Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food.

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.

Early-life exposure to tobacco, genetic susceptibility, and accelerated biological aging in adulthood.

Early-life tobacco exposure serves as a non-negligible risk factor for aging-related diseases. To understand the underlying mechanisms, we explored the associations of early-life tobacco exposure with accelerated biological aging and further assessed the joint effects of tobacco exposure and genetic susceptibility. Compared with those without in utero exposure, participants with in utero tobacco exposure had an increase in Klemera-Doubal biological age (KDM-BA) and PhenoAge acceleration of 0.26 and 0.49 years, respectively, but a decrease in telomere length of 5.34% among 276,259 participants. We also found significant dose-response associations between the age of smoking initiation and accelerated biological aging. Furthermore, the joint effects revealed that high-polygenic risk score participants with in utero exposure and smoking initiation in childhood had the highest accelerated biological aging. There were interactions between early-life tobacco exposure and age, sex, deprivation, and diet on KDM-BA and PhenoAge acceleration. These findings highlight the importance of reducing early-life tobacco exposure to improve healthy aging.

Severe drought exposure in utero associates to children's epigenetic age acceleration in a global climate change hot spot.

The goal of this study is to examine the association between in utero drought exposure and epigenetic age acceleration (EAA) in a global climate change hot spot. Calculations of EAA in adults using DNA methylation have been found to accurately predict chronic disease and longevity. However, fewer studies have examined EAA in children, and drought exposure in utero has not been investigated. Additionally, studies of EAA in low-income countries with diverse populations are rare. We assess EAA using epigenetic clocks and two DNAm-based pace-of-aging measurements from whole saliva samples in 104 drought-exposed children and 109 same-sex sibling controls in northern Kenya. We find a positive association between in utero drought exposure and EAA in two epigenetic clocks (Hannum's and GrimAge) and a negative association in the DNAm based telomere length (DNAmTL) clock. The combined impact of drought's multiple deleterious stressors may reduce overall life expectancy through accelerated epigenetic aging.

Placental DNA methylation signatures of prenatal air pollution exposure and potential effects on birth outcomes: an analysis of three prospective cohorts.

BACKGROUND: Pregnancy air pollution exposure (PAPE) has been linked to a wide range of adverse birth and childhood outcomes, but there is a paucity of data on its influence on the placental epigenome, which can regulate the programming of physiological functions and affect child development. This study aimed to investigate the association between prenatal air pollutant exposure concentrations and changes in placental DNA methylation patterns, and to explore the potential windows of susceptibility and sex-specific alterations. METHODS: This multi-site study used three prospective population-based mother-child cohorts: EDEN, PELAGIE, and SEPAGES, originating from four French geographical regions (Nancy, Poitiers, Brittany, and Grenoble). Pregnant women were included between 2003 and 2006 for EDEN and PELAGIE, and between 2014 and 2017 for SEPAGES. The main eligibility criteria were: being older than 18 years, having a singleton pregnancy, and living and planning to deliver in one of the maternity clinics in one of the study areas. A total of 1539 mother-child pairs were analysed, measuring placental DNA methylation using Illumina BeadChips. We used validated spatiotemporally resolved models to estimate PM2·5, PM10, and NO2 exposure over each trimester of pregnancy at the maternal residential address. We conducted a pooled adjusted epigenome-wide association study to identify differentially methylated 5'-C-phosphate-G-3' (CpG) sites and regions (assessed using the Infinium HumanMethylationEPIC BeadChip array, n=871), including sex-specific and sex-linked alterations, and independently validated our results (assessed using the Infinium HumanMethylation450 BeadChip array, n=668). FINDINGS: We identified four CpGs and 28 regions associated with PAPE in the total population, 469 CpGs and 87 regions in male infants, and 150 CpGs and 66 regions in female infants. We validated 35% of the CpGs available. More than 30% of the identified CpGs were related to one (or more) birth outcome and most significant alterations were enriched for neural development, immunity, and metabolism related genes. The 28 regions identified for both sexes overlapped with imprinted genes (four genes), and were associated with neurodevelopment (nine genes), immune system (seven genes), and metabolism (five genes). Most associations were observed for the third trimester for female infants (134 of 150 CpGs), and throughout pregnancy (281 of 469 CpGs) and the first trimester (237 of 469 CpGs) for male infants. INTERPRETATION: These findings highlight the molecular pathways through which PAPE might affect child health in a widespread and sex-specific manner, identifying the genes involved in the major physiological functions of a developing child. Further studies are needed to elucidate whether these epigenetic changes persist and affect health later in life. FUNDING: French Agency for National Research, Fondation pour la Recherche Médicale, Fondation de France, and the Plan Cancer.

Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy.

BACKGROUND: Diabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA. METHODS: To identify DMRs, we employed the bump hunter method in samples from young (9-16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28-33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle. RESULTS: One significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring's own adiposity. CONCLUSIONS: Our results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.

Epigenetic mechanisms linking early-life adversities and mental health.

Early-life adversities, whether prenatal or postnatal exposure, have been linked to adverse mental health outcomes later in life increasing the risk of several psychiatric disorders. Research on its neurobiological consequences demonstrated an association between exposure to adversities and persistent alterations in the structure, function, and connectivity of the brain. Consistent evidence supports the idea that regulation of gene expression through epigenetic mechanisms are involved in embedding the impact of early-life experiences in the genome and mediate between social environments and later behavioral phenotypes. In addition, studies from rodent models and humans suggest that these experiences and the acquired risk factors can be transmitted through epigenetic mechanisms to offspring and the following generations potentially contributing to a cycle of disease or disease risk. However, one of the important aspects of epigenetic mechanisms, unlike genetic sequences that are fixed and unchangeable, is that although the epigenetic markings are long-lasting, they are nevertheless potentially reversible. In this review, we summarize our current understanding of the epigenetic mechanisms involved in the mental health consequences derived from early-life exposure to malnutrition, maltreatment and poverty, adversities with huge and pervasive impact on mental health. We also discuss the evidence about transgenerational epigenetic inheritance in mammals and experimental data suggesting that suitable social and pharmacological interventions could reverse adverse epigenetic modifications induced by early-life negative social experiences. In this regard, these studies must be accompanied by efforts to determine the causes that promote these adversities and that result in health inequity in the population.

Investigating gene-environment interaction on attention in a double-hit model for Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental behavioral disorder characterized by social, communicative, and motor deficits. There is no single etiological cause for ASD, rather, there are various genetic and environmental factors that increase the risk for ASD. It is thought that some of these factors influence the same underlying neural mechanisms, and that an interplay of both genetic and environmental factors would better explain the pathogenesis of ASD. To better appreciate the influence of genetic-environment interaction on ASD-related behaviours, rats lacking a functional copy of the ASD-linked gene Cntnap2 were exposed to maternal immune activation (MIA) during pregnancy and assessed in adolescence and adulthood. We hypothesized that Cntnap2 deficiency interacts with poly I:C MIA to aggravate ASD-like symptoms in the offspring. In this double-hit model, we assessed attention, a core deficit in ASD due to prefrontal cortical dysfunction. We employed a well-established attentional paradigm known as the 5-choice serial reaction time task (5CSRTT). Cntnap2-/- rats exhibited greater perseverative responses which is indicative of repetitive behaviors. Additionally, rats exposed to poly I:C MIA exhibited premature responses, a marker of impulsivity. The rats exposed to both the genetic and environmental challenge displayed an increase in impulsive activity; however, this response was only elicited in the presence of an auditory distractor. This implies that exacerbated symptomatology in the double-hit model may situation-dependent and not generally expressed.

DNA methylation signatures of youth-onset type 2 diabetes and exposure to maternal diabetes.

OBJECTIVE: Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is known to be a specific risk factor for youth-onset T2D. DNA methylation (DNAm) changes associated with T2D but which differ between youth- and adult-onset might delineate the impacts of T2D development at different ages and could also determine the contribution of exposure to in utero diabetes. METHODS: We performed an epigenome-wide analysis of DNAm on whole blood from 218 youth with T2D and 77 normoglycemic controls from the iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) cohort. Associations were tested using multiple linear regression models while adjusting for maternal diabetes, sex, age, BMI, smoking status, second-hand smoking exposure, cell-type proportions and genetic ancestry. RESULTS: We identified 3830 differentially methylated sites associated with youth T2D onset, of which 3794 were moderately (adjusted p-value < 0.05 and effect size estimate > 0.01) associated and 36 were strongly (adjusted p-value < 0.05 and effect size estimate > 0.05) associated. A total of 3725 of these sites were not previously reported in the EWAS Atlas as associated with T2D, adult obesity or youth obesity. Moreover, three CpGs associated with youth-onset T2D in the PFKFB3 gene were also associated with maternal T2D exposure (FDR < 0.05 and effect size > 0.01). This is the first study to link PFKFB3 and T2D in youth. CONCLUSION: Our findings support that T2D in youth has different impacts on DNAm than adult-onset, and suggests that changes in DNAm could provide an important link between in utero exposure to maternal diabetes and the onset of T2D.

