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Evaluation of Macaca mulatta as a model for genotoxicity studies
Vasily N Dobrovolsky1, Joseph G Shaddock, Roberta A Mittelstaedt
1US FDA, National Center for Toxicological Research, Division of Genetic and Reproductive Toxicology, 3900 NCTR Rd., HFT-120, Jefferson, AR 72079, USA. vasily.dobrovolsky@fda.hhs.gov
Mutation Research
|December 17, 2008
Summary
Rhesus monkeys serve as a valuable model for detecting mutations, aiding in human health risk assessment. This study validates their use for identifying mutagenic agents using PIG-A and HPRT genes in blood cells.
Area of Science:
- Toxicology and Pharmacology
- Genetics and Genomics
- Primate Models
Background:
- Nonhuman primates (NHPs), specifically rhesus monkeys, offer metabolic similarities to humans, making them suitable for toxicological studies.
- Assessing mutagenicity in NHP models is crucial for human health risk assessment and hazard identification.
- Established methods for mutation detection in rodents have limitations, necessitating exploration of alternative models.
Purpose of the Study:
- To investigate the utility of rhesus monkey peripheral blood as a model system for mutation detection.
- To validate the PIG-A and HPRT genes as targets for detecting mutagenic effects in lymphocytes and erythrocytes.
- To establish flow cytometric methods for rapid and efficient detection of mutant cells.
Main Methods:
- Peripheral blood from rhesus monkeys was used to isolate and expand 6-thioguanine-resistant (6-TGr) HPRT mutant and proaerolysin-resistant (ProAERr) PIG-A mutant lymphocytes in vitro.
- Flow cytometry was employed to detect PIG-A mutant erythrocytes by enumerating cells deficient in glycosylphosphatidyl inositol (GPI)-anchored surface markers.
- Monkeys were treated with N-ethyl-N-nitrosourea (ENU) to induce mutations, and mutant frequencies were compared to control animals.
Main Results:
- Spontaneous mutant frequencies for PIG-A and HPRT in T-cells were low in control monkeys (0-8x10^-6).
- ENU treatment significantly increased the frequency of ProAERr and 6-TGr lymphocytes (up to ~28x10^-6 and ~30x10^-6, respectively).
- ENU-treated animals showed a higher frequency of GPI-deficient erythrocytes (46.5x10^-6) compared to controls (7.8±4.2x10^-6).
Conclusions:
- The rhesus monkey is a relevant and valuable model for identifying agents that may impact human health as mutagens.
- The PIG-A gene provides a useful target for mutation detection in both white blood cells (lymphocytes) and red blood cells (erythrocytes).
- The developed flow cytometric methods enable rapid and sensitive detection of mutations in NHP blood samples.
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