Structural Aspects of Potential Endocrine-Disrupting Activity of Stereoisomers for a Common Pesticide Permethrin against Androgen Receptor

Abstract

Endocrine-disrupting chemicals (EDCs) are a serious global public health and environmental concern. Pyrethroids are insecticide chemicals that are extensively used for crop protection and household purposes but have been identified as EDCs. On account of their ubiquitous environmental presence, human exposure occurs via food, dermal, or inhalation routes and is associated with health problems, including reproductive dysfunction. Permethrin is the most commonly used pyrethroid, and with two chiral centers in its structure, it has four stereoisomeric forms (two enantiomer pairs), i.e., permethrin (1R,3R)-cis, permethrin (1R,3S)-trans, permethrin (1S,3S)-cis, and permethrin (1S,3R)-trans. The current study was performed for predicting the potential endocrine-disrupting activity of the aforementioned four stereoisomers of permethrin against the androgen receptor (AR). The structural binding characterization and binding energy estimations in the AR binding pocket were done using induced fit docking. The structural binding data indicated that all stereoisomers were placed stably in the AR binding pocket and that the estimated binding energy values were comparable to the AR native ligand, except for permethrin (1S,3S)-cis. Furthermore, the commonality in the amino acid interactions to that of the AR native ligand and the binding energy values suggested the potential AR-disrupting activity of all the stereoisomers; however, stereoselective differences were not observed. Taken together, the results suggest that human exposure to permethrin, either as a racemate mixture or in individual stereoisomer form, could potentially interfere with AR function, which may lead to male reproductive dysfunction.

In silico determination of fenthion, permethrin, and carbaryl as FFAR2 inhibitors: Type 2 diabetes mellitus pathomechanism study

“…In a separate in silico examination, permethrin demonstrated its potential to inhibit androgen receptors, with the recorded values reaching -10.57. 29 It is noteworthy that variations in binding affinity values occur due to differences in ligands, receptors, and the specific computational tools employed. The binding affinity value in the interaction between a ligand and its receptor is primarily influenced by the quantity and nature of bonds formed, especially non-covalent bonds.…”

Integrated Assessment for the Estrogenic Effects of Pyrethroid Compounds: Defining the Molecular Initiating Events and Key Events for the Adverse Outcome Pathway

“…Pyrethroid exposure can result in various adverse effects including impaired neurodevelopment, major chronic diseases including cardiovascular disease, carcinogenicity, and reproductive dysfunction [ 1 ]. Specifically, due to their widespread global use, concerns regarding the potential impact of pyrethroid exposure on endocrine health are escalating, exacerbated by its stability in the environment and anticipated prolonged persistence, raising the risk of widespread contamination with potential consequences for various organisms and ecosystems [ 7 , 8 , 9 , 10 ]. Pyrethroids have been consistently detected in residential homes, food, and human samples, highlighting the pervasive nature of exposure [ 9 , 10 ].…”

“…Previous studies have elucidated various facets of pyrethroid toxicity, including their interference with androgen receptors, inhibition of steroid synthesis, modulation of the hypothalamic-pituitary-gonadal axis, action as estrogen receptor modulators, and induction of oxidative stress. Notably, evidence suggests a decrease in ovarian reserve following pyrethroid exposure [ 8 , 13 ].…”

“…Recent exposure population surveys in several countries have indicated a slight increase in environmental exposure, particularly among workers using pyrethroid insecticides, with a 1.5-2-fold rise observed in the United States [11,12]. Type I Permethrin tential impact of pyrethroid exposure on endocrine health are escalating, exacerbated by its stability in the environment and anticipated prolonged persistence, raising the risk of widespread contamination with potential consequences for various organisms and ecosystems [7][8][9][10]. Pyrethroids have been consistently detected in residential homes, food, and human samples, highlighting the pervasive nature of exposure [9,10].…”

Recent Advances in the Recognition Elements of Sensors to Detect Pyrethroids in Food: A Review

“…Pyrethroid pesticides have strong absorbability and are directly and indirectly transmitted into the food chain, which eventually poses a threat to human health and life [ 13 ]. Pyrethroid pesticides are endocrine-disrupting compounds (EDCs) that indirectly interfere with upstream endocrine signal transduction signaling pathways through direct receptor interactions by mimicking and cooperating with endogenous hormones [ 14 ]. The pyrethroid metabolite 3-phenoxybenzaldehyde (3-PBA) bioaccumulates in human breast milk, which negatively impacts babies relying on breast milk [ 15 , 16 ].…”