Article ; Online: Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.
Mutation research. Genetic toxicology and environmental mutagenesis
2017 Volume 819, Page(s) 38–46
Abstract: ... demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped ... 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 ...
| Abstract | 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. |
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| MeSH term(s) | Cell Line, Tumor ; DNA Glycosylases/genetics ; DNA Glycosylases/metabolism ; DNA Modification Methylases/antagonists & inhibitors ; DNA Modification Methylases/metabolism ; DNA Repair Enzymes/antagonists & inhibitors ; DNA Repair Enzymes/metabolism ; Dose-Response Relationship, Drug ; Hormesis ; Humans ; Methylnitrosourea/toxicity ; Micronuclei, Chromosome-Defective/chemically induced ; Models, Theoretical ; Mutagens/toxicity ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Proteins/antagonists & inhibitors ; Tumor Suppressor Proteins/metabolism |
| Chemical Substances | Mutagens ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins ; Methylnitrosourea (684-93-5) ; DNA Modification Methylases (EC 2.1.1.-) ; MGMT protein, human (EC 2.1.1.63) ; DNA Glycosylases (EC 3.2.2.-) ; DNA Repair Enzymes (EC 6.5.1.-) |
| Language | English |
| Publishing date | 2017-05-04 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ISSN | 1879-3592 |
| ISSN (online) | 1879-3592 |
| DOI | 10.1016/j.mrgentox.2017.05.002 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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