title: Atrazine treatment potentiates excretion of mutagenic urine in 2,6-dinitrotoluene-treated Fischer 344 rats.
abstract: Atrazine (ATZ), an s-triazine herbicide, is a widespread environmental contaminant. The hepatocarcinogenic component of technical grade dinitrotoluene, 2,6-dinitrotoluene (2,6-DNT, 19.5%), is a byproduct of trinitrotoluene synthesis and is found at production sites. This study explores the effect of ATZ treatment on the bioactivation of the promutagen, 2,6-DNT. Male Fischer 344 rats (5 weeks old) were administered 50 mg/kg of ATZ by gavage for 5 weeks. At 1, 3, and 5 weeks, both DMSO-control and ATZ-pretreated rats were treated p.o. with 75 mg/kg of 2,6-DNT and were housed in metabolism cages for urine collection. Sulfatase- and beta-glucuronidase-treated, concentrated urine was bioassayed for urinary mutagens in a microsuspension modification of the Salmonella assay with and without metabolic activation. No significant change in mutagen excretion was observed in ATZ-treated rats; however, an elevation in direct-acting urine mutagens from rats receiving ATZ and 2,6-DNT at weeks 1 (359 +/- 68 vs. 621 +/- 96 revertants/ml) and 5 (278 +/- 46 vs. 667 +/- 109 revertants/ml) of treatment was observed. The increase in production of urinary mutagens was accompanied by an elevation in small intestinal nitroreductase activity. Increases in large intestinal nitroreductase and beta-glucuronidase were observed after 5 weeks. There was no apparent effect of ATZ following 5 weeks of treatment on the production of 2,6-DNT-derived hepatic DNA adducts. ATZ treatment modifies intestinal enzymes responsible for promutagen bioactivation, and potentiates the excretion of mutagenic urine in 2,6-DNT-treated animals.
authors.affiliation: National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: George
authors.forename: R W
authors.initials: RW
authors.lastname: Chadwick
authors.forename: M J
authors.initials: MJ
authors.lastname: Kohan
authors.forename: J C
authors.initials: JC
authors.lastname: Allison
authors.forename: S H
authors.initials: SH
authors.lastname: Warren
authors.forename: R W
authors.initials: RW
authors.lastname: Williams
mesh_terms: D000818:Animals; D001280:Atrazine / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D001711:Biotransformation / Q000187:drug effects; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage; D004136:Dinitrobenzenes / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D004357:Drug Synergism; D004781:Environmental Exposure; D006540:Herbicides / Q000008:administration & dosage / Q000633:toxicity* / Q000652:urine; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects* / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D018736:DNA Adducts; D004136:Dinitrobenzenes; D006540:Herbicides; C023514:2,6-dinitrotoluene; D001280:Atrazine; D004121:Dimethyl Sulfoxide