Search Results (502)

Down syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer’s disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD. Full article

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring—including altered vocalizations, reduced sociability, and increased repetitive grooming—without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including Homer1 and Zswim6. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative Homer1 promoter, correlating with increased expression of the short isoform Homer1a, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring’s brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk. Full article

Background/Objectives: Low folate intake before and during pregnancy increases the risk of neural tube defects and other adverse outcomes. Gene variants such as MTHFR 677C>T (rs1801133) may increase risks associated with suboptimal folate intake. Our objective was to use BALB/cJ Mthfr^677C>T mice to evaluate the effects of the TT genotype and low folate diets on embryonic development and MTHFR protein expression in pregnant mice. Methods: Female 677CC (mCC) and 677TT (mTT) mice were fed control (2 mg folic acid/kg (2D)), 1 mg folic acid/kg (1D) and 0.3 mg folic acid/kg (0.3D) diets before and during pregnancy. Embryos and maternal tissues were collected at embryonic day 10.5. Embryos were examined for developmental delays and defects. Methyltetrahydrofolate (methylTHF) and total homocysteine (tHcy) were measured in maternal plasma, and MTHFR protein expression was evaluated in maternal liver. Results: MethylTHF decreased due to the experimental diets and mTT genotype. tHcy increased due to 0.3D and mTT genotype; mTT 0.3D mice had significantly higher tHcy than the other groups. MTHFR expression was lower in mTT liver than mCC. MTHFR protein expression increased due to low folate diets in mCC mice, whereas in mTT mice, MTHFR expression increased only due to 1D. Developmental delays were increased in the litters of mTT mice fed 1D and 0.3D. Conclusions: The Mthfr^677C>T mouse models the effects of the MTHFR 677TT genotype in humans and provides a folate-responsive model for examination of the effects of folate intake and the MTHFR 677C>T variant during gestation. Full article

The maternal–fetal environment is influenced by multiple factors, including nutrition and environmental contaminants, which can impact long-term development. Perinatal exposure to organophosphate flame retardants (OPFRs) disrupts energy homeostasis and causes maladaptive behaviors in mice. Maternal obesity affects development by impairing blood–brain barrier (BBB) formation, influencing brain regions involved in energy regulation and behavior. This study examined the combined effects of maternal obesity and perinatal OPFR treatment on offspring development. Female mice were fed either a low-fat (LFD) or a high-fat diet (HFD) for 8 weeks, mated, and treated with either sesame oil or an OPFR mixture (tris(1,3-dichloro-2-propyl)phosphate, tricresyl phosphate, and triphenyl phosphate, 1 mg/kg each) from gestational day 7 to postnatal day 14. Results showed that both maternal diet and OPFR treatment disrupted blood–brain barrier integrity, energy balance, and reproductive gene expression in the hypothalamus of neonates. The expression of hepatic genes related to lipid and xenobiotic metabolism was also altered. In adulthood, LFD OPFR-treated female offspring exhibited increased avoidance behavior, while HFD OPFR-treated females demonstrated memory impairments. Metabolic assessments revealed decreased energy expenditure and nighttime activity in LFD OPFR-treated females. These findings suggest that maternal diet and OPFR treatment alter hypothalamic and liver gene expression in neonates, potentially leading to long-term metabolic and behavioral changes. Full article

