Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt delta rats

Transgenic rodents carrying reporter genes to detect organ-specific in vivo genetic alterations are useful for risk assessment of genotoxicity that causes cancer. Thus, the Organisation for Economic Co-operation and Development (OECD) has established the guideline for genotoxicity tests using transgenic animals, which may be combined with repeated-dose toxicity studies. The present study provides evidence to support equivalence of gpt delta and wild-type (WT) rats in terms of toxicological responses to a genotoxic hepatocarcinogen, diethylnitrosamine (DEN), and a nongenotoxic hepatocarcinogen, di(2-ethylhexyl)phthalate (DEHP). DEHP-treated gpt delta rats showed similar increases in liver and kidney weights, serum albumin, albumin/globulin (A/G) ratios, and incidence of diffuse hepatocyte hypertrophy compared to WT F344 and SD rats. DEN-treated gpt 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-treated gpt delta rats also showed increased frequencies of gpt and Spi(-) mutations; such changes were not observed in DEHP-treated gpt delta rats. These results indicated that gpt delta rats (both F344 and SD backgrounds) displayed comparable DEHP-induced toxicity and DEN-induced genotoxicity as 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 ppm DEN could be detected at 2-week of administration and further increased at 4-week. These results suggested that combined assays using gpt delta rats could detect both general toxicity and genotoxicity by canonical 4-week administration protocol; therefore it would be applicable for risk assessment and then ultimately serve to reduce cancer risks of human being from environmental chemicals.

Authors: Akagi JI, Toyoda T, Cho YM, Mizuta Y, Nohmi T, Nishikawa A, Ogawa K. ;Full Source: Cancer Science. 2015 Feb 12. doi: 10.1111/cas.12634. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]