Engineering a computable epiblast for in silico modeling of developmental toxicity.

Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the CompuCell3D.

Protecting Human and Animal Health: The Road from Animal Models to New Approach Methods.

Animals and animal models have been invaluable for our current understanding of human and animal biology, including physiology, pharmacology, biochemistry, and disease pathology. However, there are increasing concerns with continued use of animals in basic biomedical, pharmacological, and regulatory research to provide safety assessments for drugs and chemicals. There are concerns that animals do not provide sufficient information on toxicity and/or efficacy to protect the target population, so scientists are utilizing the principles of replacement, reduction, and refinement (the 3Rs) and increasing the development and application of new approach methods (NAMs).

Society for birth defects research and prevention's multidisciplinary research needs workshop 2022: A call to action.

The Society for Birth Defects Research and Prevention (BDRP) strives to understand and protect against potential hazards to developing embryos, fetuses, children, and adults by bringing together scientific knowledge from diverse fields. The theme of 62nd Annual Meeting of BDRP, "From Bench to Bedside and Back Again", represented the cutting-edge research areas of high relevance to public health and significance in the fields of birth defects research and surveillance. The multidisciplinary Research Needs Workshop (RNW) convened at the Annual Meeting continues to identify pressing knowledge gaps and encourage interdisciplinary research initiatives.

Computational model for fetal skeletal defects potentially linked to disruption of retinoic acid signaling.

All-trans retinoic acid (ATRA) gradients determine skeletal patterning morphogenesis and can be disrupted by diverse genetic or environmental factors during pregnancy, leading to fetal skeleton defects. Adverse Outcome Pathway (AOP) frameworks for ATRA metabolism, signaling, and homeostasis allow for the development of new approach methods (NAMs) for predictive toxicology with less reliance on animal testing. Here, a data-driven model was constructed to identify chemicals associated with both ATRA pathway bioactivity and prenatal skeletal defects.

Identifying candidate reference chemicals for in vitro testing of the retinoid pathway for predictive developmental toxicity.

Evaluating chemicals for potential in vivo toxicity based on their in vitro bioactivity profile is an important step toward animal- free testing. A compendium of reference chemicals and data describing their bioactivity on specific molecular targets, cellular pathways, and biological processes is needed to bolster confidence in the predictive value of in vitro hazard detection. Endogenous signaling by all-trans retinoic acid (ATRA) is an important pathway in developmental processes and toxicities.

Pluripotent stem cell assays: Modalities and applications for predictive developmental toxicity.

This manuscript provides a review focused on embryonic stem cell-based models and their place within the landscape of alternative developmental toxicity assays. Against the background of the principles of developmental toxicology, the wide diversity of alternative methods using pluripotent stem cells developed in this area over the past half century is reviewed. In order to provide an overview of available models, a systematic scoping review was conducted following a published protocol with inclusion criteria, which were applied to select the assays.

Quantitative in vitro to in vivo extrapolation for developmental toxicity potency of valproic acid analogues.

Background: The developmental toxicity potential (dTP) concentration from the devTOX quickPredict (devTOX ) assay, a metabolomics-based human induced pluripotent stem cell assay, predicts a chemical's developmental toxicity potency. Here, in vitro to in vivo extrapolation (IVIVE) approaches were applied to address whether the devTOX assay could quantitatively predict in vivo developmental toxicity lowest effect levels (LELs) for the prototypical teratogen valproic acid (VPA) and a group of structural analogues.

Methods: VPA and a series of structural analogues were tested with the devTOX assay to determine dTP concentration and we estimated the equivalent administered doses (EADs) that would lead to plasma concentrations equivalent to the in vitro dTP concentrations.

Improving the quality of toxicology and environmental health systematic reviews: What journal editors can do.

Systematic reviews are fast increasing in prevalence in the toxicology and environmental health literature. However, how well these complex research projects are being conducted and reported is unclear. Since editors have an essential role in ensuring the scientific quality of manuscripts being published in their journals, a workshop was convened where editors, systematic review practitioners, and research quality control experts could discuss what editors can do to ensure the systematic reviews they publish are of sufficient scientific quality.

FutureTox IV Workshop Summary: Predictive Toxicology for Healthy Children.

FutureTox IV, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in November 2018. Building upon FutureTox I, II, and III, this conference focused on the latest science and technology for in vitro profiling and in silico modeling as it relates to predictive developmental and reproductive toxicity (DART). Publicly available high-throughput screening data sets are now available for broad in vitro profiling of bioactivities across large inventories of chemicals.

Single-cell profiling for advancing birth defects research and prevention.

Cellular analysis of developmental processes and toxicities has traditionally entailed bulk methods (e.g., transcriptomics) that lack single cell resolution or tissue localization methods (e.

Computational Biology and Toxicodynamics.

New approach methodologies (NAMs) refer to any non-animal technology, methodology, approach, or combination thereof that can be used to provide information on chemical hazard and risk assessment that avoids the use of intact animals. A spectrum of models is needed for the integrated analysis of various domains in toxicology to improve predictivity and reduce animal testing. This review focuses on approaches, computer models, and computational intelligence for developmental and reproductive toxicity (predictive DART), providing a means to measure toxicodynamics in simulated systems for quantitative prediction of adverse outcomes phenotypes.

Retinoid signaling in skeletal development: Scoping the system for predictive toxicology.

