Effects of lindane on steroidogenesis and steroidogenic acute regulatory protein expression.
Lindane, the gamma isomer of hexachlorocyclohexane (HCH), is one of the oldest synthetic pesticides still in use worldwide. Numerous reports have shown that this pesticide adversely affects reproductive function in animals. Although the pathogenesis of reproductive dysfunction is not yet fully understood, recent reports indicate that lindane can directly inhibit adrenal and gonadal steroidogenesis. Because Leydig cells play a pivotal role in male reproductive function through the production of testosterone, the mouse MA-10 Leydig tumor cell line was used to assess the potential effects of gamma-HCH and its isomers, alpha-HCH and delta-HCH, on steroid production, steroidogenic enzyme expression and activity, and steroidogenic acute regulatory (StAR) protein expression. StAR mediates the rate-limiting and acutely regulated step in hormone-stimulated steroidogenesis, the intramitochondrial transfer of cholesterol to the P450(scc) enzyme. Our studies demonstrate that alpha-, delta-, and gamma-HCH inhibited dibutyryl ([Bu](2)) cAMP-stimulated progesterone production in MA-10 cells in a dosage-dependent manner without affecting general protein synthesis; and protein kinase A or steroidogenic enzyme expression, activity, or both. In contrast, each of these isomers dramatically reduced (Bu)(2)cAMP-stimulated StAR protein levels. Therefore, our results are consistent with the hypothesis that alpha-, delta-, and gamma-HCH inhibited steroidogenesis by reducing StAR protein expression, an action that may contribute to the pathogenesis of lindane-induced reproductive dysfunction.
Walsh
L P
LP
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA.
Stocco
D M
DM
D015096:3-Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D007984:Leydig Cell Tumor; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011506:Proteins / Q000187:drug effects; D013256:Steroids / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000098682:Steroidogenic Acute Regulatory Protein
D010750:Phosphoproteins; D011506:Proteins; D013256:Steroids; D000098682:Steroidogenic Acute Regulatory Protein; C040534:alpha-hexachlorocyclohexane; D011374:Progesterone; D001556:Hexachlorocyclohexane; D015096:3-Hydroxysteroid Dehydrogenases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D017868:Cyclic AMP-Dependent Protein Kinases; C023888:beta-hexachlorocyclohexane