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.