and metabolic disorders such as obesity, diabetes, and insulin resistance. Moreover, transgenerational influences, resulting in an imbalance of gut microbial composition, epigenetic modifications, and dysregulated hepatic immune responses in offspring, play a pivotal role in pediatric NAFLD development. Maternal nutrition shapes the profile of microbiota-derived metabolites in offspring, exerting significant influence on immune system regulation and the development of metabolic syndrome in offspring. In this review, we summarize recent evidence elucidating the intricate interplay between gut microbiota, epigenetics, and immunity in fetuses exposed to maternal nutrition, and its impact on the onset of NAFLD in offspring. Furthermore, potential therapeutic strategies targeting this network are also discussed.

Fructooligosaccharides Intake during Pregnancy Improves Metabolic Phenotype of Offspring in High Fat Diet-Induced Obese Mice.

Obesity and metabolic diseases are closely associated, and individuals who become obese are also prone to type 2 diabetes and cardiovascular disorders. Gut microbiota is mediated by diet and can influence host metabolism and the incidence of metabolic disorders. Recent studies have suggested that improving gut microbiota through a fructooligosaccharide (FOS)-supplemented diet may ameliorate obesity and other metabolic disorders. Although accumulating evidence supports the notion of the developmental origins of health and disease, the underlying mechanisms remain obscure. ICR mice are fed AIN-93G formula-based cellulose -, FOS-, acetate-, or propionate-supplemented diets during pregnancy. Offspring are reared by conventional ICR foster mothers for 4 weeks; weaned mice are fed high fat diet for 12 weeks and housed individually. The FOS and propionate offspring contribute to suppressing obesity and improving glucose intolerance. Gut microbial compositions in FOS-fed mothers and their offspring are markedly changed. However, the beneficial effect of FOS diet on the offspring is abolished when antibiotics are administered to pregnant mice. The findings highlight the link between the maternal gut environment and the developmental origin of metabolic syndrome in offspring. These results open novel research avenues into preemptive therapies for metabolic disorders by targeting the maternal gut microbiota.

Dexamethasone exposure during pregnancy triggers metabolic syndrome in offspring via epigenetic alteration of IGF1

BackgroundPrevious research has reported that prenatal exposure to dexamethasone (PDE) results in organ dysplasia and increased disease susceptibility in offspring. This study aimed to investigate the epigenetic mechanism of metabolic syndrome induced by PDE in offspring.MethodsPregnant Wistar rats were administered dexamethasone, and their offspring’s serum and liver tissues were analyzed. The hepatocyte differentiation model was established to unveil the molecular mechanism. Neonatal cord blood samples were collected to validate the phenomenon and mechanism.ResultsThe findings demonstrated that PDE leads to insulin resistance and typical metabolic syndrome traits in adult offspring rats, which originated from fetal liver dysplasia. Additionally, PDE reduced serum corticosterone level and inhibited hepatic insulin-like growth factor 1 (IGF1) signaling in fetal rats. It further revealed that liver dysplasia and functional impairment induced by PDE persist after birth, driven by the continuous downregulation of serum corticosterone and hepatic IGF1 signaling. Both in vitro and in vivo experiments confirmed that low endogenous corticosterone reduces the histone 3 lysine 9 acetylation (H3K27ac) level of IGF1 and its expression by blocking glucocorticoid receptor α, special protein 1, and P300 into the nucleus, resulting in hepatocyte differentiation inhibition and liver dysplasia. Intriguingly, neonatal cord blood samples validated the link between reduced liver function in neonates induced by PDE and decreased serum cortisol and IGF1 levels.ConclusionsThis study demonstrated that low endogenous glucocorticoid level under PDE lead to liver dysplasia by downregulating the H3K27ac level of IGF1 and its expression, ultimately contributing to metabolic syndrome in adult offspring.

