Perfluorotridecanoic acid inhibits fetal Leydig cell differentiation after in utero exposure in rats via increasing oxidative stress and autophagy

Abstract

Perfluorotridecanoic acid (PFTrDA) is a long-chain perfluoroalkyl substance, and its effect on the differentiation of fetal Leydig cells remains unclear. The objective of this study is to explore the effect of in utero PFTrDA exposure on the differentiation of fetal Leydig cells and investigate its underlying mechanisms. Pregnant Sprague-Dawley female rats were daily administered by gavage of PFTrDA at doses of 0, 1, 5, and 10 mg/kg from gestational day 14 to 21. PFTrDA had no effect on the body weight of dams, but significantly reduced the body weight and anogenital distance of male pups at birth at a dose of 10 mg/kg. PFTrDA significantly decreased serum testosterone levels as low as 1 mg/kg. PFTrDA did not affect fetal Leydig cell number, but promoted abnormal aggregation of fetal Leydig cells at doses of 5 and 10 mg/kg. PFTrDA down-regulated the expression of Insl3, Lhcgr, Scarb1, Star, Hsd3b1, Cyp17a1, Nr5a1, and Dhh as well as their proteins. PFTrDA lowered the levels of antioxidants (SOD1, CAT, and GPX1), induced autophagy as shown by increased levels of LC3II and beclin1, and reduced the phosphorylation of mTOR. In conclusion, PFTrDA inhibits the differentiation of fetal Leydig cells in male pups after in utero exposure mainly through increasing oxidative stress and inducing autophagy.

Per‐ and polyfluoroalkyl substances activate UPR pathway, induce steatosis and fibrosis in liver cells

“… 68 PFTrDA also down‐regulated fetal Leydig cell (FLC) genes such as Insl3 , Lhcgr , Scarb1 , Nr5a1 , Cyp17a1 , Star , Hsd3b1 , and Dhh , antioxidants ( GPX1 , SOD1 , CAT ) and induced autophagy suggesting that PFTrDA inhibits the differentiation of fetal Leydig cells in male pups. 68 In addition, exposure to perfluorooctanoic acid (PFOA; 25 mg/kg) in female mice decreased the weight and length of the fetus, diameter, and weight of the placenta, dead fetuses, and dead macerated fetuses in PFOA‐treated animals because of mitochondria dysfunction. 69 Due to unique physicochemical properties and industrial applications graphene oxide (GO) is used as a filter material for removing perfluorinated substances and trihalomethanes from drinking water.…”

“…Similarly, exposure to PFOA affects porcine oocyte maturation, and exposure to PFOA enhanced reactive oxygen species production, protein carbonylation, and DNA damage in cumulus cells 67 . Administration of perfluorotridecanoic acid (PFTrDA) to pregnant Sprague–Dawley female rats showed decreased serum testosterone levels at 1 mg/kg and also promoted abnormal aggregation of fetal Leydig cells at doses of 5 and 10 mg/kg 68 . PFTrDA also down‐regulated fetal Leydig cell (FLC) genes such as Insl3 , Lhcgr , Scarb1 , Nr5a1 , Cyp17a1 , Star , Hsd3b1 , and Dhh , antioxidants ( GPX1 , SOD1 , CAT ) and induced autophagy suggesting that PFTrDA inhibits the differentiation of fetal Leydig cells in male pups 68 .…”

“…Administration of perfluorotridecanoic acid (PFTrDA) to pregnant Sprague–Dawley female rats showed decreased serum testosterone levels at 1 mg/kg and also promoted abnormal aggregation of fetal Leydig cells at doses of 5 and 10 mg/kg 68 . PFTrDA also down‐regulated fetal Leydig cell (FLC) genes such as Insl3 , Lhcgr , Scarb1 , Nr5a1 , Cyp17a1 , Star , Hsd3b1 , and Dhh , antioxidants ( GPX1 , SOD1 , CAT ) and induced autophagy suggesting that PFTrDA inhibits the differentiation of fetal Leydig cells in male pups 68 . In addition, exposure to perfluorooctanoic acid (PFOA; 25 mg/kg) in female mice decreased the weight and length of the fetus, diameter, and weight of the placenta, dead fetuses, and dead macerated fetuses in PFOA‐treated animals because of mitochondria dysfunction 69 .…”

“…68 PFTrDA also down-regulated fetal Leydig cell (FLC) genes such as Insl3, Lhcgr, Scarb1, Nr5a1, Cyp17a1, Star, Hsd3b1, and Dhh, antioxidants (GPX1, SOD1, CAT) and induced autophagy suggesting that PFTrDA inhibits the differentiation of fetal Leydig cells in male pups. 68 In addition, exposure to perfluorooctanoic acid (PFOA;…”

Epigenetic analysis in placentas from sickle cell disease patients reveals a hypermethylation profile

“…Interestingly, in the present study, we identified some differentially methylated genes whose deregulation by oxidative stress has already been reported. Among the genes identified we highlight LHCGR , TGFB1 , SEPT9 and BNC2 in the HbSS group [ 43 – 46 ], and CERS6 , GATA4 , HLA -G and PAX3 in the HbSC group [ 47 – 50 ]. These findings suggest that oxidative stress may be modulating these genes through methylation in the studied patients.…”