Tetrabromobisphenol A (TBBPA) is a brominated flame retardant widely used in consumer products. TBBPA is often detected in soil, water, organisms, and even in human blood and breast milk. Hence, it is accessible to developing fetuses and nursing offspring after maternal exposure. The reported evidence for the endocrine disruption of TBBPA in the brain has raised concerns regarding its effects on neurodevelopmental and behavioral functions. This study investigated the effects of TBBPA exposure on neurodevelopment. A cell-based developmental neurotoxicity assay was performed to determine whether TBBPA is a developmental neurotoxicant. The assay revealed TBBPA to be a developmental neurotoxicant. C57BL/6N maternal mice were administered TBBPA at 0, 0.24, and 2.4 mg/kg during pregnancy and lactation, and their offspring underwent behavioral testing. The behavioral experiments revealed sex-specific effects. In females, only a deterioration of the motor ability was observed. In contrast, deteriorations in motor function, memory, and social interaction were noted in males. Furthermore, we validated changes in the expression of genes associated with behavioral abnormalities, confirming that perinatal exposure to TBBPA, at the administered doses, can affect neurodevelopment and behavior in offspring. These findings highlight the need for more in-depth and multifaceted research on the toxicity of TBBPA. Full article

Background/Objectives: Maternal exposures are known to influence the risk of isolated cleft lip with or without cleft palate (CL/P)—a common and highly heritable birth defect with a multifactorial etiology. Methods: To identify new risk loci, we conducted a genome-wide gene–environment interaction (GEI) analysis of CL/P with maternal smoking and vitamin use in Filipinos (N_cases = 540, N_controls = 260). Since GEI analyses are typically low in power and the results can be difficult to interpret, we applied multiple testing frameworks to evaluate potential GEI effects: a one degree-of-freedom (1df) GxE test, the 3df joint test, and the two-step EDGE approach. Results: While no genome-wide significant interactions were detected, we identified 11 suggestive GEIs with smoking and 24 with vitamin use. Several implicated loci contain biologically plausible genes. Notable interactions with smoking include loci near FEZF1, TWIST2, and NET1. While FEZF1 is involved in early neuronal development, TWIST2 and NET1 regulate epithelial–mesenchymal transition, which is required for proper lip and palate fusion. Interactions with vitamins encompass CECR2—a chromatin remodeling protein required for neural tube closure—and FURIN, a critical protease during early embryogenesis that activates various growth factors and extracellular matrix proteins. The activity of both proteins is influenced by folic acid. Conclusions: Our findings highlight the critical role of maternal exposures in identifying genes associated with structural birth defects such as CL/P and provide new paths to explore for CL/P genetics. Full article

Background and Clinical Significance: Gliomas diagnosed during pregnancy are rare, and there are no established guidelines for their management. Effective treatment requires a multidisciplinary approach to balance maternal health and pregnancy preservation. Case Presentation: We here present a case of rapidly progressing glioma in a 33-year-old pregnant woman. The patient initially presented with a generalized tonic–clonic seizure at 21 weeks’ gestation. Imaging revealed a tumor in the right cerebral lobe, involving both cortical and subcortical structures, while magnetic resonance spectroscopy suggested a low-grade glioma. The patient remained clinically stable for two months but then developed severe headaches; MRI showed a worsening mass effect. At 34 weeks’ gestation, an emergency and premature caesarean section was performed under general anesthesia. The patient then underwent a craniotomy for maximal tumor resection, which was histologically and molecularly diagnosed as IDH wild-type glioblastoma (GB). Using qPCR, we found that the GB tissue showed upregulated expression of genes involved in cell structure (GFAP, VIM) and immune response (SSP1, TSPO), as well as increased expression of genes related to potential hormone response (AR, CYP19A1, ESR1, GPER1). After surgery, the patient showed resistance to Stupp protocol therapy, which was substituted with lomustine and bevacizumab combination therapy. Conclusions: This case illustrates that glioma may progress rapidly during pregnancy, but a favorable obstetric outcome is achievable. Management of similar cases should respect both the need for timely treatment and the patient’s informed decision. Full article

