A genomics-based framework for identifying biomarkers of human neurodevelopmental toxicity

Robinson, Joshua F.; Gormley, Mathew J.; Fisher, Susan J.

doi:10.1016/j.reprotox.2016.01.007

Cited by 8 publications

(3 citation statements)

References 56 publications

(35 reference statements)

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“…and also the chromatin condenser H1F0, which may trigger transcriptional repression (Figure S5G). VPA treatment of human neurons also dysregulated many genes that were previously reported by other teratogenic VPA models but analyzed at different time points using different experimental protocols with different VPA doses (Table S1; compare with Krug et al, 2013;Robinson et al, 2016;Zhang et al, 2017Zhang et al, , 2018.…”

Section: Intrinsic Membrane Properties Action-potential Generationmentioning

confidence: 64%

Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

et al. 2019

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Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.

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Section: Intrinsic Membrane Properties Action-potential Generationmentioning

confidence: 64%

Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

et al. 2019

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“…Within this subset of related TFs, we explored transcript abundance in CTBs isolated from second trimester versus term human placentas using an RNA-seq dataset previously generated in our laboratory (Roadmap Epigenomics et al, 2015). Expression data was processed as described previously (Robinson et al, 2016). Abundance and significance of differential expression between second trimester versus term was determined using DESeq2 and Wald's test (Chen et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

Genomic Profiling of BDE-47 Effects on Human Placental Cytotrophoblasts

Robinson

Kapidzic

Hamilton

et al. 2018

Toxicological Sciences

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Despite gradual legislative efforts to phase out flame retardants (FRs) from the marketplace, polybrominated diphenyl ethers (PBDEs) are still widely detected in human maternal and fetal tissues, e.g., placenta, due to their continued global application in consumer goods and inherent biological persistence. Recent studies in rodents and human placental cell lines suggest that PBDEs directly cause placental toxicity. During pregnancy, trophoblasts play key roles in uterine invasion, vascular remodeling and anchoring of the placenta-fetal unit to the mother. Thus, to study the potential consequences of PBDE exposures on human placental development, we used an in vitro model: primary villous cytotrophoblasts (CTBs). Following exposures, the endpoints that were evaluated included cytotoxicity, function (migration, invasion), the transcriptome, and the methylome. In a concentration-dependent manner, common PBDE congeners, BDE-47 and -99, significantly reduced cell viability and increased death. Upon exposures to sub-cytotoxic concentrations (≤ 5µM), we observed BDE-47 accumulation in CTBs with limited evidence of metabolism. At a functional level, BDE-47 hindered the ability of CTBs to migrate and invade. Transcriptomic analyses of BDE-47 effects suggested concentration-dependent changes in gene expression, involving stress pathways, e.g., inflammation and lipid/cholesterol metabolism as well as processes underlying trophoblast fate, e.g., differentiation, migration, and vascular morphogenesis. In parallel assessments, BDE-47 induced low-level global increases in methylation of CpG islands, including a subset that were proximal to genes with roles in cell adhesion/migration. Thus, using a primary human CTB model, we showed that PBDEs induced alterations at cellular and molecular levels, which could adversely impact placental development.

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“…Integrative data analysis, a systematic approach that combines diverse data types, can help unravel complex problems . Toxicogenomic integration analyses − have been used to identify toxicity biomarkers ,− and reveal common toxic effects of pollutants across species . In this study, we collected transcriptomic datasets of various animal models from public databases, processed raw data, and utilized integration analyses to identify commonly affected biological processes and signaling pathways following BPA exposure.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Integration Analyses Uncover Common Bisphenol A Effects Across Species and Tissues Primarily Mediated by Disruption of JUN/FOS, EGFR, ER, PPARG, and P53 Pathways

Yang,

Lu,

Yin

et al. 2023

Environ. Sci. Technol.

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Bisphenol A (BPA) is a common endocrine disruptor widely used in the production of electronic, sports, and medical equipment, as well as consumer products like milk bottles, dental sealants, and thermal paper. Despite its widespread use, current assessments of BPA exposure risks remain limited due to the lack of comprehensive cross-species comparative analyses. To address this gap, we conducted a study aimed at identifying genes and fundamental molecular processes consistently affected by BPA in various species and tissues, employing an effective data integration method and bioinformatic analyses. Our findings revealed that exposure to BPA led to significant changes in processes like lipid metabolism, proliferation, and apoptosis in the tissues/cells of mammals, fish, and nematodes. These processes were found to be commonly affected in adipose, liver, mammary, uterus, testes, and ovary tissues. Additionally, through an in-depth analysis of signaling pathways influenced by BPA in different species and tissues, we observed that the JUN/FOS, EGFR, ER, PPARG, and P53 pathways, along with their downstream key transcription factors and kinases, were all impacted by BPA. Our study provides compelling evidence that BPA indeed induces similar toxic effects across different species and tissues. Furthermore, our investigation sheds light on the underlying molecular mechanisms responsible for these toxic effects. By uncovering these mechanisms, we gain valuable insights into the potential health implications associated with BPA exposure, highlighting the importance of comprehensive assessments and awareness of this widespread endocrine disruptor.

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A genomics-based framework for identifying biomarkers of human neurodevelopmental toxicity

Cited by 8 publications

References 56 publications

Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

Direct Reprogramming of Human Neurons Identifies MARCKSL1 as a Pathogenic Mediator of Valproic Acid-Induced Teratogenicity

Genomic Profiling of BDE-47 Effects on Human Placental Cytotrophoblasts

Transcriptomic Integration Analyses Uncover Common Bisphenol A Effects Across Species and Tissues Primarily Mediated by Disruption of JUN/FOS, EGFR, ER, PPARG, and P53 Pathways

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