Chronic exposure of rats to the chloracetanilide herbicide alachlor causes tumor formation in multiple sites, including the olfactory mucosa, thyroid, and stomach. We have performed genomic, biochemical, and histological evaluations of this process in the olfactory mucosa, and have seen that dramatic changes in the expression of more than 100 genes precede histological changes. Genes that are upregulated 2-fold or more with acute (one day to one month) alachlor exposure include extracellular matrix (ECM) genes and genes encoding proteins involved in oxidative stress responses. We have biochemically confirmed that alachlor causes antioxidant perturbation in the olfactory mucosa over the same acute time course. Among the upregulated ECM genes are matrix metalloproteinase (MMP)-2 and MMP-9. These genes encode proteins that are important in angiogenesis and basement membrane degradation. Inhibition of MMPs is associated with reduced tumor spreading and increased survival time in several model systems. The studies proposed herein will determine whether inhibition of MMP-2 and MMP-9 using Roche 28-2653, a compound that reduces tumor growth and prolongs survival in the R3327 Dunning prostate tumor model, will similarly reduce or eliminate the olfactory mucosal carcinogenicity of alachlor. There are other commercially important chloracetanilide herbicides in wide use. We will take advantage of structure-activity data to evaluate the role of MMP activation and antioxidant perturbation in chloracetanilide olfactory mucosal carcinogenesis. These studies will use propachlor, which does not cause olfactory mucosa tumors (but shares other tumor target sites with alachlor), as well as metolachlor and acetochlor. Metolachlor is associated with antioxidant perturbation in the olfactory mucosa and an intermediate tumor response, whereas acetochlor is reported to induce a robust tumor response as is seen with chronic alachlor administration. The goal of these studies is to determine whether intervention with an agent specific to an early gene response in alachlor-treated rats will be protective against alachlor-induced carcinogenesis, as well as to correlate antioxidant perturbation and ECM upregulation/activation with known carcinogenic outcomes for other chloracetanilides. If these correlations hold, then both MMP inhibitors and antioxidants may be important chemopreventive agents for individuals highly exposed to the chloracetanilides or other toxicants with similar toxicological profiles.
| Genter, M B; Warner, B M; Medvedovic, M et al. (2009) Comparison of rat olfactory mucosal responses to carcinogenic and non-carcinogenic chloracetanilides. Food Chem Toxicol 47:1051-7 |