Background/Objectives: Fish eggs activated with UV-irradiated spermatozoa and exposed to the High Hydrostatic Pressure (HHP) shock to inhibit first cell cleavage develop as gynogenetic Doubled Haploids (DHs) that are fully homozygous individuals. Due to the expression of the recessive genes and side effects of the gamete treatment, survival of fish DHs is rather low, and most of the mitotic gynogenotes die before hatching. Nevertheless, as maternal gene products provided during oogenesis control the initial steps of embryonic development in fish, a maternal effect on the survival of gynogenotes needs to be also considered to affect efficiency of gynogenesis. Thus, the objective of this research was to apply an RNA-seq approach to discriminate transcriptional differences between rainbow trout (Oncorhynchus mykiss) eggs with varied abilities to develop after gynogenetic activation. Methods: Gynogenetic development of rainbow trout was induced in eggs originated from eight females. Maternal RNA was isolated and sequenced using RNA-Seq approach. Survival rates of gynogenotes and transcriptome profiles of eggs from different females were compared. Results: RNA-seq analysis revealed substantial transcriptional differences between eggs originated from different females, and a significant correlation between the ability of the eggs for gynogenesis and their transcriptomic profiles was observed. Genes whose expression was altered in eggs with the increased survival of DHs were mostly associated (GO BP) with the following biological processes: development, cell differentiation, cell migration and protein transport. Some of the genes are involved in the oocyte maturation (RASL11b), apoptosis (CASPASE 6, PGAM5) and early embryogenesis, including maternal to zygotic transition (GATA2). Conclusions: Inter-individual variation of the transcription of maternal genes correlated with the competence of eggs for gynogenesis suggest that at least part of the mortality of the rainbow trout DHs appear before activation of zygotic genome and expression of the lethal recessive traits. Full article

The intrauterine environment is increasingly recognised as a critical period for the emergence of mental health vulnerabilities. This review explores how adverse maternal exposures, such as psychological stress, infection, malnutrition, and environmental toxins, can disrupt foetal neurodevelopment via epigenetic mechanisms, contributing to the risk of psychiatric and neurodevelopmental disorders. Focusing primarily on human studies, we synthesise evidence on DNA methylation, histone modifications, and non-coding RNAs as key pathways through which the intrauterine environment influences gene regulation in the developing brain. We examine how timing of exposure, foetal sex, and gene–environment interactions modulate these effects, with particular attention to disorders such as schizophrenia, autism spectrum disorder, depression, and anxiety. The placenta emerges as a central mediator, both reflecting and shaping epigenetic changes in response to maternal signals. We also discuss the reversibility of epigenetic marks and highlight emerging interventions, including nutritional supplementation and maternal mental health support, that may buffer or reverse prenatal epigenetic programming. Methodological challenges are addressed, including tissue specificity and causal inference, and future directions are proposed toward integrating epigenetic biomarkers into early risk assessment and precision mental health and psychiatry. This review emphasises the importance of the prenatal period as a window of vulnerability and opportunity for shaping lifelong mental health. Full article

Epidural-related maternal fever (ERMF) occurs with significant incidence in women receiving local anesthetics such as ropivacaine via epidural catheter for pain relief during labor. The causal mechanism behind this phenomenon is still not fully resolved, but evidence suggests that these anesthetics cause sterile inflammation. In this observational study, we investigated a possible contributory role of the dual-specificity phosphatase-9 (DUSP9) controlling the activity of mitogen-activated protein kinases (MAPK), and also PH-domain and Leucine-rich repeat phosphatase (PHLPP) regulating AKT kinases. The data show that ropivacaine differentially affects the expression of these phosphatases in distinct cell types of the umbilical cord and placenta. The gene expression of DUSP9 was almost completely switched off in the presence of ropivacaine in HUVECs and extravillous trophoblasts for up to 6 h, while the expression of PHLPP1 was upregulated in HUVECs and syncytiotrophoblasts. Extravillous trophoblasts were identified as a source of pro-inflammatory mediators and regulatory miRNAs in response to ropivacaine. Placentae at term exhibited a distinct DUSP9 expression pattern, whether the patients belonged to the control group or received epidural analgesia with or without elevated body temperature. The observed data imply that ropivacaine induces complex effects on the MAPK and AKT pathways at the feto–maternal interface, which contribute to the ERMF phenomenon. Full article

