PUBLICATION
Toxicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in early development: A wide-scope metabolomics assay in zebrafish embryos
- Authors
- Merino, C., Casado, M., Piña, B., Vinaixa, M., Ramírez, N.
- ID
- ZDB-PUB-220128-9
- Date
- 2021
- Source
- Journal of hazardous materials 429: 127746 (Journal)
- Registered Authors
- Piña, Benjamin
- Keywords
- 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), Danio rerio, Early development, Metabolomics, Nucleotide metabolism
- MeSH Terms
-
- Animals
- Butanones
- Carcinogens/toxicity
- Humans
- Metabolomics
- Mice
- Nitrosamines*/toxicity
- Zebrafish*/metabolism
- PubMed
- 35086039 Full text @ J. Hazard. Mater.
Citation
Merino, C., Casado, M., Piña, B., Vinaixa, M., Ramírez, N. (2021) Toxicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in early development: A wide-scope metabolomics assay in zebrafish embryos. Journal of hazardous materials. 429:127746.
Abstract
The tobacco-specific nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a carcinogenic and ubiquitous environmental pollutant for which toxic activity has been thoroughly investigated in murine models and human tissues. However, its potential deleterious effects on vertebrate early development are yet poorly understood. In this work, we characterized the impact of NNK exposure during early developmental stages of zebrafish embryos, a known alternative model for mammalian toxicity studies. Embryos exposed to different NNK concentrations were monitored for lethality and for the appearance of malformations during the first five days after fertilization. LC-MS based untargeted metabolomics was subsequently performed for a wide-scope assay of NNK-related metabolic alterations. Our results revealed the presence of not only the parental compound, but also of two known NNK metabolites, 4-Hydroxy-4-(3-pyridyl)-butyric acid (HPBA) and 4-(Methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol (NNAL-N-oxide) in exposed embryos likely resulting from active CYP450-mediated α-hydroxylation and NNK detoxification pathways, respectively. This was paralleled by a disruption in purine and pyrimidine metabolisms and the activation of the base excision repair pathway. Our results confirm NNK as a harmful embryonic agent and demonstrate zebrafish embryos to be a suitable early development model to monitor NNK toxicity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping