Inhibition of human and rat 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase 3 activities by perfluoroalkylated substances.
Perfluoroalkylated substances (PFASs) including perfluorooctane acid (PFOA) and perfluorooctane sulfonate (PFOS) have been classified as persistent organic pollutants and are known to cause reduced testosterone production in human males. The objective of the present study was to compare the potencies of five different PFASs including PFOA, PFOS, potassium perfluorooctane sulfonate (PFOSK), potassium perfluorohexane sulfonate (PFHxSK) and potassium perfluorobutane sulfonate (PFBSK) in the inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase 3 (17beta-HSD3) activities in the human and rat testes. Human and rat microsomal enzymes were exposed to various PFASs. PFOS and PFOSK inhibited rat 3beta-HSD activity with IC(50) of 1.35 + or -0.05 and 1.77 + or - 0.04 microM, respectively, whereas PFHxSK and PFBSK had no effect at concentrations up to 250 microM. All chemicals tested weakly inhibited human 3beta-HSD activity with IC(50)s over 250 microM. On the other hand, PFOS, PFOSK and PFOA inhibited human 17beta-HSD3 activity with IC(50)s of 6.02 + or - 1.02, 4.39 + or - 0.46 and 127.60 + or - 28.52 microM, respectively. The potencies for inhibition of 17beta-HSD3 activity were determined to be PFOSK>PFOS>PFOA>PFHxSK=PFBSK for human 17beta-HSD3 activity. There appears to be a species-dependent sensitivity to PFAS-mediated inhibition of enzyme activity because the IC(50)s of PFOS(K) for inhibition of rat 17beta-HSD3 activity was greater than 250 microM. In conclusion, the present study shows that PFOS and PFOSK are potent inhibitors of rat 3beta-HSD and human 17beta-HSD3 activity, and implies that inhibition of steroidogenic enzyme activity may be a contributing factor to the effects that PFASs exert on androgen secretion in the testis.
Zhao
Binghai
B
Population Council, 1230 York Avenue, New York, NY 10065, USA.
Hu
Guo-Xin
GX
Chu
Yanhui
Y
Jin
Xiudong
X
Gong
Shouliang
S
Akingbemi
Benson T
BT
Zhang
Zhiqiang
Z
Zirkin
Barry R
BR
Ge
Ren-Shan
RS
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005466:Fluorocarbons / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051381:Rats; D013737:Testis / Q000187:drug effects / Q000201:enzymology
D004791:Enzyme Inhibitors; D005466:Fluorocarbons; D015067:17-Hydroxysteroid Dehydrogenases; D015096:3-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase