A metabolomics approach to reveal the mechanism of developmental toxicity in zebrafish embryos exposed to 6-propyl-2-thiouracil

Wilhelmi, P.; Giri, Varun; Zickgraf, Franziska Maria; Haake, Volker; Henkes, Stefan; Driemert, Peter; Michaelis, Paul; Busch, Wibke; Scholz, Stefan; Flick, Burkhard; Barenys, Marta; Birk, Barbara; Kamp, Hennicke; Landsiedel, Robert; Funk-Weyer, Dorothee

doi:10.1016/j.cbi.2023.110565

Cited by 3 publications

(6 citation statements)

References 63 publications

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“…Single-embryo untargeted metabolomics allowed for a direct correlation between morphological and metabolic phenotypes, which mutually influence each other as demonstrated in the PCA. The number of features was augmented by a factor of five compared to our targeted approach (Wilhelmi et al 2023 ). Yet, a major challenge in untargeted metabolomics resides in the annotation process.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the selection of test concentrations plays a pivotal role in elucidating a specific metabolic effect pattern. We previously applied a concentration–response modelling and point-of-departure approach to determine the test concentration depicting a specific response (Wilhelmi et al 2023 ). For a robust modeling, however, at least five test concentrations are required, which ideally include nonspecific responses to fit the lower and upper asymptote of the response curve.…”

Section: Discussionmentioning

confidence: 99%

“…The approach was further extended to in vitro systems, demonstrating that different modes of liver toxicity can be distinguished based on their metabolome response in HepG2 cells (Ramirez-Hincapie et al 2023 ). Furthermore, we previously demonstrated through targeted metabolomics in ZFE that metabolite changes provide a mechanistic link to thyroid-related developmental toxicity (Wilhelmi et al 2023 ). However, two major limiting factors emerged from this study.…”

Section: Introductionmentioning

confidence: 99%

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Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish

Wilhelmi,

Haake,

Zickgraf

et al. 2024

Arch Toxicol

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Angiogenesis is a key process in embryonic development, a disruption of this process can lead to severe developmental defects, such as limb malformations. The identification of molecular perturbations representative of antiangiogenesis in zebrafish embryo (ZFE) may guide the assessment of developmental toxicity from an endpoint- to a mechanism-based approach, thereby improving the extrapolation of findings to humans. Thus, the aim of the study was to discover molecular changes characteristic of antiangiogenesis and developmental toxicity. We exposed ZFEs to two antiangiogenic drugs (SU4312, sorafenib) and two developmental toxicants (methotrexate, rotenone) with putative antiangiogenic action. Molecular changes were measured by performing untargeted metabolomics in single embryos. The metabolome response was accompanied by the occurrence of morphological alterations. Two distinct metabolic effect patterns were observed. The first pattern comprised common effects of two specific angiogenesis inhibitors and the known teratogen methotrexate, strongly suggesting a shared mode of action of antiangiogenesis and developmental toxicity. The second pattern involved joint effects of methotrexate and rotenone, likely related to disturbances in energy metabolism. The metabolites of the first pattern, such as phosphatidylserines, pterines, retinol, or coenzyme Q precursors, represented potential links to antiangiogenesis and related developmental toxicity. The metabolic effect pattern can contribute to biomarker identification for a mechanism-based toxicological testing.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish

Wilhelmi,

Haake,

Zickgraf

et al. 2024

Arch Toxicol

Self Cite

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“…Dioxin-exposed humans vs. control Distinct metabolite profiles 24 urinary steroid-related biomarkers [69] Tributyltin in zebrafish Affected steroid biosynthesis metabolism Diverse [70,71] 6-propyl-2-thiouracil in zebrafish (Neuro-) developmental toxicity methionine↓, tyrosine↑, pipecolic acid↑ and lysophosphatidylcholine↑ [72] Arecoline in rats ∆ lipid metabolism, amino acid metabolism, and vitamin metabolism ∆ D-Lysine, N4-Acetylaminobutanal, and L-Arginine [73]…”

Section: Compound/substance and Model Mechanistic Insights Biomarkers...mentioning

confidence: 99%

Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends

Sillé,

Hartung

2024

Metabolites

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Metabolomics is emerging as a powerful systems biology approach for improving preclinical drug safety assessment. This review discusses current applications and future trends of metabolomics in toxicology and drug development. Metabolomics can elucidate adverse outcome pathways by detecting endogenous biochemical alterations underlying toxicity mechanisms. Furthermore, metabolomics enables better characterization of human environmental exposures and their influence on disease pathogenesis. Metabolomics approaches are being increasingly incorporated into toxicology studies and safety pharmacology evaluations to gain mechanistic insights and identify early biomarkers of toxicity. However, realizing the full potential of metabolomics in regulatory decision making requires a robust demonstration of reliability through quality assurance practices, reference materials, and interlaboratory studies. Overall, metabolomics shows great promise in strengthening the mechanistic understanding of toxicity, enhancing routine safety screening, and transforming exposure and risk assessment paradigms. Integration of metabolomics with computational, in vitro, and personalized medicine innovations will shape future applications in predictive toxicology.

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“…Metabolomics plays an essential role in toxicological research by providing a detailed analysis of altered metabolic pathways that are targeted by harmful chemicals [163][164][165].…”

Section: Toxicity Assessmentmentioning

confidence: 99%

Review on analytical technologies and applications in metabolomics

MENG,

LIU,

et al. 2024

BIOCELL

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Over the past decade, the swift advancement of metabolomics can be credited to significant progress in technologies such as mass spectrometry, nuclear magnetic resonance, and multivariate statistics. Currently, metabolomics garners widespread application across diverse fields including drug research and development, early disease detection, toxicology, food and nutrition science, biology, prescription, and chinmedomics, among others.Metabolomics serves as an effective characterization technique, offering insights into physiological process alterations in vivo. These changes may result from various exogenous factors like environmental conditions, stress, medications, as well as endogenous elements including genetic and protein-based influences. The potential scientific outcomes gleaned from these insights have catalyzed the formulation of innovative methods, poised to further broaden the scope of this domain. Today, metabolomics has evolved into a valuable and widely accepted instrument in the life sciences. However, comprehensive reviews focusing on the sample preparation and analytical methodologies employed in metabolomics within the life sciences are surprisingly scant. This review aims to fill that gap, providing an overview of current trends and recent advancements in metabolomics. Particular emphasis is placed on sample preparation, sophisticated analytical techniques, and their applications in life science research.

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A metabolomics approach to reveal the mechanism of developmental toxicity in zebrafish embryos exposed to 6-propyl-2-thiouracil

Cited by 3 publications

References 63 publications

Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish

Molecular signatures of angiogenesis inhibitors: a single-embryo untargeted metabolomics approach in zebrafish

Metabolomics in Preclinical Drug Safety Assessment: Current Status and Future Trends

Review on analytical technologies and applications in metabolomics

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