Development of Integrated Approaches to Testing and Assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment DOI
Antonio F. Hernández,

Paulien Adriaanse,

Annette Aldrich

et al.

EFSA Journal, Journal Year: 2021, Volume and Issue: 19(6)

Published: June 1, 2021

The EFSA Panel on Plant Protection Products and their Residues (PPR) has developed, as a self-task mandate (EFSA-Q-2019-00100), two adverse outcome pathway (AOP)-informed integrated approach to testing assessment (IATA) case studies answer developmental neurotoxicity (DNT) hazard identification characterisation problem formulation that could support the regulatory decisions for pesticide active substances deltamethrin flufenacet.The IATA were developed assess applicability of DNT in vitro battery (IVB), designed explore fundamental neurodevelopmental processes, risk pesticides.For this purpose, an evidence-based-approach methodology was applied: 1) systematic literature review critical appraisal all evidence i.e. human observational studies, vivo data from rodent models new methodologies (NAMs, including high-throughput IVB zebrafish literature) both studies; 2) quantitative uncertainty analysis using expert knowledge elicitation (EKE) probabilistic approach; 3) integration AOP conceptual framework.This stepwise resulted postulation evidencebased network one studies.A quantification weight (WoE) Bayesian allowed postulated AOP.The taken conclusions be drawn with acceptable level certainty flufenacet is not neurotoxicant, supporting relevance mechanistic understanding.The show DNT-IVB illustrate usefulness AOP-informed decision making.The overall activity led improved interpretation by providing plausible link outcomes, which would contextualisation process.This Scientific Opinion allows PPR draft several recommendations implementation pesticides.

Language: Английский

Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development DOI Creative Commons
Ariane Lismer, Sarah Kimmins

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 14, 2023

Abstract Although more studies are demonstrating that a father’s environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought sperm exclusively contributed its genome to egg. More recently, association have shown various environmental exposures including poor diet, toxicants, stress, perturbed epigenetic marks in at important reproductive developmental loci were associated with offspring phenotypes. The cellular routes underlie how transmitted fertilization, resist reprogramming embryo, drive phenotypic changes only now beginning be unraveled. Here, we provide an overview of state field intergenerational paternal mammals present new insights into relationship between embryo development three pillars inheritance: chromatin, DNA methylation, non-coding RNAs. We evaluate compelling evidence sperm-mediated transmission retention embryo. Using landmark examples, discuss sperm-inherited regions may escape impact via implicate transcription factors, chromatin organization, transposable elements. Finally, link paternally functional pre- post-implantation Understanding factors will permit greater understanding related origins disease.

Language: Английский

Citations

76
Massively parallel in vivo Perturb-seq reveals cell-type-specific transcriptional networks in cortical development DOI Creative Commons

Xinhe Zheng,

Boli Wu,

Yuejia Liu

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(13), P. 3236 - 3248.e21

Published: May 20, 2024

Leveraging AAVs' versatile tropism and labeling capacity, we expanded the scale of in vivo CRISPR screening with single-cell transcriptomic phenotyping across embryonic to adult brains peripheral nervous systems. Through extensive tests 86 vectors AAV serotypes combined a transposon system, substantially amplified efficacy accelerated gene delivery from weeks days. Our proof-of-principle utero screen identified pleiotropic effects Foxg1, highlighting its tight regulation distinct networks essential for cell fate specification Layer 6 corticothalamic neurons. Notably, our platform can label >6% cerebral cells, surpassing current state-of-the-art at <0.1% by lentivirus, achieve analysis over 30,000 cells one experiment enable massively parallel Perturb-seq. Compatible various phenotypic measurements (single-cell or spatial multi-omics), it presents flexible approach interrogate function types vivo, translating variants their causal function.

Language: Английский

Citations

21
From Cohorts to Molecules: Adverse Impacts of Endocrine Disrupting Mixtures DOI Creative Commons
Nicolò Caporale, Michelle Leemans, Lina Birgersson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2017, Volume and Issue: unknown

Published: Oct. 23, 2017

ABSTRACT Convergent evidence associates endocrine disrupting chemicals (EDCs) with major, increasingly-prevalent human disorders. Regulation requires elucidation of EDC-triggered molecular events causally linked to adverse health outcomes, but two factors limit their identification. First, experiments frequently use individual chemicals, whereas real life entails simultaneous exposure multiple EDCs. Second, population-based and experimental studies are seldom integrated. This drawback was exacerbated until recently by lack physiopathologically meaningful systems that link epidemiological data results from model organisms. We developed a novel approach, integrating evidence. Starting 1,874 mother-child pairs we identified mixtures measured during early pregnancy, associated language delay or low-birth weight in offspring. These were then tested on complementary vitro vivo models. demonstrate each EDC mixture, at levels found pregnant women, disrupts hormone-regulated disease-relevant gene regulatory networks both the cellular organismal scale.

