Steroidogenic acute regulatory protein (StAR) facilitates the translocation of cholesterol to the inner mitochondrial membrane (IMM), thereby initiating steroidogenesis. At the IMM, P450 side-chain cleavage (scc) enzyme converts cholesterol to pregnenolone, an oxidative process requiring electrons from NADPH. Pregnenolone then serves as the substrate for the formation of progesterone or dehydroepiandrosterone (DHEA) by downstream enzymes. Studies have shown that cigarette smoking (CS) influences steroid hormone levels. To better understand the underlying mechanisms, we used a mouse model to study the effects of chronic, mild CS exposure on steroidogenesis. Through radioimmunoassay and metabolic conversion assays, we found that CS reduced progesterone and DHEA without affecting P450scc or 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) expression. However, CS did reduce expression of cytochrome c oxidase IV (COX IV), a component of the mitochondrial complex that serves as the last enzyme in the electron transport chain. siRNA-mediated COX IV knockdown indeed decreased progesterone synthesis in steriodogenic cells. In summary, COX IV likely plays a role in steroidogenesis and passive smoking may negatively impact steroidogenesis by disrupting the electron transport chain.
- endocrine cells
- endocrine disrupters
- endocrine regulation
- environmental toxicology
- membrane transport
- membrane-protein interactions
- Received April 1, 2011.
- Revision received May 4, 2011.
- Accepted May 4, 2011.
- The American Society for Pharmacology and Experimental Therapeutics