Validation study of the combined repeated-dose toxicity and genotoxicity assay usinggptdelta rats

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Abstract

Transgenic rodents carrying reporter genes to detect organ-specificin vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organization for Economic Co-operation and Development has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. Here, we provide evidence to support equivalence ofgpt delta and wild type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen,N-nitrosodiethylamine (DEN), and a non-genotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP).gpt delta rats treated with DEHP showed similar increases in liver and kidney weights, serum albumin, albumin/globulin ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and Sprague–Dawley (SD) rats. DEN-treatedgpt delta rats showed equivalent increases in the number and area of precancerous GST-P-positive foci in the liver compared to WT rats. The livers of DEN-treatedgpt delta rats also showed increased frequencies ofgpt and Spi− mutations; such changes were not observed in DEHP-treatedgpt delta rats. These results indicated thatgpt delta rats (both F344 and SD backgrounds) showed comparable DEHP-induced toxicity and DEN-induced genotoxicity to those observed in WT rats. With regard to the administration period, the general toxicity of 1.2% DEHP was evident throughout the experimental period, and the genotoxicity of 10 p.p.m. DEN could be detected after 2 weeks of administration and further increased at 4 weeks. These results suggested that combined assays usinggpt delta rats could detect both general toxicity and genotoxicity by the canonical 4-week administration protocol. Therefore, this assay usinggpt delta rats would be applicable for risk assessment including early detection of genotoxic carcinogens and ultimately serve to reduce cancer risks in humans from environmental chemicals.

To support development of a combined assay for general toxicity and genotoxicty by using transgenic rodents, we provide evidences that indicate equivalence of gpt delta rats, which carry reporter genes to detect in vivo genotoxicity, to their parental wild type in terms of toxicological responses. DEN- or DEHP- treated F344 and SD strains of gpt delta rats display comparable general toxicity and genotoxicity to wild type. Our results indicate that the combined assay using gpt delta rats was applicable for simultaneous detection of both general toxicity and genotoxicity for short durations of administration.

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