DNA adduct formation in B6C3F1 mice and Fischer-344 rats exposed to 1,2,3-trichloropropane.
1,2,3-Trichloropropane (TCP) is a multispecies, multisite carcinogen which has been found to be an environmental contaminant. In this study, we have characterized and measured DNA adducts formed in vivo following exposure to TCP. [14C]TCP was administered to male B6C3F1 mice and Fischer-344 rats by gavage at doses used in the NTP carcinogenesis bioassay. Both target and nontarget organs were examined for the formation of DNA adducts. Adducts were hydrolyzed from DNA by neutral thermal or mild acid hydrolysis, isolated by HPLC, and detected and quantitated by measurement of radioactivity. The HPLC elution profile of radioactivity suggested that one major DNA adduct was formed. To characterize this adduct, larger yields were induced in rats by intraperitoneal administration of TCP (300 mg/kg). The DNA adduct was isolated by HPLC based on coelution with the radiolabeled adduct, and compared to previously identified adducts. The isolated adduct coeluted with S-[1-(hydroxymethyl)-2-(N7-guanyl)-ethyl]glutathione, an adduct derived from the structurally related carcinogen 1,2-dibromo-3-chloropropane (DBCP). Analysis by electrospray mass spectrometry suggested that the TCP-induced adduct and the DBCP-derived adduct were identical. The 14C-labeled DNA adduct was distributed widely among the organs examined. Adduct levels varied depending on species, organ, and dose. In rat organs, adduct concentrations for the low dose ranged from 0.8 to 6.6 mumol per mol guanine and from 7.1 to 47.6 mumol per mol guanine for the high dose. In the mouse, adduct yields ranged from 0.32 to 28.1 mumol per mol guanine for the low dose and from 12.2 to 208.1 mumol per mol guanine for the high dose. The relationship between DNA adduct formation and 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 that factors in addition to adduct formation may be important in TCP-induced carcinogenesis.
La
D K
DK
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill 27599, USA.
Lilly
P D
PD
Anderegg
R J
RJ
Swenberg
J A
JA
D000818:Animals; D002273:Carcinogens; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010084:Oxidation-Reduction; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D002273:Carcinogens; D018736:DNA Adducts; C009536:1,2,3-trichloropropane; D005978:Glutathione; D011407:Propane