Sex-specific effects of prenatal bisphenol A exposure on transcriptome-interactome profiles of autism candidate genes in neural stem cells from offspring hippocampus

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 22, 2025

Bisphenol A (BPA), an endocrine-disrupting chemical, is increasingly linked to the pathogenesis of autism spectrum disorder (ASD). This study investigates effects prenatal BPA exposure on neural stem cells (NSCs) from hippocampi rat offspring, a brain region critical for neurodevelopment and implicated in ASD. Pregnant rats were administered with or vehicle control once daily via oral gavage gestational day 1 until parturition. NSCs isolated offspring's postnatal 1, RNA sequencing was performed examine transcriptomic alterations. Differentially expressed genes (DEGs) identified through RNA-seq further analyzed using Ingenuity Pathway Analysis (IPA) explore disrupted pathways. In addition, vitro proliferation assays conducted, utilizing immunofluorescence staining Sox2, cell marker, BrdU quantify proliferating NSCs. Our results revealed that induced sex-specific alterations NSC gene expression, ASD-related such as Atp1a3, Nefl, Grin1 being particularly dysregulated male offspring. Moreover, changes observed. The underscores BPA's potential environmental risk factor ASD, emphasizing need research into its role neurodevelopmental effects.

Language: Английский

---

Investigation of autism-related transcription factors underlying sex differences in the effects of bisphenol A on transcriptome profiles and synaptogenesis in the offspring hippocampus

Biology of Sex Differences, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 20, 2023

Abstract Background Bisphenol A (BPA) has been linked to susceptibility autism spectrum disorder (ASD). Our recent studies have shown that prenatal BPA exposure disrupted ASD-related gene expression in the hippocampus, neurological functions, and behaviors associated with ASD a sex-specific pattern. However, molecular mechanisms underlying effects of are still unclear. Methods Transcriptome data mining docking analyses were performed identify transcription factors (TFs) their target genes exposure. Gene ontology analysis was conducted predict biological functions these genes. The levels TFs targets hippocampus rat pups prenatally exposed measured using qRT-PCR analysis. role androgen receptor (AR) BPA-mediated regulation candidate investigated human neuronal cell line stably transfected AR-expression or control plasmid. Synaptogenesis, which is function transcriptionally regulated by TFs, assessed primary hippocampal neurons isolated from male female BPA. Results We found there sex difference on transcriptome profiles offspring hippocampus. In addition known AR ESR1, could directly interact novel (i.e., KDM5B, SMAD4, TCF7L2). also ASD. Prenatal sex-dependent manner. Moreover, involved dysregulation AUTS2 , KMT2C SMARCC2 . altered synaptogenesis increasing synaptic protein males but not females, number excitatory synapses increased only. Conclusions findings suggest other differences These may play an essential endocrine-disrupting chemicals, particularly BPA, bias

Language: Английский

---

Sex-specific impacts of prenatal bisphenol A exposure on genes associated with cortical development, social behaviors, and autism in the offspring’s prefrontal cortex

Biology of Sex Differences, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 15, 2024

Abstract Background Recent studies have shown that prenatal BPA exposure altered the transcriptome profiles of autism-related genes in offspring’s hippocampus, disrupting hippocampal neuritogenesis and causing male-specific deficits learning. However, sex differences effects on developing prefrontal cortex, which is another brain region highly implicated autism spectrum disorder (ASD), not been investigated. Methods We obtained data from RNA sequencing analysis cortex male female rat pups prenatally exposed to or control reanalyzed. BPA-responsive associated with cortical development social behaviors were selected for confirmation by qRT-PCR analysis. Neuritogenesis primary cells was examined. The assessed using two-trial three-chamber tests. impact downregulation a gene (i.e., Sema5a ) vivo interrogated siRNA-mediated knockdown an utero electroporation technique. Results Genes disrupted ASD showed sex-specific dysregulation. Slc9a9 , involved behaviors, downregulated only males, while Anxa2 Junb also linked suppressed females. increased males strong inverse correlation expression levels, whereas, females, decreased correlated levels. impaired utero. Consistent downregulations, novelty observed offspring but males. Conclusion This first study show dysregulated ASD-related functions, including sex-dependent manner. Our findings suggest that, besides could exert its adverse through molecular mechanisms turn would lead neuropathology clinical manifestations, deserves further investigation.

