The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup

Gollapudi, B. Bhaskar; Lynch, Anthony M.; Heflich, Robert H.; Dertinger, Stephen D.; Dobrovolsky, Vasily N.; Frötschl, Roland; Horibata, Katsuyoshi; Kenyon, Michelle; Kimoto, Tsunenobu; Lovell, David P.; Stankowski, Leon F.; White, Paul A.; Witt, Kristine L.; Tanir, Jennifer Y.

doi:10.1016/j.mrgentox.2014.09.007

Cited by 144 publications

(158 citation statements)

References 58 publications

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“…Although statistically positive, the mutant frequency in this dose group is quite low, and its slight elevation over other dose groups appears to be driven by a single animal exhibiting a Pig-a mutant frequency that was 10-fold higher than the animals in the same dose group (animal no.16; see Supplemental Table V, available at Mutagenesis Online). Moreover, concurrent increases in the frequencies of both mutant RET and RBC are deemed important for reliably classifying a positive mutagenic response in the Pig-a assay (37). For these reasons, the response is considered to be equivocal and not biologically relevant.…”

Section: Resultsmentioning

confidence: 99%

“…Our experimental design used acrylamide exposure levels and route of exposure that mimic the cancer bioassays conducted on acrylamide in F344 rats and B6C3F1 mice (12) and measure two genotoxic endpoints-chromosomal damage and gene mutation-in the same cellular compartment (bone marrow). Although the micronucleus assay is used in regulatory genetic toxicology testing (OECD test guideline 474), recommendations for conduct and interpretation of the Pig-a assay used in this study have been developed by an expert working group formed by the International Workshop on Genotoxicity Testing (37).…”

Section: Discussionmentioning

confidence: 99%

“…The Pig-a assays were conducted according to the recommendation of the International Workshop on Genotoxicity Testing (IWGT) workgroup (37). The labeling and flow cytometry analysis of Piga gene mutation in red blood cells (RBC) was performed using a MutaFlow® kit (Litron Laboratories, Rochester, NY, USA) and a Becton-Dickinson FACSCalibur™ flow cytometer according to manufacturer's instructions.…”

Section: Pig-a Assaymentioning

confidence: 99%

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Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Hobbs¹,

Davis²,

Shepard³

et al. 2016

MUTAGE

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Acrylamide is used in many industrial processes and is present in a variety of fried and baked foods. In rodent carcinogenicity assays, acrylamide exposure leads to tumour formation at doses lower than those demonstrated to induce genotoxic damage. We evaluated the potential of acrylamide to induce structural DNA damage and gene mutations in rodents using highly sensitive flow cytometric analysis of micronucleus and Pig-a mutant frequencies, respectively. Male F344 rats and B6C3F1 mice were administered acrylamide in drinking water for 30 days at doses spanning and exceeding the range of acrylamide exposure tested in cancer bioassays-top dose of 12.0 and 24.0 mg/kg/day in mice and in rats, respectively. A positive control, N-ethyl-N-nitrosourea, was administered at the beginning and end of the study to meet the expression time for the two DNA damage phenotypes. The results of the micronucleus and Pig-a assays were negative and equivocal, respectively, for male rats exposed to acrylamide at the concentrations tested. In contrast, acrylamide induced a dose-dependent increase in micronucleus formation but tested negative in the Pig-a assay in mice. Higher plasma concentrations of glycidamide in mice than rats are hypothesized to explain, at least in part, the differences in the response. Benchmark dose modelling indicates that structural DNA damage as opposed to point mutations is most relevant to the genotoxic mode of action of acrylamide-induced carcinogenicity. Moreover, the lack of genotoxicity detected at <6.0 mg/kg/day is consistent with the notion that non-genotoxic mechanisms contribute to acrylamide-induced carcinogenicity in rodents.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Pig-a Assaymentioning

confidence: 99%

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Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Hobbs¹,

Davis²,

Shepard³

et al. 2016

MUTAGE

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“…L'International Workgroup on Genotoxicity Testing (IWGT) admet aujourd'hui la réciprocité entre une cellule mutée sur le gène PIG-A et une cellule déficiente en ancre GPI grâce à l'établissement de deux relations réciproques [11]. D'une part, les recherches sur l'HPN ont montré que le phénotype GPI-déficient était lié à une mutation de PIG-A et que la transfection d'un gène PIG-A sauvage dans une cellule de phénotype HPN restaurait la présence de l'ancre GPI et des protéines GPI-ancrées à la surface de la cellule [5].…”

Section: Fréquence Des Mutations Du Gène Pig-a Par Mesure De La Fréquunclassified

“…Chez l'animal, le séquençage du gène Pig-a a révélé la survenue de mutations induites spécifiques du mode d'action du mutagène utilisé [12][13][14]. La sensibilité et la spécificité du test PIG-A évaluées dans diverses études, incluant les principaux mutagènes connus et des agents non-mutagènes, selon divers schémas d'administration, ont accru son intérêt en toxicologie réglementaire à tel point que l'IWGT (International workshop on genotoxicity testing) a proposé sa réalisation en complément du micronoyau 7 au cours des tests réglementaires [11]. Le test PIG-A ne permettrait cependant pas de détecter l'impact potentiel, en termes de mutations géniques, d'expositions brèves et accidentelles, dans les heures ou jours qui suivent l'exposition.…”

Section: Cytométrie De Fluxunclassified

Le gènePIG-A, nouveau marqueur de mutagenèse

Castel¹,

Carcopino²,

Robert³

et al. 2017

Med Sci (Paris)

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Occupational Toxicology in the Pharmaceutical Industry

Dolan

Bercu

Graham³

et al. 2023

Patty's Toxicology

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Much of the activity in the pharmaceutical industry has its origins in the fine chemicals industry of the late nineteenth century. At that time, advances in chemistry and medicine led to the manufacture of pharmacologically active small molecules to produce desirable biological effects to treat diseases and illnesses at relatively low doses. Advances in biology and chemistry in the past quarter century have led to an increase in innovation resulting in a variety of novel modalities, especially recombinant proteins, antibody‐drug conjugates, cell and gene therapies, peptides and polypeptides, oligonucleotides, and vaccines. The roles and responsibilities of occupational toxicologists in the pharmaceutical industry have expanded dramatically in the twenty‐first century, commensurate with the changing regulatory requirements and treatment modalities. The occupational toxicologists' roles have become increasingly multidisciplinary and the scope of their involvement has expanded to encompass diverse aspects of worker safety as well as patient safety, and to include involvement throughout a molecule's development, from early development through postcommercialization.

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The in vivo Pig-a assay: A report of the International Workshop On Genotoxicity Testing (IWGT) Workgroup

Cited by 144 publications

References 58 publications

Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Differential genotoxicity of acrylamide in the micronucleus andPig-a gene mutation assays in F344 rats and B6C3F1 mice

Le gènePIG-A, nouveau marqueur de mutagenèse

Occupational Toxicology in the Pharmaceutical Industry

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