Distinct epigenetic modulation of differentially expressed genes in the adult mouse brain following prenatal exposure to low-dose bisphenol A.

Bisphenol A (BPA) is a common component in the manufacture of daily plastic consumer goods. Recent studies have suggested that prenatal exposure to BPA can increase the susceptibility of offspring to mental illness, although the underlying mechanisms remain unclear. In this study, we performed transcriptomic and epigenomic profiling in the adult mouse brain following prenatal exposure to low-dose BPA. We observed a sex-specific transcriptional dysregulation in the cortex, with more significant differentially expressed genes was observed in adult cortex from male offspring. Moreover, the upregulated genes primarily influenced neuronal functions, while the downregulated genes were significantly associated with energy metabolism pathways. More evidence supporting impaired mitochondrial function included a decreased ATP level and a reduced number of mitochondria in the cortical neuron of the BPA group. We further investigated the higher-order chromatin regulatory patterns of DEGs by incorporating published Hi-C data. Interestingly, we found that upregulated genes exhibited more distal interactions with multiple enhancers, while downregulated genes displayed relatively short-range interactions among adjacent genes. Our data further revealed decreased H3K9me3 signal on the distal enhancers of upregulated genes, whereas increased DNA methylation and H3K27me3 signals on the promoters of downregulated genes. In summary, our study provides compelling evidence for the potential health risks associated with prenatal exposure to BPA, and uncovers sex-specific transcriptional changes with a complex interplay of multiple epigenetic mechanisms.

The Molecular Basis of the Augmented Cardiovascular Risk in Offspring of Mothers with Hypertensive Disorders of Pregnancy.

The review examines the impact of maternal preeclampsia (PE) on the cardiometabolic and cardiovascular health of offspring. PE, a hypertensive disorder of pregnancy, is responsible for 2 to 8% of pregnancy-related complications. It significantly contributes to adverse outcomes for their infants, affecting the time of birth, the birth weight, and cardiometabolic risk factors such as blood pressure, body mass index (BMI), abdominal obesity, lipid profiles, glucose, and insulin. Exposure to PE in utero predisposes offspring to an increased risk of cardiometabolic diseases (CMD) and cardiovascular diseases (CVD) through mechanisms that are not fully understood. The incidence of CMD and CVD is constantly increasing, whereas CVD is the main cause of morbidity and mortality globally. A complex interplay of genes, environment, and developmental programming is a plausible explanation for the development of endothelial dysfunction, which leads to atherosclerosis and CVD. The underlying molecular mechanisms are angiogenic imbalance, inflammation, alterations in the renin-angiotensin-aldosterone system (RAAS), endothelium-derived components, serotonin dysregulation, oxidative stress, and activation of both the hypothalamic-pituitary-adrenal axis and hypothalamic-pituitary-gonadal axis. Moreover, the potential role of epigenetic factors, such as DNA methylation and microRNAs as mediators of these effects is emphasized, suggesting avenues for future research and therapeutic interventions.

Investigating GABA Neuron-Specific Androgen Receptor Knockout in two Hyperandrogenic Models of PCOS.

Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signaling in GABAergic neurons is critical in PCOS pathogenesis in 2 well-characterized hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic peripubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to gonadotropin-releasing hormone (GnRH) neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy, and impaired glucose homeostasis, was not different between GABARKO and wild-type (WT) mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinizing hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signaling in GABA neurons is largely not required for the development of PCOS-like traits in androgenized models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signaling in GABA neurons.

Prenatal psychological distress and 11ß-HSD2 gene expression in human placentas: Systematic review and meta-analysis.

