Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N -methyl- N -nitrosourea
| Autor: | Gareth J.S. Jenkins, Katherine E. Chapman, George R. Hoffmann, Shareen H. Doak |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Health Toxicology and Mutagenesis Mutagenesis (molecular biology technique) Pharmacology Biology medicine.disease_cause DNA Glycosylases 03 medical and health sciences Hormesis 0302 clinical medicine Cell Line Tumor Genetics medicine Humans DNA Modification Methylases Micronuclei Chromosome-Defective Carcinogen Dose-Response Relationship Drug Tumor Suppressor Proteins Stressor Methylnitrosourea Models Theoretical DNA Repair Enzymes 030104 developmental biology Hypoxanthine-guanine phosphoribosyltransferase 030220 oncology & carcinogenesis Micronucleus test Tumor Suppressor Protein p53 Carcinogenesis Genotoxicity Mutagens |
| Zdroj: | Mutation Research/Genetic Toxicology and Environmental Mutagenesis. 819:38-46 |
| ISSN: | 1383-5718 |
| DOI: | 10.1016/j.mrgentox.2017.05.002 |
| Popis: | Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. |
| Databáze: | OpenAIRE |
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