Abstract
Several epidemiologic studies have demonstrated an increased risk of non-Hodgkin B cell lymphoma with exposure to pesticides, including herbicides, fungicides and insecticides. Few studies have specifically demonstrated an increased risk for follicular lymphoma in individuals exposed to pesticides. The molecular mechanisms of these associations have not been fully investigated. Activation-induced cytidine deaminase (AID), which physiologically mediates somatic hypermutation in germinal center B cells, has been found to have off-target effects that play an important role in oncogenic mutagenesis driving germinal center type B cell lymphomas. Elevated levels of AID among peripheral blood mononuclear cells has been found to be associated with higher numbers of circulating follicular lymphoma-like cells in individuals exposed to pesticides. Increased AID expression and/or activity represents a possible mechanistic link between pesticide exposure and lymphomagenesis.
In order to test the hypothesis that pesticides might lead to an increased risk of germinal center neoplasia by increasing AID levels, four pesticides including isoproturon (a phenylurea herbicide), chlorpyrifos (an organophosphate insecticide), DDT (an organochlorine insecticide), and lindane (an organochlorine insecticide), were screened for their ability to increase AID expression in germinal center type B cells (Ramos and Raji, Burkitt lymphoma cell lines). After 48 hours of treatment with concentrations ranging from 50-200 μM, RNA was extracted, reverse transcribed and cDNA subject to SYBR green Realtime PCR amplification of AID.
AID was found to be expressed, at low levels, in untreated Ramos and Raji cells, compared to acute myeloid leukemia cell lines HL60 and U937, which served as negative controls showing no AID expression. Isoproturon treatment resulted in a dose dependent, up to 6-fold, increase in AID in Ramos cells. A smaller, up to 1.9 fold increase was seen in Raji cells. None of the other pesticide treatments resulted in increased expression of AID (Fig. 1).
The findings demonstrate that AID expression is induced by isoproturon, a member of the class of phenylurea herbicides which is among the most commonly used herbicides worldwide and generally considered to be relatively safe for humans. These results support a possible role for off-target AID activity in pesticide-exposure related lymphomagenesis. Future studies will investigate the mechanism by which AID is upregulated andwhether or not there is induction of oncogenic mutagenesis in germinal center B cells exposed to phenylurea herbicides.
No relevant conflicts of interest to declare.