Language: Английский

---

ERK1/2 gene expression and hypomethylation of Alu and LINE1 elements in patients with type 2 diabetes with and without cataract: Impact of hyperglycemia‐induced oxidative stress

Journal of Diabetes Investigation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

ABSTRACT Aims This study aimed to delineate the effect of hyperglycemia on Alu/LINE‐1 hypomethylation and in ERK1/2 genes expression type 2 diabetes with without cataract. Methods included 58 diabetic patients cataracts, 50 36 healthy controls. After DNA extraction bisulfite treatment, LINE‐1 Alu methylation levels were assessed using Real‐time MSP. gene was analyzed through real‐time PCR. Total antioxidant capacity (TAC), fasting plasma glucose (FPG) measured colorimetric methods. Statistical analysis performed SPSS23, setting significance level at P < 0.05. Results The TAC significantly lower for cataract groups than controls (259.31 ± 122.99, 312.43 145.46, 372.58 132.95 nanomole Trolox equivalent) a significant correlation between FPG both ( 0.05). sequences found be statistically hypomethylated compared In these groups, directly correlated 0.05) but not LINE‐1. higher patients, showing increases 2.41‐fold 1.43‐fold ERK1, 1.27‐fold 1.5 ERK2, respectively. ERK1 levels. A reverse observed expression. Conclusions Our findings indicate that hyperglycemia‐induced oxidative stress may alter patterns induce aberrant sequences. These changes play contributing role complications such as cataracts.

Language: Английский

---

Machine learning of clinical phenotypes facilitates autism screening and identifies novel subgroups with distinct transcriptomic profiles

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 5, 2025

Autism spectrum disorder (ASD) presents significant challenges in diagnosis and intervention due to its diverse clinical manifestations underlying biological complexity. This study explored machine learning approaches enhance ASD screening accuracy identify meaningful subtypes using assessments from AGRE database integrated with molecular data GSE15402. Analysis of ADI-R scores a large cohort 2794 individuals demonstrated that deep models could achieve exceptional 95.23% (CI 94.32-95.99%). Notably, comparable performance was maintained streamlined set just 27 sub-items, suggesting potential for more efficient diagnostic tools. Clustering analyses revealed three distinct subgroups identifiable through both symptoms gene expression patterns. When were grouped based on features, stronger associations emerged between profiles compared grouping alone. These findings suggest starting detailed observations may be effective identifying biologically than beginning data. approach combining offers promising directions developing precise methods personalized strategies ASD.

Language: Английский

---

Transcripts derived from AmnSINE1 repetitive sequences are depleted in the cortex of autism spectrum disorder patients

Frontiers in Bioinformatics, Journal Year: 2025, Volume and Issue: 5

Published: April 9, 2025

Autism spectrum disorder (ASD) is a brain developmental disability with not-fully clarified etiogenesis. Current ASD research largely focuses on coding regions of the genome, but up to date much less known about contribution non-coding elements risk. The genome made DNA repetitive sequences (RS). Although RS were considered slightly more than "junk DNA", today have recognized role in almost every aspect human biology, especially developing brain. Our aim was test if transcription may play ASD. Global firstly investigated postmortem dorsolateral prefrontal cortex 13 patients and 39 matched controls. Results validated independent datasets. AmnSINE1 only significantly downregulated specimens. has been at multiple levels, showing that 1,416 genes containing are associated nervous system development autism susceptibility. This confirmed different experimental setting, such as organoid models cerebral cortex, harboring causative mutations. related transcriptionally co-regulated involved not formation can specifically be development. Looking for possible direct transcripts ASD, we report alter miRNA regulatory landscape neurogenesis. findings provide preliminary evidence supporting

