Perfluoroheptanoic acid induces Leydig cell hyperplasia but inhibits spermatogenesis in rats after pubertal exposure. (30th January 2021)

• Record Type: Journal Article
• Authors: Li, Zengqiang; Li, Changchang; Wen, Zina; Yan, Haoni; Zou, Cheng; Li, Yang; Tian, Lili; Lei, Zhen; Li, Huitao; Wang, Yiyan; Zhong, Ying; Ge, Ren-shan
• Is Part Of: Toxicology. Volume 448(2021)
• Publication Date: 2021-01-30
• Subjects: Perfluoroheptanoic acid -- PFHpA -- Immature Leydig cells -- Testosterone short-chain perfluoroalkyl substances; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2020.152633
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: PFHpA induces Leydig cell hyperplasia during puberty. PFHpA induces hypergonadotropic hypogonadism in rats. PFHpA down-regulates Cyp11a1, Cyp17a1, Hsd3b1 expression in individual Leydig cells. PFHpA induces AKT1, AKT2, ERK1/2 and JNK phosphorylation. PFHpA increases BCL2 and decreases BAX in the testis. Abstract: Perfluoroheptanoic acid (PFHpA) is a short-chain alternative to long-chain perfluoroalkyl substances, which have been reported to possess reproductive toxicity. However, it is unclear whether PFHpA affects Leydig cell development during puberty. The 35-day-old Sprague Dawley male rats were exposed to PFHpA by gavage with 0 (corn oil), 10, 50, and 100 mg/kg/day for 21 days. PFHpA did not affect the body weight of rats, but it reduced testis weight, relative testis weight, and epididymis weight at 100 mg/kg. It significantly increased serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels at a dose of 100 mg/kg without affecting serum estradiol levels. PFHpA suppressed sperm production at a dose of 100 mg/kg. PFHpA induced Leydig cell hyperplasia (increased number of CYP11A1-positive Leydig cells) at a dose of 100 mg/kg, but down-regulated the expression of Cyp11a1, Hsd3b1, and Cyp17a1 in individual Leydig cell pe se and up-regulated the expression of Fshr in the Sertoli cell pe se. PFHpA did not affect the number of HSD11B1 (a biomarker for more mature Leydig cells) positive Leydig cells and SOX9 positive Sertoli cells. PFHpA increased BCL2, and the phosphorylation of AKT1, AKT2, ERK1/2, and JNK, but decreased BAX levels. However, it had no effect on SIRT1 and PGC-1α levels. In conclusion, PFHpA induces Leydig cell hyperplasia due to the increase in the secretion of luteinizing hormone through negative feedback after down-regulating the expression of steroidogenic enzymes and inhibiting testosterone production in individual Leydig cells. This proliferation may be mediated by increasing BCL2 and phosphorylation of AKT, ERK1/2, and JNK, and decreasing BAX level.