In recent years, the silent yet pervasive threat posed by pesticides to male reproductive health has garnered mounting scientific attention. These chemical agents, spanning classifications such as insecticides, herbicides, and fungicides, are ubiquitous in modern agriculture and industry, yet their lingering effects on human physiology, particularly on testicular function, are only now being unraveled through advanced molecular and cellular studies. Emerging evidence reveals a complex interplay between pesticide exposure, oxidative stress, and autophagy dysregulation—a trio implicated in the deterioration of testicular integrity and consequent fertility challenges.
One of the most potent classes of insecticides, pyrethroids, exemplifies this risk. Lambda-cyhalothrin, a widely applied pyrethroid, is notorious for its rapid insecticidal action and efficacy as an acaricide. Detected in surface water at concentrations ranging from 0.35 to 0.80 micrograms per liter, human exposure to lambda-cyhalothrin is plausible and concerning. Experimental investigations have demonstrated that this compound exacerbates reactive oxygen species (ROS) accumulation, instigating oxidative stress within testicular cells. Such oxidative insults facilitate direct damage to DNA molecules, notably through the formation of 8-oxoguanine lesions, perturbing genomic integrity. Moreover, heightened oxidative stress correlates with mitochondrial dysfunction, a hallmark of testicular injury linked to disturbed autophagic pathways as evidenced by fluctuating levels of key markers like p62 and LC3.
Closely related pyrethroids like cypermethrin further underscore the vulnerability of male reproductive health to environmental toxins. Cypermethrin exerts its detrimental effects by compromising mitochondrial membrane integrity in critical somatic cells of the testes—Leydig and Sertoli cells. This mitochondrial perturbation partly manifests via subtle changes in mitophagy markers such as Sqstm1/p62, suggesting a suppressed clearance of damaged mitochondria that cumulatively leads to cellular dysfunction. Given the lipophilic nature of such pyrethroids, their accumulation within cellular membranes worsens ROS-mediated damage, underscoring oxidative stress as a converging pathway of toxicity intrinsic to these compounds.
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Beyond pyrethroids, avermectins—broad-spectrum antiparasitic agents—have been implicated in male reproductive impairment. Among them, abamectin stands out, with occupational and environmental exposure levels linked to reduced sperm quality, particularly sperm concentration. Mechanistically, abamectin triggers oxidative stress that cascades into endoplasmic reticulum stress, inflammation, apoptosis, and autophagy. This is orchestrated through the accumulation of ROS, which suppresses the phosphoinositide 3-kinase (PI3K)/AKT/mTOR signaling pathway, thereby activating programmed cell death and autophagic processes in Leydig cells. Such insights reveal the multifaceted and cellular compartment-specific toxicities imposed by avermectins on spermatogenic support systems.
Neonicotinoid insecticides, another prevalent pesticide class represented by imidacloprid, pose substantial ecological and human health risks. Designated by the WHO as a Class II hazardous pesticide, imidacloprid is renowned for its persistence and systemic toxicity, linked not only to environmental disruption but also to male reproductive detriments. In vivo studies demonstrate that imidacloprid exposure induces oxidative stress within the testes, provoking mitochondrial damage and activating lysosomal autophagic vacuoles in Leydig cells. These pathological responses culminate in the stimulation of the nuclear factor-kappa B (NF-κB)/c-Jun N-terminal kinase (JNK) signaling axis, which regulates mitochondrial apoptosis and BNIP3-mediated mitophagy—a targeted mitochondrial degradation route critical in maintaining cellular homeostasis.
Herbicides, indispensable for modern agricultural productivity, also represent a shadowed frontier of reproductive toxicity. Glyphosate, representative of this group, remains one of the most scrutinized pesticides worldwide. Despite regulatory bodies suggesting limited risk from dietary residues under established thresholds, glyphosate’s impacts on male fertility are increasingly documented. Experimental models link glyphosate exposure to the disruption of the blood-testis barrier (BTB), deterioration of sperm parameters, and a marked suppression of testosterone synthesis. At the cellular level, glyphosate compromises mitochondrial integrity within testicular cells, evidenced by morphological abnormalities, altered dynamics, and elevated mitochondrial ROS production. Fascinatingly, these mitochondrial perturbations are linked to enhanced autophagic activity, especially mitophagy, driven by the activation of Parkin, an E3 ubiquitin ligase pivotal in mitochondrial quality control.
