Effect of pentachlorophenol on the activation of 2,6‐dinitrotoluene to genotoxic urinary metabolites in CD‐1 mice: A comparison of GI enzyme activities and urine mutagenicity

Abstract

2,6-Dinitrotoluene (2,6-DNT) and pentachlorophenol (PCP) are used for industrial purposes and are found in the environment as hazardous contaminants. Because concurrent exposure to both compounds can occur, it is of interest to determine if organochlorine compounds potentiate the effect of nitroaromatic chemicals. CD-1 mice were treated with PCP (42.8 mg/kg) for 4 weeks. On weeks 1, 2, and 4 after the initial PCP dose, mice were treated p.o. with 2,6-DNT (75 mg/kg) and 24 hr urines were collected. After concentration, the urines were tested for their mutagenic activity in Salmonella typhimurium strain TA98 without metabolic activation in a microsuspension bioassay. A significant increase (P less than .05) in mutagenicity was observed in urines from mice treated with 2,6-DNT alone and in combination with PCP. By week 4, mice that received both 2,6-DNT and PCP excreted urine that was more mutagenic than that from animals which received only 2,6-DNT. At weeks 2 and 4, mice were sacrificed and intestinal enzyme activities (nitroreductase, azo reductase, beta-glucuronidase, dechlorinase, and dehydrochlorinase) were quantitated. The enhanced genotoxicity observed in urines from 2,6-DNT/PCP-treated mice coincided with a decrease in nitroreductase and an increase in beta-glucuronidase activities in the small intestine.

Potentiation of 2,6‐dinitrotoluene genotoxicity in fischer 344 rats by pretreatment with coal tar creosote

“…Therefore, reduced nitroreductase activity in the small intestine would favor the transport of more unaltered DNT to the liver and its subsequent conversion to genotoxic metabolites. Previously it has been found that reduced nitroreductase in the small intestine preceded the elevated excretion of mutagenic DNT metabolites in the urine and enhanced formation of hepatic DNA adducts in animals pretreated with various environmental toxicants (Chadwick et al, , 1993George et al, 1991). Many variables can influence the extent of DNA adduct formation, such as competition between metabolic activation and detoxication, DNA repair, the extent of cell replication, and cell death.…”

“…In this study, the genotoxic effects of two of these environmental contaminants, 2,6-dinitrotoluene (DNT) and creosote, are investigated. Previous work in this laboratory indicated that pretreatment of rats with pentachlorophenol (PCP) George et al, 1991) or with Aroclor 1254 (Chadwick et al, 1993) potentiated the genotoxicity of the industrial chemical DNT. On the other hand, pretreatment with the organochlorine herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) produced only a transient antagonism of DNT toxicity (George et al, 1992).…”

Chlorophenol stress affects aromatic amino acid biosynthesis—a genome‐wide study

“…PCP has been shown to affect the endocrine system of vertebrate life forms (Beard et al , 1999) and is also reported to inhibit RNA and ribosome synthesis (Ehrlich et al , 1987). It causes adverse effects to the liver (Umemura et al , 1999; Kimbrough et al , 1978; Wang et al , 2001), kidneys, lungs, immune system (Blakley et al , 1998; Colosia et al , 1993) and gastrointestinal tract (Deichmann et al , 1942; George et al , 2006). Several in vivo (Yin et al , 2006) and in vitro (Wang et al , 2001; Wispriyono et al , 2002; Chen J et al , 2004; Chan X et al , 2004; Fernandez et al , 2005; Yang et al , 2005) studies regarding chlorophenol exposure have established that PCP‐mediated toxicity is still little understood with regard to the molecular basis of the toxicity.…”

Atrazine treatment potentiates excretion of mutagenic urine in 2, 6‐dinitrotoluene‐treated fischer 344 rats

“…2,6-DNT is also a by-product of trinitrotoluene synthesis and is found in waste streams at production or loading facilities [Spanggord et al, 19821. 2,6-DNT is generally reported either negative or weakly positive in short-term bacterial and mammalian cell bioassays, but is a causative agent in the generation of carcinomas [Abernethy and Couch, 1982;Couch et al, 1981;George et al, 1991;Leonard et al, 19871.…”