BACKGROUND: The placenta acts as a buffer to regulate the degree of fetal exposure to maternal cortisol through the 11-Beta Hydroxysteroid Dehydrogenase isoenzyme type 2 (11-ß HSD2) enzyme. We conducted a systematic review and meta-analysis to assess the effect of prenatal psychological distress (PPD) on placental 11-ß HSD2 gene expression and explore the related mechanistic pathways involved in fetal neurodevelopment. METHODS: We searched PubMed, Embase, Scopus, APA PsycInfo®, and ProQuest Dissertations for observational studies assessing the association between PPD and 11-ß HSD2 expression in human placentas. Adjusted regression coefficients (ß) and corresponding 95% confidence intervals (CIs) were pooled based on three contextual PPD exposure groups: prenatal depression, anxiety symptoms, and perceived stress. RESULTS: Of 3159 retrieved records, sixteen longitudinal studies involving 1869 participants across seven countries were included. Overall, exposure to PPD disorders showed weak negative associations with the placental 11-ß HSD2 gene expression as follows: prenatal depression (ß -0.01, 95% CI 0.05-0.02, I2=0%), anxiety symptoms (ß -0.02, 95% CI 0.06-0.01, I2=0%), and perceived stress (ß -0.01 95% CI 0.06-0.04, I2=62.8%). Third-trimester PPD exposure was more frequently associated with lower placental 11-ß HSD2 levels. PPD and placental 11-ß HSD2 were associated with changes in cortisol reactivity and the development of adverse health outcomes in mothers and children. Female-offspring were more vulnerable to PPD exposures. CONCLUSION: The study presents evidence of a modest role of prenatal psychological distress in regulating placental 11-ß HSD2 gene expression. Future prospective cohorts utilizing larger sample sizes or advanced statistical methods to enhance the detection of small effect sizes should be planned. Additionally, controlling for key predictors such as the mother's ethnicity, trimester of PPD exposure, mode of delivery, and infant sex is crucial for valid exploration of PPD effects on fetal programming.

Differential impact of prenatal PTSD symptoms and preconception trauma exposure on placental NR3C1 and FKBP5 methylation.

Perinatal stress is associated with altered placental methylation, which plays a critical role in fetal development and infant outcomes. This proof-of-concept pilot study investigated the impact of lifetime trauma exposure and perinatal PTSD symptoms on epigenetic regulation of placenta glucocorticoid signaling genes (NR3C1 and FKBP5). Lifetime trauma exposure and PTSD symptoms during pregnancy were assessed in a racially/ethnically diverse sample of pregnant women (N = 198). Participants were categorized into three groups: (1) No Trauma (-T); (2) Trauma, No Symptoms (T - S); and (3) Trauma and Symptoms (T + S). Placental tissue was analyzed via bisulfite pyrosequencing for degree of methylation at the NR3C1 promoter and FKBP5 regulatory regions. Analyses of covariance were used to test group differences in percentages of NR3C1 and FKBP5 methylation overall and at each CpG site. We found a significant impact of PTSD symptoms on placental NR3C1 methylation. Compared to the -T group, the T + S group had greater NR3C1 methylation overall and at CpG6, CpG8, CpG9, and CpG13, but lower methylation at CpG5. The T + S group had significantly higher NR3C1 methylation overall and at CpG8 compared to the T - S group. There were no differences between the T - S group and - T group. Additionally, no group differences emerged for FKBP5 methylation. Pregnant trauma survivors with PTSD symptoms exhibited differential patterns of placental NR3C1 methylation compared to trauma survivors without PTSD symptoms and pregnant women unexposed to trauma. Results highlight the critical importance of interventions to address the mental health of pregnant trauma survivors.

Pre-eclamptic foetal programming predisposes offspring to hepatic steatosis via DNA methylation.