P07-067-23 The Effect of Source of Protein Fed During Pregnancy on Development of Characteristics of Metabolic Syndrome in Offspring of Obese Wistar Rats

P07-067-23 The Effect of Source of Protein Fed During Pregnancy on Development of Characteristics of Metabolic Syndrome in Offspring of Obese Wistar Rats

RBM15 suppresses hepatic insulin sensitivity of offspring of gestational diabetes mellitus mice via m6A-mediated regulation of CLDN4

BackgroundGestational diabetes Mellitus (GDM) is a common pregnancy-specific disease with high morbidity, which is linked to a high risk of obesity and diabetes in offspring. N6-methyladenosine modification of RNA is emerging as an important epigenetic mechanism that is widely manifested in many diseases. This study aimed to investigate the mechanism of m6A methylation in metabolic syndrome in offspring result from intrauterine hyperglycemia.MethodsGDM mice were established by feeding a high-fat diet 1 weeks before pregnancy. The m6A RNA methylation quantification kit was used to detect liver tissue methylation levels. PCR array was used to determine the expression of the m6A methylation modification enzyme. Immunohistochemistry, qRT-PCR, and western blot were used to examine the expression of RBM15, METTL13, IGF2BP1, and IGF2BP2. Subsequently, methylated RNA immunoprecipitation sequencing combined with mRNA sequencing, followed by dot blot and glucose uptake tests, were performed.ResultsIn this study, we found that offspring from a GDM mother were more vulnerable to glucose intolerance and insulin resistance. GC–MS revealed significant metabolic changes including saturated fatty acids and unsaturated fatty acids in liver of GDM offspring. We also demonstrated that global mRNA m6A methylation level was significantly increased in the fetal liver of GDM mice, indicating epigenetic change may have a strong relationship with the mechanism of metabolism syndrome. Concordantly, RBM15, the RNA binding methyltransferase, was upregulated in the liver. In vitro, RBM15 suppressed insulin sensitivity and increased insulin resistance through m6A-regulated epigenetic inhabitation of CLDN4. Moreover, MeRIP-sequencing and mRNA-sequencing revealed that differently regulated genes with differential m6A peaks were enriched in metabolic pathways.ConclusionOur study revealed the essential role of RBM15 in insulin resistance and the effect of RBM15-regulated m6A modification in the metabolic syndrome of offspring of GDM mice.

RF22 | PSUN318 Hepatocytes Exposed to PFOA Prior to Differentiation Leads to Epigenetic Changes in Genes Linked With NAFLD

Abstract Background Perfluorooctanoic acid (PFOA), is a persistent fluorinated compound with oil and water repelling properties found in cookware, food packaging and municipal water systems. Adult animals exposed to PFOA develop hepatomegaly, fatty liver, peroxisome proliferation, and immunotoxicity. Rodents exposed to PFOA in utero have altered hepatic lipid metabolism, increased hepatic de novo lipogenesis and susceptibility to non-alcoholic fatty liver disease (NAFLD), but underlying molecular mechanisms remain unknown. With increasing rates of obesity, diabetes, and NAFLD it is critical to examine the mechanisms by which in utero exposure to PFOA contributes to the development of metabolic syndrome in offspring. Objectives To characterize how PFOA exposure during hepatocyte differentiation leads to the development of NAFLD through alterations in DNA methylation profiles and changes in the availability of transcription factor binding sites. Methods HepaRG cells (human-derived hepatocyte progenitor cells) were treated with 0.5uM PFOA or vehicle for 48 hours followed by differentiation. Undifferentiated and differentiated hepatocytes exposed to PFOA were assessed relative to controls (n=4). RNASeq was completed; DESeq2 identified differentially expressed genes via false discovery rate (FDR) of <0.05 after Bonferroni correction. Genome-wide DNA methylation analysis via MethylSeq was completed to identify differentially methylated regions (DMRs) defined as minimum number of CpN =5, absolute change in percent methylation >10%, and FDR of <0.05. Enrichment analysis of transcription factor binding motifs within DMRs and single CpG sites (± 200 bp) was performed using HOMER. Results PFOA treatment resulted in decreased expression of the transcription factors early growth response protein 1 (EGR1), nuclear receptor Nur77 (NR4A1), early growth response protein 2 (EGR2), krueppel-like factor 10 (KLF10) and fos-related antigen 1 (FOSL1), which are key genes linked to impaired hepatic insulin signaling, lipid metabolism, steatosis and fibrosis (q<0.05) in undifferentiated hepatocytes. Differentiated hepatocytes showed decreased expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), peroxisome proliferator-activated receptor γ (PPARγ), forkhead box protein O1 (FOXO1) and increased expression of pyruvate dehydrogenase kinase isozyme 4 (PDK4), genes linked to regulation of lipid metabolism and insulin signaling (q <0.05). MethylSeq analysis identified changes in DMRs located in exons, introns, and intergenic regions, with 57 DMRs in undifferentiated hepatocytes (46 with gains; 11 with losses; q <0.05) and 75 DMRs in differentiated hepatocytes (32 with gains; 41 with losses; q<0.05). HOMER identified 29 known transcription factor binding motifs with changes in methylation in undifferentiated hepatocytes (p<0.05) and 19 in differentiated hepatocytes after PFOA treatment (p<0.05), with significant changes in the EGR1 consensus sequence identified in both comparisons. Conclusions We conclude hepatocyte progenitor cells exposed to low dose PFOA results in changes in DNA methylation and expression of key metabolic genes linked to NAFLD, notably EGR1, a gene previously linked to NAFLD, suggesting PFOA exposure in utero has lasting effects. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 12:48 p.m. - 12:53 p.m.