Another herbicide, flurochloridone, used selectively to manage broadleaf weeds and grasses in diverse crop systems, has attracted concern for its endocrine-disrupting potential. Investigations in rodent models denote that flurochloridone leads to significant ROS accumulation and mitochondrial dysfunction within Sertoli cells—the somatic support cells essential for spermatogenesis. This cellular stress precipitates apoptotic pathways and stimulates autophagosome formation, indicated by elevated LC3II/LC3I ratios and increased expression of autophagic markers such as Beclin-1 and p62. The coupling of these processes underscores an adaptive yet pathological response to sustained oxidative injury in the testicular microenvironment.
Fungicides, integral to protection against pathogenic fungi in crops, display their own shadowed profile in male reproductive toxicity. Thiram, a notable member of the dimethyldithiocarbamate fungicide family, is extensively utilized across industries, including agriculture and rubber manufacturing. However, its improper storage and handling facilitate environmental dissemination, contributing to human exposure. Chronic thiram exposure induces reproductive toxicity through mechanisms involving oxidative stress and disruption of autophagy. Studies documenting altered gene expression patterns within testicular cells highlight the activation of pathways encompassing mTOR, Atg5, and p62, heralding autophagy induction, especially at elevated concentrations. In addition, thiram compromises BTB integrity by downregulating junctional proteins such as ZO-1 and Occludin, fostering fibrosis and histological damage within the testes. Oxidative stress parameters, including elevated ROS and depleted glutathione (GSH) levels, further exacerbate cellular injury.
Taken together, the emerging narrative from these multifarious toxicants paints a consistent picture: oxidative stress and autophagy dysregulation form the core mechanistic threads linking pesticide exposure to testicular damage. Reactive oxygen species serve both as mediators and amplifiers of mitochondrial dysfunction, DNA damage, and cellular apoptosis. Autophagic responses—typically cytoprotective—may become maladaptive or overwhelmed in the face of chronic toxic insults, leading to impaired clearance of damaged organelles and fostering cellular demise. Importantly, signaling pathways such as PI3K/AKT/mTOR and NF-κB/JNK emerge as central conduits modulating these processes, offering potential therapeutic targets.
This nuanced understanding carries immense implications for public health, regulatory policies, and agricultural practices. It compels a reevaluation of permitted pesticide levels, encourages the development of safer alternatives, and underscores the necessity of protective measures for populations at risk of occupational or environmental exposure. Furthermore, insights into the molecular underpinnings open avenues for biomarker discovery and targeted interventions aimed at safeguarding male reproductive health in an increasingly pesticide-laden world.
In the broader context, these findings exemplify the intricate interconnectedness between environmental toxins and human biology, revealing the susceptibility of even the most resilient biological barriers to chemical disruption. The convergence of oxidative stress and autophagy in testicular injury also echoes themes in diverse pathological states, underlining a universal cellular language of stress response and adaptation. Future research must delve deeper into dose-response relationships, polymorphic susceptibilities, and longitudinal outcomes to fully delineate these complex interactions and translate them into effective clinical and environmental strategies.
In conclusion, the accumulating evidence underscores that pesticide exposure, through a cascade of oxidative and autophagic disturbances, constitutes a formidable threat to male reproductive health. As modern societies continue to rely extensively on these chemical agents, the imperative to understand, mitigate, and remediate their impact on fertility becomes ever more pressing. Multidisciplinary efforts integrating toxicology, molecular biology, epidemiology, and environmental sciences are crucial to navigate this challenge and secure reproductive wellness for generations to come.
Subject of Research: Environmental pesticide exposure and its effects on male reproductive toxicity mediated by oxidative stress and autophagy imbalance.
Article Title: Unveiling the nexus between environmental exposures and testicular damages: revelations from autophagy and oxidative stress imbalance.
Article References:
Kong, X., Wang, X., Xia, Q. et al. Unveiling the nexus between environmental exposures and testicular damages: revelations from autophagy and oxidative stress imbalance. Cell Death Discov. 11, 258 (2025). https://doi.org/10.1038/s41420-025-02543-4
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02543-4
Tags: agricultural chemicals and human healthautophagy dysregulation in testicular cellsenvironmental exposure and reproductive toxicityenvironmental toxins and sperm healthlambda-cyhalothrin exposure effectsmitochondrial dysfunction in fertilitymolecular studies on testicular functionOxidative stress and DNA damagepesticides and male reproductive healthpyrethroid insecticides and fertilityreactive oxygen species in testistesticular damage and oxidative stress
