Strain-Specific Effects of Alachlor on Murine Olfactory Mucosal Responses

Abstract

Chloracetanilide herbicides are multisite carcinogens in rodents. Progression of alachlor-induced olfactory tumors in rats is accompanied by cytoplasmic accumulation and nuclear localization of β-catenin, suggesting activation of Wnt signaling. Female CD-1 mice were resistant to alachlorinduced olfactory carcinogenesis. The current studies were performed to determine whether Apc Min/+ mice, which have activated Wnt signaling due to mutation of the second allele of Apc, would be susceptible to alachlor olfactory carcinogenesis. Female and male Apc Min/+ mice, as well as Apc +/+ littermates received alachlor in the diet (260 mg/kg/d) for up to 3 months. Female A/J and C57BL/6J wild-type mice were also treated (for 10 and 14 months, respectively), as these strains vary in sensitivity to many respiratory tract insults. No olfactory mucosal tumors were observed in any of the mice, although alachlor-treated Apc Min/+ mice developed histological changes similar to those in alachlor-treated rats. Alachlor-treated A/J mice developed pronounced intracellular accumulation of amorphous eosinophilic material in the olfactory mucosa, foci of respiratory-like metaplasia, and hyperplasia of nasal mucus glands. A similar but less intense response was seen in C57BL/6J mice. Mice and rats had equivalent levels of the putative bioactivating enzyme (CYP2A) in olfactory mucosa, and mice had induced hepatic CYP3A and CYP2B enzymes with alachlor treatment, which may increase alachlor elimination. These studies extend previous observations by describing alachlor-induced olfactory mucosal changes in mice and suggest that hepatic metabolic enzyme induction may be responsible for resistance of mice to alachlor-induced olfactory carcinogenesis.

Nasal Cytotoxic and Carcinogenic Activities of Systemically Distributed Organic Chemicals

“…The rodent NM possesses substantial chemical biotrans-formation capability (Hadley and Dahl, 1982; Dahl, 1985; Longo et al, 1988; Dahl and Hadley, 1991; Bereziat et al, 1995; Genter et al, 1995b; Thornton-Manning and Dahl, 1997; Genter, 2004), which may play a role in olfaction (Anholt, 1989; Nef et al, 1989; Carr et al, 1990). Species differ in their specific levels of biotransformation capability (Hadley and Dahl, 1983; Thornton-Manning and Dahl, 1997).…”

“…N-acetyltransferase transcripts, specifically the N-acetyltransferase 1 enzyme, which is widely distributed in the body, is present in the RE and OE, as well as the BGs (Debiec-Rychter et al, 1996). In fact, activity in the OM of Long–Evans rats is markedly higher than in the liver (Genter, 2004). Other enzymes, such as epoxide hydrolase, are higher in rats when compared to other species such as mice (Green et al, 2001).…”

“…No report of an association of nasal tumors in humans has been made for exposure to either 2,6-DMA or lidocaine. This is in spite of theoretical concerns raised by the fact that lidocaine is used as a nasal spray for the treatment of migraine headaches, as well as a local anesthetic during nasal surgery (Genter, 2004). Smokers exhibit NM alterations and have increased risk of sinonasal squamous cell carcinoma (Feron et al, 2001).…”

“…Alachlor, acetochlor, and butachlor (Figure 20) are herbicides that are 2,6-dialkyl aniline derivatives in which the nitrogen is disubstituted. At chronic dosages of >15 mg/kg bw/day, they have induced nasal and other tumors in rats, but not in mice (US EPA, 1997; Heydens et al, 1999;Genter et al, 2000;Green et al, 2000;Genter et al, 2004). The tumors appear to arise from OE cells (Genter et al, 2000).…”

Molecular Biology of the Nasal Airways: How Do We Assess Cellular and Molecular Responses in the Nose?

“…Alachlor is one of a class of herbicides known as the chloracetanilides; these compounds (e.g., acetochlor, butachlor, metolachlor, and propachlor), together with alachlor, have a range of toxic and carcinogenic responses in rodents. In rats, these compounds are associated with olfactory mucosal, thyroid, stomach, and/or liver tumors; mice appear to be refractory to the development of these tumors, but instead have an elevated incidence of lung tumors following chronic exposure to alachlor (United States Environmental Protection Agency 1985, 1998; Genter et al, 2004). We hypothesized that target tissue bioactivation to a mutagenic metabolite was critical to alachlor carcinogenesis.…”