Epigenetic Mediators of Risk for Metabolic Disease Across Generations

Obesity and type 2 diabetes (T2D) are leading global health threats and innovative multi‐pronged approaches are needed to combat both epidemics. Many risk factors for obesity and T2D – beyond genetics – are present before birth, reflecting the influence of environmental factors on germ cells and on the developing infant. For example, parental obesity or diabetes, prenatal undernutrition, and both low and high birth weight, are linked to offspring’s obesity and T2D risk later in life. Such prenatal exposures increase obesity risk not only in the individual exposed to the stressor, but also in their offspring. The result is a vicious cycle of risk to subsequent generations.The concept that the maternal perinatal environment shapes childhood chronic diseases is well‐recognized. However, mounting evidence demonstrates that fathers can also contribute to obesity and diabetes risk to their offspring. While genetic factors are important, additional non‐genetic impacts of paternal metabolism have been demonstrated both in rodent models and in humans. Paternal metabolism can influence epigenetic signals in sperm, including DNA methylation, histone modification, and/or noncoding RNA (ncRNA), which can impact gene expression and development in the offspring. We and others have shown that epigenetic marks are altered in sperm from rodents exposed to prenatal undernutrition, postnatal overnutrition, and other stimuli. While human data are more limited, paternal BMI at the time of conception is associated with infant birth weight and DNA methylation of infant cord blood; differential DNA methylation at some loci persisted to age 7. Our new preliminary data demonstrate that T2D also modifies the sperm methylome.Given that sperm epigenetic marks may be modifiable, this suggests a potential novel approach and untapped opportunity for multigenerational prevention of metabolic disease. We demonstrate that interventions in male mice, including exercise and pharmacological lowering of glucose levels, result in amelioration of obesity, glucose tolerance and metabolic syndrome in offspring.

Development of pups born to rats established as a model of underweight Japanese women and the onset of impaired glucose tolerance

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers.

Effects of paternal exposure to cigarette smoke on sperm DNA methylation and long-term metabolic syndrome in offspring

