Chlorpyrifos (CPF) is a widely used organophosphorus pesticide known for its detrimental effects on human health. It enters the body through dermal contact, ingestion, or the food chain, leading to accumulation and metabolism. Its primary metabolite, 3,5,6-trichloro-2-pyridinol (TCP), can cause significant damage to multiple organs and systems.

Recent studies suggest that CPF has negative implications on male reproduction, as evidenced by decreased levels of serum testosterone, follicle-stimulating hormone, and luteinizing hormone, along with reduced sperm count and quality. However, its toxic effects and the specific mechanisms underlying the junctional function of Sertoli cells requires further investigation.
In a recent study, published in the Genes & Diseases journal, researchers at the Children's Hospital of Chongqing Medical University and the Second Affiliated Hospital of Chongqing Medical University demonstrated that CPF exposure induces spermatogenesis dysfunction by impairing blood-testis barrier (BTB) integrity, which is regulated by clockophagy-mediated ferroptosis.

Preliminary findings showed that CPF impairs spermatogenesis by compromising the BTB integrity in SD rats. In vitro results suggest that exposure to TCP disrupts junctional function in Sertoli cells, contributing to the loss of BTB integrity. RNA sequencing of Sertoli cells exposed to TCP, followed by KEGG analysis, identified DEGs primarily enriched in metabolic pathways, glycolysis, and ferroptosis. Further experimentation confirmed that TCP disrupts Sertoli cell junctional function by inducing ferroptosis.

Clockophagy is a newly identified type of selective autophagy that triggers ferroptosis by degrading ARNTL, a core circadian clock protein, and thereby causing instability of HIF-1α. Following TCP exposure, the protein expression of ARNTL, GPx4, and light chain3 beta (LC3B) II/I decreased with a concomitant increase in the protein levels of p62 and prolyl hydroxylase 1 (PHD1), suggesting that TCP exposure induces ferroptosis in Sertoli cells by activating clockophagy. Additionally, in vivo experiments further confirmed that CPF exposure induces ferroptosis in the testes via clockophagy.

The authors acknowledge that the study has certain limitations, such as: i) the use of higher CPF doses than those encountered in realistic human exposure scenarios; ii) the use of only pre-pubertal male rats (including rats of all age groups would provide a better understanding of the toxic effects of CPF on male reproduction); and iii) not investigating the roles of secretion and phagocytosis, both of which play crucial roles in spermatogenesis.

In conclusion, the findings of this study provide molecular insights into how CPF exposure induces male infertility by compromising the BTB integrity, highlighting the potential influence of clockophagy- mediated ferroptosis in spermatogenic dysfunction.

Reference

Title of the original paper: Chlorpyrifos induces spermatogenic dysfunction via ferroptosis in Sertoli cells

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101601

Funding Information:

National Natural Science Foundation of China (No. 81801521)
Chongqing Science and Technology Bureau of China (No. CSTB2022NSCQ-LZX0019, 2022ZDXM033)
Chongqing Municipal Education Commission of China (No. KJQN202200410)

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