During 2022, AIDS claimed a life every minute and about 9.2 million HIV-infected people were not on treatment. In addition, a person living with HIV is estimated to be 20–30 times more susceptible to developing active tuberculosis. Every year, 130,000 infants are newly infected, with vertical transmission being the main cause of pediatric HIV infection. Thus, the development of an effective, safe, and accessible vaccine for neonates and/or adults is an urgent need to prevent or control HIV infection or progression to AIDS. An effective HIV vaccine should induce long-lasting mucosal immunity, broadly neutralizing antibodies, innate immunity, and robust stimulation of CD4+ and CD8+ T-cell responses. Recombinant BCG is a promising live-attenuated bacterial vaccine vector because of its capacity to stimulate T-cell immunity. As a slow-growing microorganism, it provides prolonged low-level antigenic exposure upon infecting macrophages and APCs, potentially stimulating both effector and memory T-cell responses. BCG is considered safe and is currently administered to 80% of infants in countries where it is part of the national immunization program. Additionally, BCG offers several benefits as a live vaccine vehicle since it is cost-effective, easy to mass-produce, and heat stable. It is also well-suited for newborns, as maternal antibodies do not interfere with its efficacy. Furthermore, BCG has a strong safety profile, having been administered to over three billion people as a TB vaccine. In this review, we provide an extensive summary of the literature relating to immunogenicity studies in animal models performed since 2011. Moreover, we provide a comprehensive analysis of the key factors influencing the design of recombinant BCG as a live vaccine vehicle: (i) expression vectors; (ii) selection of HIV immunogen; (iii) promoters to regulate gene expression; (iv) BCG strain and BCG codon optimization; (v) genetic plasmid stability; (vi) influence of preexisting immunity, route, and dose immunization; and (vii) safety profile. Full article

A 2 × 3 factorial design was used to examine the effects of maternal probiotic supplementation (Bacillus subtilis and Bacillus amyloliquefaciens) and/or piglet dietary Trp levels on sow performance and fecal microbiota composition, as well as offspring pre-weaning performance and intestinal health parameters on the day of weaning. On day 83 of gestation, 48 sows were allocated to either: (1) control, or (2) control + probiotic (1.1 × 10⁹ colony forming units/kg of feed). Their litters were assigned to 0.22, 0.27, or 0.33% standardized ileal digestible (SID) Trp diets (0.17, 0.21 and 0.25 SID ratio of Trp to lysine (Trp:Lys), SID lysine = 1.3%). At weaning, one piglet per litter was sacrificed for intestinal health analysis. Diet had no effect on sow reproductive or offspring growth performance pre-weaning (p > 0.05). Maternal probiotic supplementation led to distinct microbial communities in the sow feces on day 114 of gestation, increasing the relative abundance of Anaerocella and Sporobacter, while decreasing Lactobacillus, Ruminococcus, and Christensenella (p < 0.05). In the offspring colonic digesta, maternal probiotic supplementation increased Dorea, Sporobacter, and Anaerobacterium, while reducing the potentially harmful phylum Proteobacteria, specifically the family Enterobacteriaceae (p < 0.05), with a tendency for a reduction in the genus Escherichia (p < 0.1). Maternal probiotic supplementation enhanced duodenal morphology and modulated the expression of genes in the ileum, including a downregulation of certain immune and barrier defense genes (p < 0.05). Piglets from probiotic sows had reduced branch chain fatty acids (BCFA) in the cecal digesta and an increase in the total VFA and acetate in the colonic digesta (p < 0.05). There were limited effects of Trp level in the offspring’s creep diet or maternal × creep interactions, though this analysis was likely confounded by the low creep feed intake (total of ~0.83 kg/litter). Full article