OBJECTIVES: Gamete and embryo-foetal origins of adult diseases hypothesis proposes that adulthood chronic disorders are associated with adverse foetal and early life traits. Our study aimed to characterise developmental changes and underlying mechanisms of metabolic disorders in offspring of pre-eclampsia (PE) programmed pregnancy. METHODS: Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME) induced pre-eclampsia-like C57BL/6J mouse model was used. Lipid profiling, histological morphology, indirect calorimetry, mRNA sequencing, and pyrosequencing were performed on PE offspring of both young and elderly ages. RESULTS: PE offspring exhibited increased postnatal weight gain, hepatic lipid accumulation, enlarged adipocytes, and impaired energy balance that continued to adulthood. Integrated RNA sequencing of foetal and 52-week-old livers revealed that the differentially expressed genes were mainly enriched in lipid metabolism, including glycerol-3-phosphate acyl-transferase 3 (Gpat3), a key enzyme for de novo synthesis of triglycerides (TG), and carnitine palmitoyltransferase-1a (Cpt1a), a key transmembrane enzyme that mediates fatty acid degradation. Pyrosequencing of livers from PE offspring identified hypomethylated and hypermethylated regions in Gpat3 and Cpt1a promoters, which were associated with upregulated and downregulated expressions of Gpat3 and Cpt1a, respectively. These epigenetic alterations are persistent and consistent from the foetal stage to adulthood in PE offspring. CONCLUSION: These findings suggest a methylation-mediated epigenetic mechanism for PE-induced intergenerational lipid accumulation, impaired energy balance and obesity in offspring, and indicate the potential benefits of early interventions in offspring exposed to maternal PE to reduce their susceptibility to metabolic disorder in their later life.

Translational toxicoepigenetic Meta-Analyses identify homologous gene DNA methylation reprogramming following developmental phthalate and lead exposure in mouse and human offspring.

Although toxicology uses animal models to represent real-world human health scenarios, a critical translational gap between laboratory-based studies and epidemiology remains. In this study, we aimed to understand the toxicoepigenetic effects on DNA methylation after developmental exposure to two common toxicants, the phthalate di(2-ethylhexyl) phthalate (DEHP) and the metal lead (Pb), using a translational paradigm that selected candidate genes from a mouse study and assessed them in four human birth cohorts. Data from mouse offspring developmentally exposed to DEHP, Pb, or control were used to identify genes with sex-specific sites with differential DNA methylation at postnatal day 21. Associations of human infant DNA methylation in homologous mouse genes with prenatal DEHP or Pb were examined with a meta-analysis. Differential methylation was observed on 6 cytosines (adjusted-p < 0.05) and 90 regions (adjusted-p < 0.001). This translational approach offers a unique method that can detect conserved epigenetic differences that are developmentally susceptible to environmental toxicants.

Associations between maternal serum neonicotinoid pesticide exposure during pregnancy and newborn telomere length: Effect modification by sampling season.

BACKGROUND: An increasing amount of evidence suggests that telomere length (TL) at birth can predict lifespan and is associated with chronic diseases later in life, but newborn TL may be affected by environmental pollutants. Neonicotinoids (NEOs) are widely used worldwide, and despite an increasing number of studies showing that they may have adverse effects on birth in mammals and even humans, few studies have examined the effect of NEO exposure on newborn TLs. OBJECTIVE: To investigate the effects of prenatal exposure to NEOs and the interactions between NEOs and sampling season on newborn TL. METHODS: We conducted a prospective cohort study of 500 mother-newborn pairs from the Guangxi Zhuang Birth Cohort. Ultraperformance liquid chromatographymass spectrometry was used to detect ten NEOs in maternal serum, and fluorescence quantitative PCR was used to estimate the newborn TL. A generalized linear model (GLM) was used to evaluate the relationships between individual NEO exposures and TLs , and quantile g-computation (Qgcomp) model and Bayesian kernel machine regression (BKMR) model were used to evaluate the combined effect of mixtures of components. RESULTS: The results of the GLM showed that compared with maternal TMX levels < LOD, maternal TMX levels < median were negatively correlated with newborn TL (-6.93%, 95% CI%: -11.92%, -1.66%), and the decrease in newborn TL was more pronounced in girls (-9.60%, 95% CI: -16.84%, -1.72%). Moreover, different kinds of maternal NEO exposure had different effects on newborn TL in different sampling seasons, and the effect was statistically significant in all seasons except in autumn. Mixed exposure analysis revealed a potential positive trend between NEOs and newborn TL, but the association was not statistically significant. CONCLUSION: Prenatal exposure to TMX may shorten newborn TL, and this effect is more pronounced among female newborns. Furthermore, the relationship between NEO exposure and TL may be modified by the sampling season.

In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

Circular RNA Gtdc1 Protects Against Offspring Osteoarthritis Induced by Prenatal Prednisone Exposure by Regulating SRSF1-Fn1 Signaling.

