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 harmfuleffects. 2,6-DNT is recognized as a hepatotoxicant while 2,4,5-T,a component of Agent Orange, is also suspect. 2,6-DNT requiresboth oxidative and reductive metabolism to elicit genotoxiceffects. To determine what effect 2,4,5-T had on 2,6-DNT metabolism,intestinal enzymes, microbial populations, and urine mutagenicitywere examined during 2,4,5-T treatment. Weanling Fischer 344male rats were treated daily with 54.4 mg/kg 2,4,5-T by gavagefor 4 weeks. One, two, and four weeks after the initial 2,4,5-Tdose, rats were administered (po) 2,6-DNT (75 mg/kg) and urinewas collected for 24 hr in metabolism cages. Azo reductase,nitroreductase, ß-glucuronidase, dechlorinase, anddehydrochlorinase activities were examined concurrently. Treatmentof rats for 1 week reduced the transformation of 2,6-DNT tomutagenic urinary metabolites. This was accompanied by a decreasein the fecal anaerobic microorganisms. The elimination ofLactobacillusfermentum from the small intestine and cecum of treated animalsaccompanied a significant increase in oxygen-tolerant lactobacilliand other unidentified aerobic microorganisms. However, therewere no significant alterations in the intestinal enzyme activitiesexamined. By 2 weeks of 2,4,5-T treatment, microbiota and urinegenotoxicity returned to the levels observed in control animals.This trend continued for the duration of the experiment After2 weeks, while cecal nitroreductase and azo reductase activitiesincreased, small intestinal ß-glucuronidase activitydecreased. By 4 weeks, treated and untreated animal intestinalenzyme activities were indistinguishable. The transient increasein azo reductase and nitroreductase after treatment with 2,4,5-Tfor 2 weeks may have been counteracted by the reduced ß-glucuronidaseactivity, thus resulting in no change in 2,6-DNT-derived urinemutagenicity. However, other environmental chemicals, unaffectedby ß-glucuronidase, potentially could be activatedby 2,4,5-T exposure.