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Deoxynivalenol Inhibits Progenitor Leydig Cell Development by Stimulating Mitochondrial Fission in Rats
Jin Yang1,2,3, Lei Ye1,2,3, Rong Cui1,2,3
1Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Abstract:
Deoxynivalenol (DON) is a common food contaminant that can impair male reproductive function. This study investigated the effects and mechanisms of DON exposure on progenitor Leydig cell (PLC) development in prepubertal male rats. Rats were orally administrated DON (0-4 mg/kg) from postnatal days 21-28. DON increased PLC proliferation but inhibited PLC maturation and function, including reducing testosterone levels and downregulating biomarkers like HSD11B1 and INSL3 at ≥2 mg/kg. DON also stimulated mitochondrial fission via upregulating DRP1 and FIS1 protein levels and increased oxidative stress by reducing antioxidant capacity (including NRF2, SOD1, SOD2, and CAT) in PLCs in vivo. In vitro, DON (2-4 μM) inhibited PLC androgen biosynthesis, increased reactive oxygen species production and protein levels of DRP1, FIS1, MFF, and pAMPK, decreased mitochondrial membrane potential and MFN1 protein levels, and caused mitochondrial fragmentation. The mitochondrial fission inhibitor mdivi-1 attenuated DON-induced impairments in PLCs. DON inhibited PLC steroidogenesis, increased oxidative stress, perturbed mitochondrial homeostasis, and impaired maturation. In conclusion, DON disrupts PLC development in prepubertal rats by stimulating mitochondrial fission.
Insights
Deoxynivalenol (DON) exposure harms male reproductive health by disrupting progenitor Leydig cell development. This common food contaminant impairs Leydig cell maturation and function through mitochondrial fission and oxidative stress.
Area of Science:
- Reproductive Toxicology
- Endocrinology
- Mitochondrial Biology
Background:
- Deoxynivalenol (DON) is a prevalent mycotoxin contaminant in food.
- DON exposure is linked to adverse effects on male reproductive function.
- Understanding DON's impact on Leydig cell development is crucial for male reproductive health.
Purpose of the Study:
- To investigate the effects of DON on progenitor Leydig cell (PLC) development in prepubertal rats.
- To elucidate the mechanisms underlying DON-induced testicular toxicity, focusing on mitochondrial function and oxidative stress.
Main Methods:
- Oral administration of DON to prepubertal male rats.
- In vivo and in vitro assessments of PLC proliferation, maturation, and function.
- Analysis of testosterone levels, gene/protein expression (HSD11B1, INSL3, DRP1, FIS1, NRF2, SODs, CAT, MFF, pAMPK, MFN1), oxidative stress markers, and mitochondrial parameters.
- Treatment with a mitochondrial fission inhibitor (mdivi-1).
Main Results:
- DON increased PLC proliferation but inhibited maturation and testosterone production at doses ≥2 mg/kg.
- DON induced mitochondrial fission by upregulating DRP1 and FIS1, and increased oxidative stress by reducing antioxidant capacity in PLCs.
- In vitro, DON impaired androgen biosynthesis, increased reactive oxygen species, altered mitochondrial dynamics (fragmentation, reduced membrane potential), and affected key protein levels.
- Mdivi-1 treatment mitigated DON-induced PLC damage.
Conclusions:
- Deoxynivalenol disrupts progenitor Leydig cell development and function in prepubertal rats.
- DON exerts toxicity by stimulating mitochondrial fission, increasing oxidative stress, and perturbing mitochondrial homeostasis.
- These findings highlight DON as a significant risk factor for male reproductive health impairment.
