4 research outputs found
STopTox: An in Silico Alternative to Animal Testing for Acute Systemic and Topical Toxicity
BACKGROUND: Modern chemical toxicology is facing a growing need to Reduce, Refine, and Replace animal tests (Russell 1959) for hazard identification. The most common type of animal assays for acute toxicity assessment of chemicals used as pesticides, pharmaceuticals, or in cosmetic products is known as a "6-pack" battery of tests, including three topical (skin sensitization, skin irritation and corrosion, and eye irritation and corrosion) and three systemic (acute oral toxicity, acute inhalation toxicity, and acute dermal toxicity) end points. METHODS: We compiled, curated, and integrated, to the best of our knowledge, the largest publicly available data sets and developed an ensemble of quantitative structure-activity relationship (QSAR) models for all six end points. All models were validated according to the Organisation for Economic Co-operation and Development (OECD) QSAR principles, using data on compounds not included in the training sets. RESULTS: In addition to high internal accuracy assessed by cross-validation, all models demonstrated an external correct classification rate ranging from 70% to 77%. We established a publicly accessible Systemic and Topical chemical Toxicity (STopTox) web portal (https://stoptox.mml.unc.edu/) integrating all developed models for 6-pack assays. CONCLUSIONS: We developed STopTox, a comprehensive collection of computational models that can be used as an alternative to in vivo 6-pack tests for predicting the toxicity hazard of small organic molecules. Models were established following the best practices for the development and validation of QSAR models. Scientists and regulators can use the STopTox portal to identify putative toxicants or nontoxicants in chemical libraries of interest. https://doi.org/10.1289/EHP9341
Loss of CD4+ T cell-intrinsic arginase 1 accelerates Th1 response kinetics and reduces lung pathology during influenza infection
Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies
Decoding the Molecular Universe -- Workshop Report
On August 9-10, 2023, a workshop was convened at the Pacific Northwest
National Laboratory (PNNL) in Richland, WA that brought together a group of
internationally recognized experts in metabolomics, natural products discovery,
chemical ecology, chemical and biological threat assessment, cheminformatics,
computational chemistry, cloud computing, artificial intelligence, and novel
technology development. These experts were invited to assess the value and
feasibility of a grand-scale project to create new technologies that would
allow the identification and quantification of all small molecules, or to
decode the molecular universe. The Decoding the Molecular Universe project
would extend and complement the success of the Human Genome Project by
developing new capabilities and technologies to measure small molecules
(defined as non-protein, non-polymer molecules less than 1500 Daltons) of any
origin and generated in biological systems or produced abiotically. Workshop
attendees 1) explored what new understanding of biological and environmental
systems could be revealed through the lens of small molecules; 2) characterized
the similarities in current needs and technical challenges between each science
or mission area for unambiguous and comprehensive determination of the
composition and quantities of small molecules of any sample; 3) determined the
extent to which technologies or methods currently exist for unambiguously and
comprehensively determining the small molecule composition of any sample and in
a reasonable time; and 4) identified the attributes of the ideal technology or
approach for universal small molecule measurement and identification. The
workshop concluded with a discussion of how a project of this scale could be
undertaken, possible thrusts for the project, early proof-of-principle
applications, and similar efforts upon which the project could be modeled
STopTox: An In-Silico Alternative to Animal Testing for Acute Systemic and TOPical TOXicity
Since 2009, animal testing for cosmetic products has
been prohibited in Europe, and in 2016, US EPA announced their intent to
modernize the so-called "6-pack" of acute toxicity tests (acute oral
toxicity, acute dermal toxicity, acute inhalation toxicity, skin irritation and
corrosion, eye irritation and corrosion, and skin sensitization) and expand
acceptance of alternative methods to reduce animal testing of pesticides. We
have compiled, curated, and integrated the largest publicly available dataset and
developed an ensemble of QSAR models for all six endpoints. All models were
validated according to the OECD QSAR principles and tested using newly
identified data on compounds not included in the training sets. We have
established a publicly accessible Systemic and Topical chemical Toxicity (STopTox)
web portal (https://stoptox.mml.unc.edu/) integrating all developed models for “6-pack”
assays. This portal can be used by
scientists and regulators to identify putative toxicants or non-toxicants in
chemical libraries of interest.</p