Identifying the landscape of developmental toxicity new approach methodologies

Becker, Richard A.; Bianchi, Enrica; LaRocca, Jessica; Marty, M. Sue; Mehta, Vatsal

doi:10.1002/bdr2.2075

Cited by 7 publications

(2 citation statements)

References 37 publications

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“…Some advantages of working with SMOs for DART studies is the ability to quickly study the direct effects of chemicals on progeny in the absence of maternal metabolism and toxicity, the vast amount of information available about their embryology, and the opportunity to work with complete embryo models instead of less complex cell culture models [ 13 ]. As attention is increasingly being focused on designing integrated approaches to DART testing and assessment using NAMs, SMO-based assays can be used as a complementary component to cell-based assays and existing mammalian DART studies in support of safety assessment, hazard identification, and regulatory decision making [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Reproductive-Toxicity-Related Endpoints in C. elegans Are Consistent with Reduced Concern for Dimethylarsinic Acid Exposure Relative to Inorganic Arsenic

Camacho

Welch

Sprando

et al. 2023

JDB

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Exposures to arsenic and mercury are known to pose significant threats to human health; however, the effects specific to organic vs. inorganic forms are not fully understood. Caenorhabditis elegans’ (C. elegans) transparent cuticle, along with the conservation of key genetic pathways regulating developmental and reproductive toxicology (DART)-related processes such as germ stem cell renewal and differentiation, meiosis, and embryonic tissue differentiation and growth, support this model’s potential to address the need for quicker and more dependable testing methods for DART hazard identification. Organic and inorganic forms of mercury and arsenic had different effects on reproductive-related endpoints in C. elegans, with methylmercury (meHgCl) having effects at lower concentrations than mercury chloride (HgCl2), and sodium arsenite (NaAsO2) having effects at lower concentrations than dimethylarsinic acid (DMA). Progeny to adult ratio changes and germline apoptosis were seen at concentrations that also affected gravid adult gross morphology. For both forms of arsenic tested, germline histone regulation was altered at concentrations below those that affected progeny/adult ratios, while concentrations for these two endpoints were similar for the mercury compounds. These C. elegans findings are consistent with corresponding mammalian data, where available, suggesting that small animal model test systems may help to fill critical data gaps by contributing to weight of evidence assessments.

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Section: Introductionmentioning

confidence: 99%

Reproductive-Toxicity-Related Endpoints in C. elegans Are Consistent with Reduced Concern for Dimethylarsinic Acid Exposure Relative to Inorganic Arsenic

Camacho

Welch

Sprando

et al. 2023

JDB

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“…The rate of toxicological testing has not yet caught up to the rate of new chemicals being commercially introduced (Daston et al, 2022;Krewski et al, 2020). It is therefore imperative that rapid, reliable, and affordable higher-throughput toxicity screening methods be developed (Bal-Price, Hogberg, et al, 2018;Becker et al, 2022;Maertens et al, 2021). US government initiatives support the development and evaluation of new approach methodologies (NAMs) for use in hazard identification for regulatory purposes (EPA, 2020;FDA, 2017).…”

Section: Introductionmentioning

confidence: 99%

The worm Adult Activity Test (wAAT): A de novo mathematical model for detecting acute chemical effects in Caenorhabditis elegans

Hunt

Welch

Camacho

et al. 2023

J of Applied Toxicology

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We have adapted a semiautomated method for tracking Caenorhabditis elegans spontaneous locomotor activity into a quantifiable assay by developing a sophisticated method for analyzing the time course of measured activity. The 16‐h worm Adult Activity Test (wAAT) can be used to measure C. elegans activity levels for efficient screening for pharmacological and toxicity‐induced effects. As with any apical endpoint assay, the wAAT is mode of action agnostic, allowing for detection of effects from a broad spectrum of response pathways. With caffeine as a model mild stimulant, the wAAT showed transient hyperactivity followed by reversion to baseline. Mercury chloride (HgCl2) produced an early dose–response hyperactivity phase followed by pronounced hypoactivity, a behavior pattern we have termed a toxicant “escape response.” Methylmercury chloride (meHgCl) produced a similar pattern to HgCl2, but at much lower concentrations, a weaker hyperactivity response, and more pronounced hypoactivity. Sodium arsenite (NaAsO2) and dimethylarsinic acid (DMA) induced hypoactivity at high concentrations. Acute toxicity, as measured by hypoactivity in C. elegans adults, was ranked: meHgCl > HgCl2 > NaAsO2 = DMA. Caffeine was not toxic with the wAAT at tested concentrations. Methods for conducting the wAAT are described, along with instructions for preparing C. elegans Habitation Medium, a liquid nutrient medium that allows for developmental timing equivalent to that found with C. elegans grown on agar with OP50 Escherichia coli feeder cultures. A de novo mathematical parametric model for adult C. elegans activity and the application of this model in ranking exposure toxicity are presented.

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Identifying the landscape of developmental toxicity new approach methodologies

Becker

Bianchi

LaRocca

et al. 2022

Birth Defects Research

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Background The dynamics and complexities of in utero fetal development create significant challenges in transitioning from lab animal‐centric developmental toxicity testing methods to assessment strategies based on new approach methodologies (NAMs). Nevertheless, considerable progress is being made, stimulated by increased research investments and scientific advances, such as induced pluripotent stem cell‐derived models. To help identify developmental toxicity NAMs for toxicity screening and potential funding through the American Chemistry Council's Long‐Range Research Initiative, a systematic literature review was conducted to better understand the current landscape of developmental toxicity NAMs. Methods Scoping review tools were used to systematically survey the literature (2010–2021; ~18,000 references identified), results and metadata were then extracted, and a user‐friendly interactive dashboard was created. Results The data visualization dashboard, developed using Tableau® software, is provided as a free, open‐access web tool. This dashboard enables straightforward interactive queries and visualizations to identify trends and to distinguish and understand areas or NAMs where research has been most, or least focused. Conclusions Herein, we describe the approach and methods used, summarize the benefits and challenges of applying the systematic‐review techniques, and highlight the types of questions and answers for which the dashboard can be used to explore the many different facets of developmental toxicity NAMs.

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Identifying the landscape of developmental toxicity new approach methodologies

Cited by 7 publications

References 37 publications

Reproductive-Toxicity-Related Endpoints in C. elegans Are Consistent with Reduced Concern for Dimethylarsinic Acid Exposure Relative to Inorganic Arsenic

Reproductive-Toxicity-Related Endpoints in C. elegans Are Consistent with Reduced Concern for Dimethylarsinic Acid Exposure Relative to Inorganic Arsenic

The worm Adult Activity Test (wAAT): A de novo mathematical model for detecting acute chemical effects in Caenorhabditis elegans

Identifying the landscape of developmental toxicity new approach methodologies

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