The effects of short‐term (24 h) exposure to triethylenemelamine on cellular DNA in five tissues (bone marrow, spleen, kidney, large intestine, and testis) of the rat were studied using flow cytometry. Mean coefficients of variation of the G1 peaks were increased in both the low and high dosage groups relative to controls. Bone marrow exhibited the highest degree of effect, possibly due to the rapid rate of cell division in that tissue, and spleen was next highest. Thus, hematopoietic tissues are highly responsive to short‐term, acute exposure to this mutagen. The results of the flow‐cytometry assay closely paralleled a simultaneous chromosomal assay conducted on bone marrow of the same rats. These data are interpreted to be consistent with the hypothesis that the observed increase in mean coefficients of variation is due to the clastogenic effects of the mutagen and subsequent unequal distribution of DNA among the daughters of affected cells.
Exposure to the mutagen triethylenemelamine on rat bone marrow, blood, and testis was studied using flow cytometry of DAPI-stained nuclei. Increased coefficients of variation (CVs) of the GI peaks were observed in bone marrow and blood after both 1 d and 5 d exposures. After 5 d exposure and 7 d recovery both tissues had recovered, in some cases to significantly lower CVs. Increased CVs of the 1C peak of testis were observed only after 5 d exposure to the high dose with no subsequently observed recovery. Bone marrow cells also were stained with Hoechst 33258 and Propidium Iodide. No differences among dyes were observed indicating that increased CVs likely are due to DNA damage resulting from interactions with the mutagen rather than differences in how the dyes bind to DNA relative to mutagen binding. This study demonstrates that differences occur among tissues in how quickly they respond and recover from mutagen exposure. Increased CVs, cell cycle alterations, and decreased CVs after recovery are all potentially useful biomarkers of effect for laboratory and field studies in environmental toxicology. 0 1994 Wiley-Liss, Inc.
The major urinary metabolite of 14C-epichlorohydrin, after oral administration to rats, was identified previously (Gingell et al. 1985) to be N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine (ACPC) at 36% of the administered dose. In a similar study reported here, 1,2-dibromo-3-chloropropane (DBCP) was metabolized to at least 20 radioactive urinary metabolites. ACPC was only a minor metabolite (4%) of DBCP. Epichlorohydrin was metabolized in vitro by rat liver microsomes to alpha-chlorohydrin, but DBCP was not metabolized to epichlorohydrin or alpha-chlorohydrin under similar conditions. Covalent binding of radioactivity to liver microsomal proteins occurred for both substrates, but was less for 14C-epichlorohydrin than for 14C-DBCP. Addition of 3,3,3-trichloropropylene oxide, an inhibitor of epoxide hydrolase, increased the extent of protein binding of epichlorohydrin, but decreased the amount of 14C-DBCP which was bound. The data indicate the epichlorohydrin is not a significant in vivo nor in vitro metabolite of DBCP in the rat, and is unlikely to be responsible for the toxicity of DBCP.
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