2. Academic Validation
  3. Triadimefon increases fetal Leydig cell proliferation but inhibits its differentiation of male fetuses after gestational exposure

Triadimefon increases fetal Leydig cell proliferation but inhibits its differentiation of male fetuses after gestational exposure

  • Ecotoxicol Environ Saf. 2021 Oct 30:228:112942. doi: 10.1016/j.ecoenv.2021.112942.
Liben Lin 1,  Qiang Xu 2,  Quanxu Chen 3,  Haiqiong Chen 4,  Yingfen Ying 5,  Zengqiang Li 6,  Song Zhang 7,  Feifei Ma 8,  Yige Yu 9,  Ren-Shan Ge 10
Affiliations

Affiliations

  • 1 Department of Pathology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: linliben@126.com.
  • 2 Department of Pathology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: wzfeyxq@163.com.
  • 3 Department of Pathology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: chenquanxu126@163.com.
  • 4 Department of Pediatrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: chenhaiqiong1994@163.com.
  • 5 Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: yingyingfen@126.com.
  • 6 Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: lizengqiang0608@163.com.
  • 7 Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: SophiaSongZ@163.com.
  • 8 Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: mafeifei181@163.com.
  • 9 Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: yuyige321@163.com.
  • 10 Department of Gynecology and Obstetrics, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: renshan_ge@wmu.edu.cn.
PMID: 34737156 DOI: 10.1016/j.ecoenv.2021.112942
Abstract

Triadimefon is a broad-spectrum fungicide widely applied in the agriculture. It is believed to be an endocrine disruptor. Whether triadimefon can inhibit the development of fetal Leydig cells and the underlying mechanisms are unknown. Thirty-two female pregnant Sprague-Dawley rats were randomly assigned into four groups and were dosed via gavage of triadimefon (0, 25, 50, and 100 mg/kg/day) for 9 days from gestational day (GD) 12-20. Triadimefon significantly reduced serum testosterone level in male fetuses at 100 mg/kg. The double immunofluorescence staining of proliferating cell nuclear antigen (PCNA) and Cytochrome P450 cholesterol side-chain cleavage (a biomarker for fetal Leydig cells) was used to measure PCNA-labeling in fetal Leydig cells. It markedly increased fetal Leydig cell number primarily via increasing single cell population and elevated the PCNA-labeling of fetal Leydig cells in male fetuses at 100 mg/kg while it induced abnormal aggregation of fetal Leydig cells. The expression levels of fetal Leydig cell genes, Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, CYP17A1, Hsd17b3, Insl3 and Nr5a1, were determined to explore its effects on fetal Leydig cell development. We found that triadimefon markedly down-regulated the expression of Leydig cell genes, Hsd17b3, Insl3, and Nr5a1 as low as 25 mg/kg and Scarb1 and Cyp11a1 at 100 mg/kg. It did not affect Sertoli cell number but markedly down-regulated the expression of Sertoli cell gene Amh at 50 and 100 mg/kg. Triadimefon significantly down-regulated the expression of antioxidant genes Sod1, Gpx1, and Cat at 25-100 mg/kg, suggesting that it can induce oxidative stress in fetal testis, and it reduced the phosphorylation of ERK1/2 and Akt2 at 100 mg/kg, indicating that it can inhibit the development of fetal Leydig cells. In conclusion, gestational exposure to triadimefon inhibits the development of fetal Leydig cells in male fetuses by inhibiting its differentiation.

Keywords

Fetal Leydig cell development; Fungicide; Proliferation; Steroidogenesis; Triadimefon.

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