BackgroundAlthough paternal exposure to cigarette smoke may contribute to obesity and metabolic syndrome in offspring, the underlying mechanisms remain uncertain.MethodsIn the present study, we analyzed the sperm DNA-methylation profiles in tobacco-smoking normozoospermic (SN) men, non-tobacco-smoking normozoospermic (N) men, and non-smoking oligoasthenozoospermic (OA) men. Using a mouse model, we also analyzed global methylation and differentially methylated regions (DMRs) of the DLK1 gene in paternal spermatozoa and the livers of progeny. In addition, we quantified DLK1 expression, executed an intra-peritoneal glucose tolerance test (IPGTT), measured serum metabolites, and analyzed liver lipid accumulation in the F1 offspring.ResultsGlobal sperm DNA-methylation levels were significantly elevated (p < 0.05) in the SN group, and the methylation patterns were different among N, SN, and OA groups. Importantly, the methylation level of the DLK1 locus (cg11193865) was significantly elevated in the SN group compared to both N and OA groups (p < 0.001). In the mouse model, the group exposed to cigarette smoke extract (CSE) exhibited a significantly higher global methylation DNA level in spermatozoa (p < 0.001) and on the DMR sites of Dlk1 in 10-week-old male offspring (p < 0.05), with a significant increase in Dlk1 expression in their livers (p < 0.001). In addition, IPGTT and LDL levels were significantly altered (p < 0.001), with elevated liver fat accumulation (p < 0.05) in F1 offspring.ConclusionPaternal exposure to cigarette smoke led to increased global methylation of sperm DNA and alterations to the DMR of the DLK1 gene in the F1 generation, which may be inherited parentally and may perturb long-term metabolic function.

Association of Prenatal Maternal Anemia with Tics and Tourette's Syndrome in Offspring.

Iron deficiency anemia (IDA) accounts for most of the anemia in pregnancy, and iron is essential for neurodevelopment. Tics and Tourette’s syndrome (TS) are neurodevelopmental disorders that manifest in childhood. A few studies reported an inconclusive association between iron deficiency and tics in children. No study has investigated the relationship between prenatal maternal anemia and tics in children. We aimed to assess the relationship between prenatal anemia exposure and the incidence of tics or TS in offspring. We linked the Taiwan National Health Insurance Research Database to the Maternal and Child Health Database for the analysis and identified 153,854 children with prenatal anemia exposure and 2,014,619 children without prenatal anemia exposure from 2004 to 2016 and followed them through 2017. Cox regression models were applied to compare the risk of tics or TS between the exposed and nonexposed groups. Among the exposed group, 37,832 were exposed at ≤12 weeks of gestational age (GA) and 116,022 at >12 weeks of GA. We observed an increased risk of tics and TS in those exposed at ≤12 weeks compared with the nonexposed group (adjusted hazard ratio (aHR) = 1.23, 95% confidence interval (CI): 1.12–1.34). The result remained consistent after adjusting for birth year, sex, birth order, maternal age, low-income levels, gestational age, birth weight, and alcohol use and smoking during pregnancy (aHR = 1.16, CI: 1.04–1.28). Fetuses exposed to maternal anemia at ≤12 weeks of GA are at high risk of tics or TS. However, this effect was attenuated to insignificance in the sibling comparison. Our study highlights the importance of detection of anemia during pregnancy and proper timing of iron supplementation.

PFOA Exposure Prior to Hepatocyte Differentiation Leads to Gene Expression Changes Implicated in Non-Alcoholic Fatty Liver Disease

Background: Perfluorooctanoic acid (PFOA), is a persistent fluorinated compound with oil and water repelling properties found in cookware, food packaging and municipal water systems. Adult animals exposed to PFOA develop hepatomegaly, fatty liver, peroxisome proliferation, and immunotoxicity. Rodents exposed to PFCs in utero have altered hepatic lipid metabolism, increased hepatic de novo lipogenesis and susceptibility to non-alcoholic fatty liver disease (NAFLD), but underlying molecular mechanisms remain unknown. With increasing rates of obesity, diabetes, and NAFLD it is critical to examine the mechanisms by which in utero exposure to PFOA contributes to the development of metabolic syndrome in offspring. Objective: To determine mechanism by which PFOA alters gene expression in undifferentiated hepatic progenitor cells. Design/methods: HepaRG cells, a human derived hepatocyte progenitor cell line, was treated with 0.5uM PFOA or vehicle for 48 hours followed by differentiation into hepatocytes. Total RNA was extracted using the RNeasy (Qiagen) [total RNA A260/280>2 and RNA integrity number >7 (Agilent Bioanalyzer)] to generate libraries with the Illumina TruSeq stranded total RNA kit. RNA-Seq was performed using 85 bp single-end read sequencing to generate >20 million reads per sample. RNAseq data was aligned to hg38 using STAR v2.6.1a and then quantified with featureCounts v1.6.2. DESeq2 identified differentially expressed genes via FDR (false discovery rate) after Bonferroni correction. Differentially expressed gene lists were used for Ingenuity Pathway Analysis (IPA) to identify pathways of biological significance.Results: PFOA treatment resulted in increased expression of transcription factors EGR1 (early growth response protein 1), NR4A1 (nuclear receptor Nur77), EGR2 (early growth response protein 2), KLF10 (Krueppel-like factor 10) and FOSL1 (Fos-related antigen 1), key genes linked to impaired hepatic insulin signaling, hepatic lipid metabolism, steatosis and fibrosis (fold change > 1.5; q <0.05). IPA identified enrichment of canonical pathways with biological relevance including hepatic fibrosis signaling, stellate cell activation, VDR/RXR/TR activation, and Type 2 diabetes mellitus signaling (p<0.01). Conclusion: Hepatocyte progenitor cells exposed to low dose PFOA for 48 hours prior to differentiation results in changes in expression of key metabolic genes linked to the development of NAFLD and enrichment of biologically relevant pathways associated with hepatic fibrosis and hepatocellular carcinoma. These results suggest that PFOA exposure in utero may have lasting effects on hepatic glucose and lipid metabolism after differentiation. Further studies are needed to characterize the longstanding metabolic effects of in utero PFOA exposure in offspring and the mechanisms driving the persistence of these changes.

