Cyclopiazonic acid suppresses the function of Leydig cells in prepubertal male rats by disrupting mitofusin 1-mediated mitochondrial function

Hang Lin; Ming Su; He Zhu; Yang Yu; Jianmin Sang; Yiyan Wang; Qiqi Zhu; Yang Zhu; Xiaoheng Li; Xingwang Li; Ren-Shan Ge; Huitao Li

Ecotoxicology and Environmental Safety (Jan 2025)

Cyclopiazonic acid suppresses the function of Leydig cells in prepubertal male rats by disrupting mitofusin 1-mediated mitochondrial function

Hang Lin,
Ming Su,
He Zhu,
Yang Yu,
Jianmin Sang,
Yiyan Wang,
Qiqi Zhu,
Yang Zhu,
Xiaoheng Li,
Xingwang Li,
Ren-Shan Ge,
Huitao Li

Affiliations

Hang Lin: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Ming Su: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
He Zhu: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Yang Yu: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Jianmin Sang: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Yiyan Wang: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Qiqi Zhu: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Yang Zhu: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Xiaoheng Li: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Xingwang Li: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
Ren-Shan Ge: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Correspondence to: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital the Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Huitao Li: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Pediatric Anesthesiology, Ministry of Education, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Anesthesiology of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Zhejiang Engineering Research Center for Innovation and Application of Intelligent Radiotherapy Technology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Wenzhou key Laboratory of basic science and translational research of radiation oncology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Key Laboratory of Environment and Male Reproductive Medicine of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Correspondence to: Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital the Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.

Journal volume & issue: Vol. 289
p. 117503

Abstract

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This research investigated the impact of cyclopiazonic acid (CPA), a mycotoxin, on the function of progenitor Leydig cells (PLCs) in prepubertal male rats, focusing on its potential disruption of mitochondrial integrity through mitofusin 1 (MFN1) modulation. In vivo, Sprague Dawley rats received CPA (0.2, 1, 5 mg/kg/day) via gavage from postnatal days 21–28 to evaluate PLC function and mitochondrial morphology using serum hormone levels, histology, qPCR, and Western blot analyses. In vitro, rat R2C cells were treated with CPA (0.1, 1, 10 μM) alone or in combination with 100 μM leflunomide to assess PLC development through testosterone measurements, Western blotting, flow cytometry, and Mito-Tracker Green Staining. The findings from in vivo experiments showed that CPA reduced serum testosterone and progesterone levels at 1 mg/kg/day. The qPCR and Western blotting analyses revealed significant alterations in the expression of genes and proteins pertinent to PLC function, such as Scarb1, Star, Cyp11a1, and Cyp17a1. Immunofluorescence staining further revealed a reduction in MFN1 expression following exposure to CPA. In vitro experiments corroborated these observations, demonstrating that CPA induced mitochondrial fragmentation by downregulating SIRT1, PGC1-α, MFN1, and OPA1, increase reactive oxygen species, and inhibit testosterone synthesis in R2C cells. The administration of leflunomide was shown to mitigate the detrimental effects of CPA on PLCs. In conclusion, this research sheds new light on the deleterious effects of CPA on the reproductive development of prepubertal males.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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