Retroviruses insert DNA copies of themselves into the chromosomes of their hosts forming proviruses that can synthesize new transmissible viruses. Exogenous retroviruses (XRVs) insert into the DNA of somatic cells and are transmitted infectiously. Endogenous retroviruses (ERVs) become inserted in the DNA of germline cells and are transmitted genetically. ERVs can spread through the genome by transposition. ERVs originate from an initial copy of an XRV inserted into the genome of an organism infected by the XRV. Many XRVs are transmitted maternally as well as horizontally; therefore, we consider the effect of maternal transmission on the evolution of virulence of an XRV. Our model shows that the XRV either evolves high virulence with low maternal transmission, or vice versa. We then consider the spread of ERV genes in conjunction with the infectious spread of an XRV. Beginning from a single copy of an ERV, we calculate the probability that it spreads to fixation (i.e., the state where all individuals contain ERV genes). This depends on its virulence and transposition rate. If the XRV is present, the fixation probability also depends on the virulence of the XRV and whether the ERV provides resistance to the XRV. An ERV with only a small deleterious effect on host fitness has a high fixation probability, particularly if it provides resistance to the XRV. We also show that, if an ERV does not spread to fixation, it can still cause elimination of the XRV, with the end result that the population is cleared of both XRV and ERV. Full article

As an emerging endocrine-disrupting agent and structural analog of bisphenol A (BPA), bisphenol B (BPB) raises significant concerns due to its potential to induce male reproductive toxicity. Despite its presence in maternal bodily fluids, the effects of BPB exposure on the reproductive system and its mechanisms in adult male offspring are poorly understood. By establishing a maternal BPB exposure model in mice, we found that the exposure reduced the relative weights of seminal vesicles and preputial glands, decreased the thickness of the seminiferous epithelium, enlarged the lumen area of seminiferous tubules, and lowered testosterone concentration and synthesis, as well as sperm count in 10-week-old male offspring. Bioinformatic analyses revealed that the differentially expressed genes were significantly associated with major histocompatibility complex I (MHC I)-mediated immunological processes, including immune system processes, antigen processing and presentation of exogenous peptide antigens via MHC class I, and interleukin-2 production. Importantly, molecular docking proposed a potential mechanistic model wherein BPB bound to estrogen receptor α (ERα) suppressed its testicular expression and triggered MHC class I gene overexpression, potentially promoting macrophage infiltration, CD4+/CD8+ T cell activation, and pro-inflammatory cytokine production. Our findings provide critical insights into the adverse effects of maternal BPB exposure on male reproductive development, suggesting that impairments in testicular morphology and spermatogenesis may be attributed to MHC I-mediated immunological responses and hormonal imbalances resulting from inhibited ERα signaling. These results underscore not only the toxicological risks associated with BPB but also potential therapeutic targets for mitigating male reproductive dysfunction. Full article

Genetic variations in the COL1A1 and COL1A2 genes have been linked to bone mineral density (BMD) and metabolic disorders. This study analyzed the associations of COL1A1 (rs1107946, rs1800012) and COL1A2 (rs42524) polymorphisms with BMD, obesity, and type 2 diabetes (T2D) in 554 postmenopausal women. Dual-energy X-ray absorptiometry assessed BMD, and genotyping was performed alongside an evaluation of metabolic and lifestyle factors. The COL1A1 rs1107946 AA genotype was associated with higher femoral neck BMD (p < 0.05), an over 10-fold increased obesity prevalence (p = 0.038), and a 3.5-fold higher T2D risk (p = 0.011)—a novel finding. The rs1800012 polymorphism showed age-dependent BMD effects: A allele carriers had lower femoral neck BMD in the 60–69 age group but higher total hip BMD in the 70–79 age group. Additionally, COL1A2 rs42524 GG homozygotes had a significantly higher incidence of maternal fractures (p < 0.05). These results highlight COL1A1 rs1107946 as a potential marker for both skeletal and metabolic risk, demonstrate the age-specific effects of rs1800012 on BMD, and identify rs42524 as a possible genetic indicator of familial fracture risk. These insights may inform personalized approaches to osteoporosis and metabolic disease prevention. Full article