Supplemental Berberine in a High-Fat Diet Reduces Adiposity and Cardiac Dysfunction in Offspring of Mouse Dams with Gestational Diabetes Mellitus

There are few evidence-based strategies to attenuate the risk of metabolic syndrome in offspring exposed to gestational diabetes mellitus (GDM). Berberine (BBR) is an isoquinoline alkaloid extracted from Chinese herbs and exhibits glucose lowering properties. We hypothesized that dietary BBR would improve health outcomes in the mouse offspring of GDM dams. Wild-type C57BL/6 female mice were fed either a Lean-inducing low-fat diet (L-LF,10% kcal fat, 35%kcal sucrose) or a GDM-inducing high-fat diet (GDM-HF, 45%kcal fat, 17.5% sucrose) for 6 wk prior to breeding with wild-type C57BL/6 male mice throughout pregnancy and the suckling period. The resulting Lean and GDM-exposed male and female offspring were randomly assigned an LF (10%kcal fat, 35%kcal sucrose), HF (45%kcal fat, 17.5% sucrose), or high-fat berberine (HFB) (45%kcal fat, 17.5% sucrose diet) containing BBR (160mg/kg/d, HFB) at weaning for 12 wk. The main outcome was to evaluate the effects of BBR on obesity, pancreatic islet function, and cardiac contractility in GDM-exposed HF-fed offspring. Significance between measurements was determined using a 2 (gestational exposure) × 3 (diet) factorial design by a 2- way ANOVA using Tukey post-hoc analysis. In the GDM-HF group, body weights were significantly increased (16%) compared with those in baseline (L-LF) animals (P<0.05). Compared with the L-LF animals, the GDM-HF group had a reduction in pancreatic insulin glucose-stimulated insulin secretion (74%) and increased cardiac isovolumetric contraction time (IVCT; ∼150%) (P<0.05). Compared with GDM-HF animals, the GDM-HFB group with the dietary addition of BBR had significantly reduced body weight (16%), increased glucose-stimulated insulin secretion from pancreatic islets (254%), and reduced systolic heart function (46% IVCT) (P<0.05). In a mouse model of GDM, dietary BBR treatment provided protection from obesity and the development of pancreatic islet and cardiac dysfunction.