Language: Английский

---

Regulatory roles of transposable elements on autism molecular neuropathology

Epigenomics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 9

Published: May 6, 2025

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by challenges in social communication and the presence of repetitive behaviors, typically diagnosed early childhood. In this review, we searched PubMed Google Scholar databases for relevant articles. ASD displays considerable heterogeneity symptomatology more common males, though shifting demographics indicate rising rates among minority populations. Transposable elements (TEs), which constitute approximately 50% mammalian genome, are increasingly recognized their contribution to disorders, including ASD. These mobile genetic can induce genomic instability modulate gene expression, thereby influencing pathology. Evidence suggests that specific TEs, such as L1 Alu elements, disrupt genes critical neurodevelopment contribute disorder's complexity. Furthermore, prenatal environmental exposures may activate potentially contributing neuroinflammation observed While precise regulatory roles non-coding TEs still under investigation require careful interpretation, integrating epigenetic aging markers like clocks holds promise advancing field. Future research focused on intricate relationship between factors, mechanisms, processes essential identifying novel biomarkers therapeutic targets, ultimately improving diagnosis interventions

Language: Английский

---

Epigenetic Gene-Regulatory Loci in Alu Elements Associated with Autism Susceptibility in the Prefrontal Cortex of ASD

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7518 - 7518

Published: April 19, 2023

Alu elements are transposable that can influence gene regulation through several mechanisms; nevertheless, it remains unclear whether dysregulation of contributes to the neuropathology autism spectrum disorder (ASD). In this study, we characterized element expression profiles and their sequence characteristics in prefrontal cortex tissues ASD unaffected individuals using RNA-sequencing data. Our results showed most differentially expressed belong family, with 659 loci corresponding 456 genes individuals. We predicted cis- trans-regulation host/distant by conducting correlation analyses. The level correlated significantly 133 host (cis-regulation, adjusted p < 0.05) associated as well cell survival death neuronal cells. Transcription factor binding sites promoter regions conserved candidate genes, including RORA. COBRA analyses postmortem brain significant hypomethylation global methylation subphenotypes DNA located near RNF-135 (p 0.05). addition, found density, which was increased = 0.042), ASD. Finally, determined a relationship between these findings severity (i.e., ADI-R scores) provide better understanding impact on molecular individuals, deserves further investigation.

Language: Английский

---

Investigation of chimeric transcripts derived from LINE-1 and Alu retrotransposons in cerebellar tissues of individuals with autism spectrum disorder (ASD)

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 19, 2024

Language: Английский

---

Host fecal DNA specific methylation signatures mark gut dysbiosis and inflammation in children affected by autism spectrum disorder

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Oct. 24, 2023

The gut-brain axis involves several bidirectional pathway communications including microbiome, bacterial metabolites, neurotransmitters as well immune system and is perturbed both in brain gastrointestinal disorders. Consistently, microbiota-gut-brain has been found altered autism spectrum disorder (ASD). We reasoned that such alterations occurring ASD may impact on methylation signatures of human host fecal DNA (HFD) possibly the types cells shed stools from intestinal tract giving origin to HFD. To test this hypothesis, we have performed whole genome analysis HFD an age-restricted cohort young children with (N = 8) healthy controls 7). In same previously investigated microbiota composition here refined searched for eventual associations data derived methylome analysis. Our results showed specific epigenetic DNA, especially at genes related inflammation, associated disease. By applying methylation-based deconvolution algorithm, mainly relative abundance those differed between patients controls. most differentially methylated regions fitted involved inflammatory response. Interestingly, using Horvath clock, affected age accelerated. believe present unprecedented approach be useful identification potentially extended other disorders diseases.

Language: Английский

---