Mechanism of 2,4‐Dichlorophenoxyacetic acid‐induced damage to rat testis via Fas/FasL pathway and the protective effect of Lycium barbarum polysaccharides

Abstract

The herbicide 2,4-Dichlorophenoxyacetic acid (2,4-D) is widely used to control broadleaved weeds and has been associated with male infertility. We studied the molecular mechanisms of 2,4-D induced male reproductive system damage and the protective effects of Lycium barbarum polysaccharides (LBP) using Sprague Dawley rats and TM4 cells. Treatment with 2,4-D caused architectural and functional changes in the testis, including collapsed and atrophied seminiferous tubules with reduced number of spermatozoa, scarce sperm in the epididymal duct, low levels of serum testosterone, decreased superoxide dismutase and glutathione peroxidase activity, high malondialdehyde content, and increased apoptosis in the testis and epididymis. The expression of Fas, FasL, FADD, Pro-caspase-8, Cleaved-Caspase-8, Pro-Caspase-3, and Cleaved-Caspase-3 were significantly increased in the testicular tissue of 2,4-D-treated rats. The proliferative activity of TM4 cells decreased with an increase in dose and time of 2,4-D exposure, along with enhanced Fas/Fas ligand expression and a decreased concentration of inhibin B in TM4 cell culture medium. Depletion of Fas by specific shRNA transfection reversed the effects of 2,4-D in TM4 cells, further confirming the involvement of death receptor pathway in 2,4-Dmediated apoptosis of sertoli cells. Treatment with LBP also reversed the effects of 2,4-D in testicular cells, resulting in improved cell architecture along with enhanced proliferative capacity. Moreover, in response to LBP treatment of Sertoli cells, the content of inhibin B increased, the level of reactive oxygen species and malondialdehyde decreased, the activities of superoxide dismutase and glutathione peroxidase increased, and the rate of apoptosis as well as the expression of Fas/Fas ligand signaling pathway proteins decreased.

SARS-CoV-2 Structural Proteins Modulated Blood-Testis Barrier-Related Proteins through Autophagy in the Primary Sertoli Cells

“…In a herbicide model, 2, 4-dichlorophenoxyacetic acid (2, 4-D) induced testicular injury and mouse Setoli cell (TM4) apoptosis, and the expression of Fas and FasL was significantly upregulated. Depletion of Fas by specific shRNA transfection reversed the effects of 2, 4-D in TM4 cells [ 43 ]. TGF-β modulates immune factors to inhibit the immune response in the testis [ 44 ].…”

The Medicinal Species of the Lycium Genus (Goji Berries) in East Asia: A Review of Its Effect on Cell Signal Transduction Pathways

“…Additionally, LBPs can significantly inhibit the activation of Fas/Fasl induced by 2,4-Dichlorophenoxyacetic acid (2,4-D) in rats. This inhibition leads to a reduction in the levels of caspase-8, caspase-3, and other proteins in the related signaling pathway, ultimately ameliorating germ cell apoptosis and mitigating testicular tissue damage [ 56 ]. ( Figure 3 ) These findings suggest that goji berries could be utilized as a daily supplement for fertility protection.…”

A mixture of glyphosate and 2,4‐D herbicides enhances the deleterious reproductive outcomes induced by Western diet in obese male mice

“…[23][24][25][26] Thus, the biological effects of these herbicides in non-vertebrate and vertebrate organisms are widely investigated and discussed, including reports of deleterious effects on different organs/systems, including reproductive repercussions. [27][28][29][30][31][32][33][34][35][36][37] The in vitro exposure to glyphosate (0,36 mg/L) reduced sperm motility. 38 Male rats exposed to glyphosate (250 mg/kg body weight, 8 weeks) also impaired sperm motility, reduced the number of spermatogenic cells, and caused intraepithelial vacuolization.…”

“…The widespread use of these herbicides may result in daily human exposure 23–26 . Thus, the biological effects of these herbicides in non‐vertebrate and vertebrate organisms are widely investigated and discussed, including reports of deleterious effects on different organs/systems, including reproductive repercussions 27–37 . The in vitro exposure to glyphosate (0,36 mg/L) reduced sperm motility 38 .…”