DNA ADDUCT FORMATION IN B6C3F1 MICE AND FISCHER-344 RATS EXPOSED TO 1,2,3-TRICHLOROPROPANE

Citation
Dk. La et al., DNA ADDUCT FORMATION IN B6C3F1 MICE AND FISCHER-344 RATS EXPOSED TO 1,2,3-TRICHLOROPROPANE, Carcinogenesis, 16(6), 1995, pp. 1419-1424
Citations number
39
Categorie Soggetti
Oncology
Journal title
ISSN journal
01433334
Volume
16
Issue
6
Year of publication
1995
Pages
1419 - 1424
Database
ISI
SICI code
0143-3334(1995)16:6<1419:DAFIBM>2.0.ZU;2-R
Abstract
1,2,3-Trichloropropane (TCP) is a multispecies, multisite carcinogen w hich has been found to be an environmental contaminant. In this study, we have characterized and measured DNA adducts formed in vivo followi ng exposure to TCP. [C-14]TCP was administered to male B6C3F1 mice and Fischer-344 rats by gavage at doses used in the NTP carcinogenesis bi oassay. Both target and nontarget organs were examined for the formati on of DNA adducts. Adducts were hydrolyzed from DNA by neutral thermal or mild acid hydrolysis, isolated by HPLC, and detected and quantitat ed by measurement of radioactivity. The HPLC elution profile of radioa ctivity suggested that one major DNA adduct was formed. To characteriz e this adduct, larger yields were induced in rats by intraperitoneal a dministration of TCP (300 mg/kg). The DNA adduct was isolated by HPLC based on coelution with the radiolabeled adduct, and compared to previ ously identified adducts. The isolated adduct coeluted with S- (hydrox ymethyl)-2-(N-7-guanyl)-ethyl]-glutathione, an adduct derived from the structurally related carcinogen 1,2-dibromo-3-chloropropane (DBCP). A nalysis by electrospray mass spectrometry suggested that the TCP-induc ed adduct and the DBCP-derived adduct were identical. The C-14-labeled DNA adduct was distributed widely among the organs examined. Adduct l evels varied depending on species, organ, and dose. In rat organs, add uct concentrations for the low dose ranged from 0.8 to 6.6 mu mol per mol guanine and from 7.1 to 47.6 mu mol per mol guanine for the high d ose. In the mouse, adduct yields ranged from 0.32 to 28.1 mu mol per m ol guanine for the low dose and from 12.2 to 208.1 mu mol per mol guan ine for the high dose. The relationship between DNA adduct formation a nd organ-specific tumorigenesis was unclear, Although relatively high concentrations of DNA adducts were detected in target organs, several nontarget sites also contained high adduct levels. Our data suggest th at factors in addition to adduct formation may be important in TCP-ind uced carcinogenesis.