Multiple Targets of Neonicotinoid Insecticide Metabolites

EPA Grant Number: FP917128
Title: Multiple Targets of Neonicotinoid Insecticide Metabolites
Investigators: Clark, Tami Lynn
Institution: University of California - Berkeley
EPA Project Officer: Lee, Sonja
Project Period: September 1, 2010 through August 31, 2013
Project Amount: $111,000
RFA: STAR Graduate Fellowships (2010) RFA Text |  Recipients Lists
Research Category: Academic Fellowships , Fellowship - Pesticides and Toxic Substances


Neonicotinoids are the newest major class of insecticides. They have been shown to generate a large number and great variety of metabolites in mammals and plants. This project will investigate the toxicological mechanisms and targets of neonicotinoid insecticide metabolites.


Neonicotinoids account for more than 20 percent of the worldwide insecticide market. From the seven commercial neonicotinoids, over 100 metabolites have been identified in plants and mammals, many of which have not been evaluated for toxicity. This project examines the multiple targets of neonicotinoid metabolites and their potential mechanisms of toxicity. The findings will be important in determining the safest and most effective use of neonicotinoids as their use in agriculture expands.


This research will involve several methods to investigate the potential of neonicotinoid metabolites to inhibit essential mammalian enzymes based on previous research and/or unique chemical features. In addition, the biochemical impact of these effects will be assessed. First, this project will analyze the ability of nitroguanidine neonicotinoid metabolites to inhibit nitric oxide synthase (NOS) and determine how altered levels of nitric oxide may potentiate hepatotoxic and hepatocarcinogenic effects of other metabolites. Next, nitrosoguanidine and aminoguanidine metabolites of a specific neonicotinoid, imidacloprid, will be examined as potential tissue aldehyde- and ketone-depleting agents and as irreversible inhibitors of the xenobiotic-metabolizing enzyme, aldehyde oxidase (AOX). Third, the production of glucuronide- or glucoside-sequestered neonicotinoid metabolites will be analyzed in mammals and plants, respectively. Finally, neonicotinoid phase I and phase II metabolites will be evaluated for their ability to chelate and inhibit metallo-oxidase enzymes.

Expected Results:

The ability of neonicotinoid metabolites to alter the function of key regulatory mammalian enzymes will clarify their role in the secondary mechanisms of neonicotinoid toxicity. NOS inhibition may potentiate the hepatotoxic and hepatocarcinogenic effects of other neonicotinoid metabolites. AOX inhibition may prevent further metabolism of imidacloprid and other neonicotinoids since AOX is implicated as a key enzyme in neonicotinoid metabolism. Glucuronide- or glucoside-sequestered metabolites may serve as masked nicotinic acetylcholine receptor agonists and metallo-oxidase inhibition would greatly alter important biochemical functions in mammalian systems.

Potential to Further Environmental/Human Health Protection:

The world relies on pesticides to generate the amount of food necessary to sustain expanding populations. Evaluating the mechanisms of toxicity of neonicotinoid insecticide metabolites will facilitate safe and effective use of these chemicals. Results from this project may ultimately lead to the creation of safer, less toxic insecticides and implementation of new regulations for future pest control.

Supplemental Keywords:

neonicotinoids, insecticide, metabolites, imidacloprid, nitric oxide synthase, aldehyde oxidase, metallo-oxidase,

Progress and Final Reports:

  • 2011
  • 2012
  • Final