Chondrodysplasia is closely associated with low birth weight and increased susceptibility to osteoarthritis in adulthood. Prenatal prednisone exposure (PPE) can cause low birth weight; however, its effect on offspring cartilage development remains unexplored. Herein, rats are administered clinical doses of prednisone intragastrically on gestational days (GDs) 0-20 and underwent long-distance running during postnatal weeks (PWs) 24-28. Knee cartilage is assayed for quality and related index changes on GD20, PW12, and PW28. In vitro experiments are performed to elucidate the mechanism. PPE decreased cartilage proliferation and matrix synthesis, causing offspring chondrodysplasia. Following long-distance running, the PPE group exhibited more typical osteoarthritis-like changes. Molecular analysis revealed that PPE caused cartilage circRNomics imbalance in which circGtdc1 decreased most significantly and persisted postnatally. Mechanistically, prednisolone reduced circGtdc1 expression and binding with Srsf1 to promote degradation of Srsf1 via K48-linked polyubiquitination. This further inhibited the formation of EDA/B+Fn1 and activation of PI3K/AKT and TGFß pathways, reducing chondrocyte proliferation and matrix synthesis. Finally, intra-articular injection of offspring with AAV-circGtdc1 ameliorated PPE-induced chondrodysplasia, but this effect is reversed by Srsf1 knockout. Altogether, this study confirms that PPE causes chondrodysplasia and susceptibility to osteoarthritis by altering the circGtdc1-Srsf1-Fn1 axis; in vivo, overexpression of circGtdc1 can represent an effective intervention target for ameliorating PPE-induced chondrodysplasia.

Maternal nicotine exposure promotes hippocampal CeRNA-mediated excitotoxicity and social barriers in adolescent offspring mice.

Nicotine, an addictive component of cigarettes, causes cognitive defects, particularly when exposure occurs early in life. However, the exact mechanism through which nicotine causes toxicity and alters synaptic plasticity is still not fully understood. The aim of the current study is to examine how non-coding developmental regulatory RNA impacts the hippocampus of mice offspring whose mothers were exposed to nicotine. Female C57BL/6J mice were given nicotine water from one week before pregnancy until end of lactation. Hippocampal tissue from offspring at 20 days post-birth was used for LncRNA and mRNA microarray analysis. Differential expression of LncRNAs and mRNAs associated with neuronal development were screened and validated, and the CeRNA pathway mediating neuronal synaptic plasticity GM13530/miR-7119-3p/mef2c was predicted using LncBase Predicted v.2. Using protein immunoblotting, Golgi staining and behavioral tests, our findings revealed that nicotine exposure in offspring mice increased hippocampal NMDAR receptor, activated receptor-dependent calcium channels, enhanced the formation of NMDAR/nNOS/PSD95 ternary complexes, increased NO synthesis, mediated p38 activation, induced neuronal excitability toxicity. Furthermore, an epigenetic CeRNA regulatory mechanism was identified, which suppresses Mef2c-mediated synaptic plasticity and leads to modifications in the learning and social behavior of the offspring during adolescence. This study uncovers the way in which maternal nicotine exposure results in neurotoxicity in offspring.

Gestational Intermittent Hypoxia Enhances Mammary Stem Cells and Alters Tumor Phenotype in Adult Female Offspring.

An adverse perinatal environment can increase long-term cancer risk, although the precise nature of associated perinatal triggers remain unknown. Sleep apnea is a common condition during pregnancy, characterized by recurrent cessations in breathing during sleep, and the potential consequences of sleep apnea during pregnancy as it relates to breast cancer risk in offspring have not been explored. To model sleep apnea, Sprague-Dawley dams were exposed during gestation to nightly intermittent hypoxia (GIH) or normoxia (GNx), and the mammary glands of female offspring were examined. GIH offspring demonstrated increased epithelial stem and progenitor cell populations, which are associated with diminished transforming growth factor beta (TGFß) activity. Elevations in adipose tissue stem cells in the mammary gland were also identified in GIH offspring. In aging females, mammary tumors formed in GIH offspring. These tumors displayed a dramatic increase in stroma compared to tumors from GNx offspring, as well as distinct patterns of expression of stem cell-related pathways. Together, these results suggest that exposure to sleep apnea during pregnancy leads to lasting changes in the mammary glands of female offspring. Increased stem and progenitor cell populations as a result of GIH exposure could enhance long-term breast cancer risk, as well as alter the clinical behavior of resulting breast tumors.