Effects of exogenous adiponectin supplementation in early pregnant PCOS mice on the metabolic syndrome of adult female offspring

ObjectivePCOS is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities. At present, PCOS has been confirmed to have a certain genetic background. Compared with healthy women, the vast majority of PCOS patients have hyperandrogenemia, and this excessive androgen exposure during pregnancy may affect the development of female fetuses. The aim of the current study was to investigate the effect of adiponectin intervention during early pregnancy of obese mice with PCOS on the metabolic phenotype of adult female offspring.MethodsAfter the PCOS model was established, C57BL/6J mice were divided into maternal-control, maternal-PCOS, and maternal-PCOS + APN groups. DHEA-induced PCOS mice were supplemented with adiponectin (10 mg/kg/day) in the early pregnancy in order to eliminate adverse hormone exposure and then traced for endocrine indicators in their adult female offspring, which were observed for metabolism syndrome or endocrine disturbance and exhibited the main effects of APN. To further explore the underlying mechanism, the relative expressions of phosphorylated AMPK, PI3K, and Akt were detected in the ovaries of offspring mice.ResultsThe serum testosterone level of the maternal-PCOS + APN group in early pregnancy was significantly lower than that of the maternal-PCOS group (p < 0.01). The serum testosterone level in the offspring-PCOS + APN group was significantly lower than in the offspring-PCOS group (p <0.05), the diestrus time characterized by massive granulocyte aggregation in the estrus cycle was significantly shorter than in the offspring-PCOS group (p<0.05), and the phenotypes of PCOS-like reproductive disorders and metabolic disorders, such as obesity, insulin resistance, impaired glucose tolerance, and hyperlipidemia, were also significantly improved in the offspring-PCOS + APN group (p < 0.05). Compared with the control group, the expression levels of phosphorylated AMPK, PI3K, and Akt in the offspring-PCOS group were significantly decreased (p < 0.05), while those in the offspring-PCOS + APN group were significantly increased (p < 0.05).ConclusionsAPN intervention in early pregnancy significantly reduced the adverse effects of maternal obesity and high androgen levels during pregnancy on female offspring and corrected the PCOS-like endocrine phenotype and metabolic disorders of adult female offspring. This effect may be caused by the activation of the AMPK/PI3K-Akt signaling pathway in PCOS offspring mice.

Metabolic Syndrome in Offspring of Parents with Metabolic Syndrome: A Meta-Analysis

Background: The metabolic syndrome (MetS) represents a clustering of risk factors for cardiovascular diseases that includes abdominal obesity, hypertension, dyslipidemia, and insulin resistance. Objectives: The objective of this study was to reassess the parent-offspring association of MetS since the available findings are still controversial. Methods: The Cochrane Library, PubMed, Embase, and Web of Science databases were searched to identify relevant articles. All studies comparing MetS status between the offspring of parents with MetS and offspring of parents without MetS were included in the analysis. Results: A total of 9 studies met the inclusion criteria and they were analyzed. Offspring of at least 1 parent with MetS had a higher risk of MetS (OR 3.88, 95% CI 2.58–5.83, p < 0.001). Sons and daughters of fathers with MetS both had a higher risk of MetS (OR 2.31, 95% CI 1.70–3.12, p < 0.001, and OR 1.73, 95% CI 1.37–2.18, p < 0.001, respectively). Sons and daughters of mothers with MetS both had a higher risk of MetS (OR 1.95, 95% CI 1.37–2.76, p = 0.0002, and OR 1.91, 95% CI 1.54–2.35, p < 0.001, respectively). Conclusion: This meta-analysis showed that there is a higher risk of MetS in the offspring of parents with MetS. However, there was no differential association of MetS according to gender and/or age of the offspring.

In utero exposure to maternal stressful life events and risk of polycystic ovary syndrome in the offspring: The Raine Study

