Abstract A49: Induction of the lymphomagenic enzyme activation-induced cytidine deaminase (AID) upon in vitro exposure to phenylurea herbicides

Abstract

Abstract Many studies have drawn associations between pesticide exposures and lymphomagenesis, both in occupational settings and in the general population. The specific compounds responsible for an increased risk of non-Hodgkin lymphoma in pesticide-exposed individuals have not been entirely established. Furthermore, the biologic mechanisms by which pesticides act as lymphomagens are unknown. One mechanism of B-cell genomic instability that plays a role in lymphomas derived from germinal center (GC)-type B cells, including follicular lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma, is the off-target/aberrant activity of activation-induced cytidine deaminase (AID). AID damages DNA through deamination of cytidine. This occurs on a physiologic basis within GC B cells and is responsible for both class switch recombination (CSR) and somatic hypermutation (SHM). AID can also target nonimmunoglobulin loci, including several proto-oncogenes, resulting in both mutations (aberrant somatic hypermutation; aSHM) and chromosomal translocations. Overexpression of AID has previously been found to increase B-cell genomic instability. In this study, GC-type B cell lines (Ramos, Raji, and CL-01) were treated with pesticides, including herbicides and insecticides from various classes, to determine the effect on AID expression. Real-time RT-PCR was used to determine the degree of AID mRNA expression after chemical treatment. Two representative phenylurea herbicides, linuron and diuron, were found to induce AID expression, in a time- and dose-dependent manner, at concentrations ranging from 50-200 micromolar, with maximal induction of 2- to 6-fold depending on the compound and time point. Additional pesticides that were tested but not found to induce AID expression, at concentrations that were minimally toxic in vitro, included representative organochlorine, organophosphate, phenoxy, and phosphanoglycine pesticides. The findings raise the possibility of increased AID-mediated genomic instability in GC type B cells exposed to phenylurea herbicides. Future studies will investigate the possible link between the observed phenylurea herbicide-related induction of AID, B-cell genomic instability, and lymphomagenesis. Citation Format: Rebecca J. Leeman-Neill, Uttiya Basu. Induction of the lymphomagenic enzyme activation-induced cytidine deaminase (AID) upon in vitro exposure to phenylurea herbicides [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr A49.