# Neonicotinoids and the Androgen Receptor: Structural Dynamics and Potential Signaling Disruption

## TL;DR

This study investigates how neonicotinoid insecticides may disrupt the androgen receptor, potentially affecting male reproductive functions.

## Contribution

The study uses molecular modeling to show that neonicotinoids bind stably to the androgen receptor, potentially disrupting testosterone signaling.

## Key findings

- Neonicotinoids (except THI) showed strong binding to the androgen receptor with high energy and affinity.
- Molecular dynamics simulations confirmed the stability of neonicotinoid-androgen receptor complexes.
- Binding may interfere with testosterone's natural interaction with the receptor, risking male reproductive dysfunction.

## Abstract

Neonicotinoids are chemicals structurally similar to nicotine and commonly used globally as insecticides for the prevention of insect-related losses on many vegetable and horticulture crops. Neonicotinoid sales constitute about a third of the global insecticide industry. Because of their extensive use, human exposure through neonicotinoid residue contamination of foods and the environment is a significant public health concern. The current study was conducted to assess androgen receptor disruption by these common neonicotinoid compounds and to predict their potential adverse effects on male reproductive functions. The study involved molecular modeling using molecular docking and molecular dynamics simulation.

Neonicotinoids are synthetic nicotine-like compounds extensively used globally as insecticides for agricultural and urban purposes. Neonicotinoid-contaminated produce is a major public health concern worldwide. Limited epidemiological studies have shown an association of neonicotinoid exposure with abnormal semen analysis. This study aimed to elucidate the potential disruption of the androgen receptor (AR) by eight common neonicotinoids, including imidacloprid (IMI), acetamiprid, clothianidin, thiamethoxam, dinotefuran, thiacloprid (THI), nitenpyram, and nithiazine using docking and molecular dynamics (MD) simulation. The results showed good binding strength of all compounds (except THI) with AR, as indicated by high binding energy, high binding affinity, and number of bonding interactions. The results of MD simulation supported the conformational stability and structural dynamic behavior of the AR-IMI (receptor-neonicotinoid) complex upon binding. This was indicated by root mean square deviation showing stability of the complex; the root mean square fluctuation showing minimized residual fluctuations upon binding; the radius of gyration showing greater compactness of the protein structure; the solvent-accessible surface area showing no changes upon binding; and the Gibbs funnel energy of the landscape showing a stable conformation state with minimum energy and slight change in size and position of the sampled energy basin of the AR, with a stable equilibrium. Taken together, the structural dynamics results showed that neonicotinoids are bound stably in the same ligand-binding domain of the AR as the native ligand testosterone. This may perturb the natural binding of testosterone with the AR and potentially disrupt downstream signaling and biological pathways, leading to male reproductive dysfunction.