All-trans retinoic acid (ATRA), the biologically active form of vitamin A, is instrumental in regulating the patterning and specification of the vertebrate embryo. Various animal models demonstrate adverse developmental phenotypes following experimental retinoid depletion or excess during pregnancy. Windows of vulnerability for altered skeletal patterning coincide with early specification of the body plan (gastrulation) and regional specification of precursor cell populations forming the facial skeleton (cranial neural crest), vertebral column (somites), and limbs (lateral plate mesoderm) during organogenesis.

Meeting report on the NIDDK/AUA Workshop on Congenital Anomalies of External Genitalia: challenges and opportunities for translational research.

Congenital anomalies of the external genitalia (CAEG) are a prevalent and serious public health concern with lifelong impacts on the urinary function, sexual health, fertility, tumor development, and psychosocial wellbeing of affected individuals. Complications of treatment are frequent, and data reflecting long-term outcomes in adulthood are limited. To identify a path forward to improve treatments and realize the possibility of preventing CAEG, the National Institute of Diabetes and Digestive and Kidney Diseases and the American Urological Association convened researchers from a range of disciplines to coordinate research efforts to fully understand the different etiologies of these common conditions, subsequent variation in clinical phenotypes, and best practices for long term surgical success.

An ontology for developmental processes and toxicities of neural tube closure.

In recent years, the development and implementation of animal-free approaches to chemical and pharmaceutical hazard and risk assessment has taken off. Alternative approaches are being developed starting from the perspective of human biology and physiology. Neural tube closure is a vital step that occurs early in human development.

A cross-platform approach to characterize and screen potential neurovascular unit toxicants.

Development of the neurovascular unit (NVU) is a complex, multistage process that requires orchestrated cell signaling mechanisms across several cell types and ultimately results in formation of the blood-brain barrier. Typical high-throughput screening (HTS) assays investigate single biochemical or single cell responses following chemical insult. As the NVU comprises multiple cell types interacting at various stages of development, a methodology combining high-throughput results across pertinent cell-based assays is needed to investigate potential chemical-induced disruption to the development of this complex cell system.

New ideas for non-animal approaches to predict repeated-dose systemic toxicity: Report from an EPAA Blue Sky Workshop.

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a 'Blue Sky Workshop' on new ideas for non-animal approaches to predict repeated-dose systemic toxicity. The aim of the Workshop was to formulate strategic ideas to improve and increase the applicability, implementation and acceptance of modern non-animal methods to determine systemic toxicity. The Workshop concluded that good progress is being made to assess repeated dose toxicity without animals taking advantage of existing knowledge in toxicology, thresholds of toxicological concern, adverse outcome pathways and read-across workflows.

Profiling the ToxCast Library With a Pluripotent Human (H9) Stem Cell Line-Based Biomarker Assay for Developmental Toxicity.

The Stemina devTOX quickPredict platform is a human pluripotent stem cell-based assay that predicts the developmental toxicity potential based on changes in cellular metabolism following chemical exposure [Palmer, J. A., Smith, A.

Systems Modeling of Developmental Vascular Toxicity.

The more than 80,000 chemicals in commerce present a challenge for hazard assessments that toxicity testing in the 21 century strives to address through high-throughput screening (HTS) assays. Assessing chemical effects on human development adds an additional layer of complexity to the screening, with a need to capture complex and dynamic events essential for proper embryo-fetal development. HTS data from ToxCast/Tox21 informs systems toxicology models, which incorporate molecular targets and biological pathways into mechanistic models describing the effects of chemicals on human cells, 3D organotypic culture models, and small model organisms.

Identification and Profiling of Environmental Chemicals That Inhibit the TGFβ/SMAD Signaling Pathway.

The transforming growth factor beta (TGFβ) superfamily of secreted signaling molecules and their cognate receptors regulate cell fate and behaviors relevant to many developmental and disease processes. Disruption of TGFβ signaling during embryonic development can, for example, affect morphogenesis and differentiation through complex pathways that may be SMAD (Small Mothers Against Decapentaplegic) dependent or SMAD independent. In the present study, the SMAD Binding Element (SBE)-beta lactamase () HEK 293T cell line, which responds to the activation of the SMAD2/3/4 complex, was used in a quantitative high-throughput screening (qHTS) assay to identify potential TGFβ disruptors in the Tox21 10K compound library.

Molecular characterization of a toxicological tipping point during human stem cell differentiation.

Endoderm gives rise to the gut tube in the early embryo. We differentiated human induced pluripotent stem cells (hiPSCs) to embryonic endoderm to identify a "tipping point" at which the developing system did not recover from perturbations caused by exposure to all-trans retinoic acid (ATRA). Differentiating hiPSC-derived endoderm exposed to five concentrations of ATRA between 0.

Characterizing cleft palate toxicants using ToxCast data, chemical structure, and the biomedical literature.

Cleft palate has been linked to both genetic and environmental factors that perturb key events during palatal morphogenesis. As a developmental outcome, it presents a challenging, mechanistically complex endpoint for predictive modeling. A data set of 500 chemicals evaluated for their ability to induce cleft palate in animal prenatal developmental studies was compiled from Toxicity Reference Database and the biomedical literature, which included 63 cleft palate active and 437 inactive chemicals.

The Next Generation Blueprint of Computational Toxicology at the U.S. Environmental Protection Agency.

The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data.