Language: Английский

Citations

139
Toward a Better Testing Paradigm for Developmental Neurotoxicity: OECD Efforts and Regulatory Considerations DOI Creative Commons

Magdalini Sachana,

Timothy J. Shafer,

Andrea Terron

et al.

Biology, Journal Year: 2021, Volume and Issue: 10(2), P. 86 - 86

Published: Jan. 23, 2021

Characterization of potential chemical-induced developmental neurotoxicity (DNT) hazard is considered for risk assessment purposes by many regulatory sectors. However, due to test complexity, difficulty in interpreting results and need substantial resources, the use vivo DNT guidelines has been limited animal data on are scarce. To address challenging endpoints such as DNT, Organisation Economic Co-Operation Development (OECD) chemical safety program working lately toward development integrated approaches testing (IATA) that rely a combination multiple layers (e.g., vitro, silico non-mammalian models) supported mechanistic knowledge organized according adverse outcome pathway (AOP) framework. In 2017, OECD convened dedicated expert group develop guidance document application interpretation derived from battery relies key neurodevelopmental processes complemented zebrafish assays. This review will provide brief overview project summarize various achievements relevance project. The also presents an opportunity describe considerations uptake vitro context.

Language: Английский

Citations

56
New advances in the diagnosis and treatment of autism spectrum disorders DOI Creative Commons
Lei Qin, Haijiao Wang,

Wenjing Ning

et al.

European journal of medical research, Journal Year: 2024, Volume and Issue: 29(1)

Published: June 10, 2024

Language: Английский

Citations

14
The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome—a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men DOI Creative Commons
Ariane Lismer, Xiaojian Shao, Marie-Charlotte Dumargne

et al.

Environmental Health Perspectives, Journal Year: 2024, Volume and Issue: 132(1)

Published: Jan. 1, 2024

The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT applied, well the Arctic, endocrine disrupting metabolite, p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) accumulates marine mammals and fish. p,p′-DDE exposures are linked birth defects, infertility, cancer, neurodevelopmental delays. Of particular concern potential of use impact generations come via heritable sperm epigenome.

Language: Английский

Citations

11
Potential similarities in gut microbiota composition between autism spectrum disorder and neurotypical siblings: Insights from a comprehensive meta-analysis DOI

Hongli Xiao,

Han Zhu,

Tong-Ao Zeng

et al.

Neuroscience, Journal Year: 2025, Volume and Issue: 567, P. 172 - 181

Published: Jan. 8, 2025

Language: Английский

Citations

1
Molecular switch of the dendrite-to-spine transport of TDP-43/FMRP-bound neuronal mRNAs and its impairment in ASD DOI Creative Commons
Pritha Majumder,

Biswanath Chatterjee,

Khadiza Akter

et al.

Cellular & Molecular Biology Letters, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 15, 2025

Abstract Background Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity learning/memory development. The trafficking mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into spines upon glutamate-induced receptor activation. However, molecular mechanism(s) behind spine entry under metabotropic glutamate (mGluR)-mediated neuroactivation long-term depression (LTD) as well fate these inside still elusive. Method Different imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence situ hybridization (FISH), live cell imaging, tracking using beacon, mouse model study used to elucidate a novel mechanism regulating mammalian neurons. Results We demonstrate here that brief mGluR1 activation-mediated dephosphorylation pFMRP (S499) results dissociation FMRP from TDP-43 handover TDP-43/ Rac1 mRNA complex track on microtubules myosin V actin filaments. thus enters translational reactivation increases mature density. In contrast, during mGluR1-mediated neuronal LTD, phosphorylated complex, being associated with kinesin 1-FMRP/cortactin/drebrin, owing Ca 2+ -dependent microtubule invasion spines, but without reactivation. VPA-ASD model, this regulation become anomalous. Conclusions This study, first time, highlights importance posttranslational modification RBPs, such neurodevelopmental disease-related protein FMRP, switch dendrite-to-spine specific neurotransmissions. misregulation could contribute pathogenesis FMRP-related neurodisorders including autism spectrum disorder (ASD). It also indicate connection between ASD neurodegenerative opens up new perspective research proteinopathy among patients ASD.

Language: Английский

Citations

1
Can Memantine Treat Autism? Answers from Preclinical and Clinical Studies DOI

Sawsan Aboul‐Fotouh,

Sohir M Zohny,

Esraa M. Elnahas

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2025, Volume and Issue: 169, P. 106019 - 106019

Published: Jan. 16, 2025

Language: Английский

Citations

1
Capsule DenseNet++: Enhanced autism detection framework with deep learning and reinforcement learning-based lifestyle recommendation DOI
Ahmed I. Alutaibi, Sunil Kumar Sharma, Ahmad Raza Khan

et al.

Computers in Biology and Medicine, Journal Year: 2025, Volume and Issue: 190, P. 110038 - 110038

Published: March 21, 2025

Language: Английский

Citations

1