Computational modeling and simulation of genital tubercle development

Leung, Maxwell C.K.; Hutson, M. Shane; Seifert, Ashley W.; Spencer, Richard M.; Knudsen, Thomas B.

doi:10.1016/j.reprotox.2016.05.005

Cited by 39 publications

(25 citation statements)

References 80 publications

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“…Using this platform, a computer model of somite development has been explored with and without the traditional clock‐and‐wavefront mechanism (Dias, de Almeida, Belmonte, Glazier, & Stern, ; Hester, Belmonte, Gens, Clendenon, & Glazier, ). Other embryological events that have been similarly modeled in dynamical computer simulations including urethral fusion during sexual diversification of the genital tubercle (Leung, Hutson, Seifert, Spencer, & Knudsen, ) and fusion of the secondary palatal processes (Hutson, Leung, Baker, Spencer, & Knudsen, ). Manipulation of these dynamic computer models can simulate exposures that interfere with development; for example, the effects of perturbing the androgen‐dependent growth of the genital tubercle (Leung et al, ) or the TGF / EGF switch that controls fusion of palatal shelves (Hutson et al, ) can be used to predict critical effects of chemical exposures.…”

Section: Revolutionmentioning

confidence: 99%

Rethinking developmental toxicity testing: Evolution or revolution?

Scialli

Daston

Chen

et al. 2018

Birth Defects Research

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Background Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo‐fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? Methods A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). Results The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. The revolution could start with hypothesis‐driven testing where we take what we know about a compound or close analog and answer specific questions using targeted experimental techniques rather than a one‐protocol‐fits‐all approach. Central to the idea of hypothesis‐driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. Discussion Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach.

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Section: Revolutionmentioning

confidence: 99%

Rethinking developmental toxicity testing: Evolution or revolution?

Scialli

Daston

Chen

et al. 2018

Birth Defects Research

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“…The outcomes of this testing battery can then be fed into the model to predict adverse health effects. The virtual embryo project at US EPA has successfully shown the feasibility of this approach for selected aspects of embryogenesis (18)(19)(20).…”

Section: Lecture Summariesmentioning

confidence: 99%

Workshop on acceleration of the validation and regulatory acceptance of alternative methods and implementation of testing strategies

Piersma

Burgdorf

Louekari

et al. 2018

Toxicology in Vitro

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This report describes the proceedings of the BfR-RIVM workshop on validation of alternative methods which was held 23 and 24 March 2017 in Berlin, Germany. Stakeholders from governmental agencies, regulatory authorities, universities, industry and the OECD were invited to discuss current problems concerning the regulatory acceptance and implementation of alternative test methods and testing strategies, with the aim to develop feasible solutions. Classical validation of alternative methods usually involves one to one comparison with the gold standard animal study. This approach suffers from the reductionist nature of an alternative test as compared to the animal study as well as from the animal study being considered as the gold standard. Modern approaches combine individual alternatives into testing strategies, for which integrated and defined approaches are emerging at OECD. Furthermore, progress in mechanistic toxicology, e.g. through the adverse outcome pathway approach, and in computational systems toxicology allows integration of alternative test battery results into toxicity predictions that are more fine-tuned to the human situation. The road towards transition to a mechanistically-based human-focused hazard and risk assessment of chemicals requires an open mind towards stepping away from the animal study as the gold standard and defining human biologically based regulatory requirements for human hazard and risk assessment.

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“…In addition to investigating molecular and cellular effects of toxicant exposure, in vitro platforms that capture embryonic BBB development or represent all cells of the NVU are valuable for informing “virtual tissue models” (VTMs) of BBB development. VTMs are computational representations of tissue development (e.g., angiogenesis (Kleinstreuer et al, ), genital tubercle fusion (Leung, Hutson, Seifert, Spencer, & Knudsen, ), or palate fusion (Hutson, Leung, Baker, Spencer, & Knudsen, )), which can be interrogated by simulated toxicant exposure, as long as the molecular targets of the toxicant have been identified (e.g., through ToxCast testing).…”

Section: Adverse Outcome Pathways For Developmental Bbb Disruptionmentioning

confidence: 99%

Blood‐brain barrier development: Systems modeling and predictive toxicology

Saili

Zurlinden

Schwab

et al. 2017

Birth Defects Research

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The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the brain. Here, we review BBB development with regard to the microphysiology of the neurovascular unit (NVU) and the impact of BBB disruption on brain development. Our focus is on modeling these complex systems. Extant in silico models are available as tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening and high-content imaging provide novel data streams for profiling chemical-biological interactions; and engineered human cell-based microphysiological systems provide empirical models with which to investigate the dynamics of NVU function. Computational models are needed that bring together kinetic and dynamic aspects of NVU function across gestation and under various physiological and toxicological scenarios. This integration will inform adverse outcome pathways to reduce uncertainty in translating in vitro data and in silico models for use in risk assessments that aim to protect neurodevelopmental health.

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Computational modeling and simulation of genital tubercle development

Cited by 39 publications

References 80 publications

Rethinking developmental toxicity testing: Evolution or revolution?

Rethinking developmental toxicity testing: Evolution or revolution?

Workshop on acceleration of the validation and regulatory acceptance of alternative methods and implementation of testing strategies

Blood‐brain barrier development: Systems modeling and predictive toxicology

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