BackgroundPCOS is the most common endocrine disorder in reproductive age women. The origins of PCOS are unknown but experimental and limited human evidence suggests that greater prenatal exposure to androgens may predispose to PCOS. Experimental evidence suggests that maternal stressors may affect reproductive function in the offspring via changes in prenatal androgen exposure. In this present study, we aim to investigate whether maternal stressful life events during pregnancy are associated with polycystic ovary morphology (PCOM) or polycystic ovary syndrome (PCOS) in adolescent offspring. MethodIn a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between maternal stressful life events during pregnancy in both early and late gestation, and subsequent circulating concentrations of ovarian and adrenal androgens, PCOM and PCOS in the normal menstrual cycle of offspring age 14–16 years. Maternal stressful life events were prospectively recorded during pregnancy at 18 and 34 weeks using a 10-point questionnaire. Female offspring (n = 223) completed a questionnaire about their menstrual cycles, underwent a clinical examination for hirsutism (Ferriman-Gallwey score) and transabdominal pelvic ultrasound examination to determine ovarian morphology according to standardized criteria for classification of PCOM. Plasma samples were obtained at day 2–6 of the normal menstrual cycle for measurement of androgens. PCOM was defined according to the international consensus definition, 2003 and the evidence-based guideline for the assessment and management of PCOS, 2018. PCOS was diagnosed according to Rotterdam criteria and National Institute of Health (NIH) criteria. Multivariate linear and logistic regression analyses were used to examine the associations between maternal stressful life event exposure and ovarian morphology (PCOM), circulating ovarian and adrenal androgens (clinical and biochemical hyperandrogenism (hirsutism)) and presence of PCOS. ResultsOf 223 recruited adolescent girls, 78 (35.9%) and 68 (31.3%) had PCOM by the 2003 and 2018 criteria respectively, while 66 (29.6%) and 37 (16.6%) had PCOS, using Rotterdam and NIH criteria, respectively. Most girls (141/223, 63.2%) were exposed to at least one stressful life event in early gestation and around half (121/223, 54.3%) were exposed to at least one stressful life event in late gestation. Maternal stressful life events in early gestation were associated with a statistically significant lower prevalence of PCOM when applying the 2003 criteria [adjusted odds ratio [aOR] and 95% confidence intervals (CI): 0.74 (95% CI: 0.55; 0.99)], and a similar association was detected when applying the 2018 PCOM criteria (aOR, 0.69, 95% CI: 0.50; 0.95)]. Maternal stressful life events in early gestation were also associated with lower circulating concentrations of testosterone (β = −0.05, 95% CI: −0.09; −0.004) and androstenedione (β = −0.05, 95% CI: −0.10; −0.002) in the offspring. No similar effects for PCOM or circulating androgens were detected in late gestation. No statistically significant associations between maternal stressful life events in early or late gestation with PCOS (neither Rotterdam nor NIH criteria) in adolescence were detected. The prospective collection of maternal stressful life events during both early and late gestation and direct measurement of PCOM, PCOS and circulating androgens in adolescence and key co-variates implies minimal possibility of recall, information bias and selection bias. ConclusionMaternal exposure to stressful life events in early gestation is associated with significantly reduced circulating ovarian and adrenal androgen concentrations in adolescence (testosterone and androstenedione), and an indication of fewer cases of polycystic ovary morphology (PCOM) defined by the 2003 international consensus definition and by the 2018 international evidence-based guideline, but has no effect on polycystic ovary syndrome (PCOS), diagnosed using either Rotterdam or NIH criteria.

Association Between Maternal Lifestyle and Risk of Metabolic Syndrome in Offspring-A Cross-Sectional Study From China.

BackgroundThe prevalence of MS among children and adolescents continues to rise, which has become an escalating serious health issue worldwide. It had been reported that maternal current lifestyle had a strong independent correlation with offspring health. However, it is not clear whether comprehensive lifestyle of mother has an impact on the MS risk in offspring and the role of offspring’s lifestyle in it.Methods and ResultsWe included 4,837 mother-child pairs from a multi-centered cross-sectional study conducted in China. The information of maternal lifestyle was obtained by self-reported questionnaire, and metabolic syndrome (MS) in offspring was determined by anthropometric measurements and blood tests. Logistic regression models were employed to evaluate the association between maternal lifestyle and risk of MS in offspring. We found maternal healthy lifestyle was independently associated with lower risk of offspring MS, and the risk of MS in offspring decreased with the increased number of maternal ideal lifestyle factors. Although adolescents’ lifestyle did not fully explain the relationship between maternal lifestyle and risk of offspring MS, compared with those had less ideal lifestyle factors in both mothers and offspring, the risk of offspring MS was lower in those had more ideal lifestyle factors in both mothers and adolescents.ConclusionsHealthy lifestyle in mothers was associated with a lower risk of MS in offspring, which was independent of offspring’s lifestyle. These findings support mother-based lifestyle intervention could be an effective strategy to reduce the MS risk in adolescents.