Disrupting mitochondrial function with surfactants inhibits MA-10 Leydig cell steroidogenesis.
It is well established that surfactants can elicit cytotoxic effects at threshold concentrations by changing the permeability and solubilizing components of cell membranes. The purpose of this study was to characterize the relationship between perturbation of the mitochondrial membrane resulting from treatment with representative cationic, nonionic, and anionic surfactants and the extent to which this perturbation affects steroid formation and StAR protein expression and activity in MA-10 Leydig cells. The StAR protein is synthesized as an active 37 kDa extramitochondrial form, which is processed into a 30 kDa intramitochondrial form after cholesterol transfer and mitochondrial import and processing. It has been shown in several in vitro studies that the mitochondrial electrochemical gradient is required for the StAR protein to transfer cholesterol to the inner mitochondrial membrane. Each substance that was tested produced a concentration-dependent decrease in steroid formation in hCG-stimulated MA-10 cells. Decreases in progesterone production were accompanied by loss of mitochondrial membrane potential and by a decrease in the levels of the 30 kDa form of the StAR protein. However, levels of the 37 kDa form of the StAR protein did not decrease, indicating no effect on StAR protein expression. These results demonstrate how perturbation of the mitochondrial membrane by surfactants inhibits import, processing, and cholesterol transfer activity and underscore the importance of including sensitive assays that evaluate mitochondrial function when screening for potential effects on steroidogenesis with in vitro test systems.
Levine
S L
SL
Monsanto Company, St. Louis, MO 63167, USA. steven.l.levine@monsanto.com
Han
Z
Z
Liu
J
J
Farmer
D R
DR
Papadopoulos
V
V
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020128:Inhibitory Concentration 50; D007985:Leydig Cells / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D011374:Progesterone / Q000096:biosynthesis; D013256:Steroids / Q000096:biosynthesis*; D013501:Surface-Active Agents / Q000494:pharmacology*
D006063:Chorionic Gonadotropin; D026901:Membrane Transport Proteins; D013256:Steroids; D013501:Surface-Active Agents; D011374:Progesterone