2,4,5-trichlorophenoxyacetic acid influence on 2,6-dinitrotoluene-induced urine genotoxicity in Fischer 344 rats: effect on gastrointestinal microflora and enzyme activity.
2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) and 2,6-dinitrotoluene (2,6-DNT) are hazardous chemicals that have potential harmful effects. 2,6-DNT is recognized as a hepatotoxicant while 2,4,5-T, a component of Agent Orange, is also suspect. 2,6-DNT requires both oxidative and reductive metabolism to elicit genotoxic effects. To determine what effect 2,4,5-T had on 2,6-DNT metabolism, intestinal enzymes, microbial populations, and urine mutagenicity were examined during 2,4,5-T treatment. Weanling Fischer 344 male rats were treated daily with 54.4 mg/kg 2,4,5-T by gavage for 4 weeks. One, two, and four weeks after the initial 2,4,5-T dose, rats were administered (po) 2,6-DNT (75 mg/kg) and urine was collected for 24 hr in metabolism cages. Azo reductase, nitroreductase, beta-glucuronidase, dechlorinase, and dehydrochlorinase activities were examined concurrently. Treatment of rats for 1 week reduced the transformation of 2,6-DNT to mutagenic urinary metabolites. This was accompanied by a decrease in the fecal anaerobic microorganisms. The elimination of Lactobacillus fermentum from the small intestine and cecum of treated animals accompanied a significant increase in oxygen-tolerant lactobacilli and other unidentified aerobic microorganisms. However, there were no significant alterations in the intestinal enzyme activities examined. By 2 weeks of 2,4,5-T treatment, microbiota and urine genotoxicity returned to the levels observed in control animals. This trend continued for the duration of the experiment. After 2 weeks, while cecal nitroreductase and azo reductase activities increased, small intestinal beta-glucuronidase activity decreased. By 4 weeks, treated and untreated animal intestinal enzyme activities were indistinguishable.(ABSTRACT TRUNCATED AT 250 WORDS)
George
S E
SE
Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Chadwick
R W
RW
Chang
J J
JJ
Kohan
M J
MJ
Allison
J C
JC
Dekker
J P
JP
Hayes
Y
Y
D015085:2,4,5-Trichlorophenoxyacetic Acid / Q000494:pharmacology* / Q000652:urine; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004136:Dinitrobenzenes / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D005243:Feces / Q000382:microbiology; D005796:Genes / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009152:Mutagenicity Tests; D051381:Rats; D011916:Rats, Inbred F344
D004136:Dinitrobenzenes; D015085:2,4,5-Trichlorophenoxyacetic Acid; C023514:2,6-dinitrotoluene