Abstract
Chronic inflammatory disease and acute infection are well known to inhibit gonadal steroidogenesis. Previous studies have demonstrated that immune activation in response to lipopolysaccharide (LPS) results in reductions in serum testosterone, and this is a direct effect on the Leydig cell. We hypothesize that during the early onset of LPS endotoxemia in vivo, testicular macrophages produce reactive oxygen species (ROS) leading to perturbation of Leydig cell mitochondria and an inhibition in steroidogenesis. To investigate the mechanism of LPS inhibition of Leydig cell steroidogenesis, alterations in mitochondria and markers of oxidative stress were assessed in vivo and in Leydig cell primary culture. After a single injection of mice with LPS, serum testosterone was significantly decreased within 2 h. LPS injection of mice resulted in significant reductions in steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydogenase-Δ4-Δ5 isomerase (3β-HSD) proteins. LPS significantly increased lipid peroxidation of Leydig cell membranes, indicating that LPS results in oxidative damage in vivo. Mitochondria in Leydig cells isolated from LPS-injected mice were disrupted and showed a marked reduction in the mitochondrial membrane potential (Δψm). Similar to the effects of LPS, treatment of Leydig cells with hydrogen peroxide acutely inhibited steroidogenesis, reduced StAR and 3β-HSD protein levels, and disrupted Δψm. These results suggest that LPS acutely inhibits Leydig cell function by ROS-mediated disruption of Leydig cell mitochondria. Taken together, these results demonstrate the necessity of having respiring mitochondria with an intact Δψm to facilitate StAR function and Leydig cell steroidogenesis. The acute effects of LPS demonstrate how sensitive Leydig cell mitochondrial steroidogenesis is to inflammation-induced oxidative stress.
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References
Rivier, C. and Rivest, S. (1991). Biol. Reprod. 45, 523–532.
Ogilvie, K. M., Held Hales, K., Roberts, M. E., Hales, D. B., and Rivier, C. (1999). Biol. Reprod. 60, 527–533.
Sharma, A. C., Bosmann, H. B., Motew, S. J., et al. (1996). Shock 6, 150–154.
Sam, A. D. 2nd, Sharma, A. C., Lee, L. Y., et al. (1999). Shock 11, 298–301.
Bosmann, H. B., Hales, K. H., Li, X., Liu, Z., Stocco, D. M., and Hales, D. B. (1996). Endocrinology 137, 4522–4525.
Hales, K. H., Diemer, T., Ginde, S., et al. (2000). Endocrinology 141, 4000–4012.
Stocco, D. M. and Clark, B. J. (1996). Biochem. Pharmacol. 51, 197–205.
Payne, A. H. and O’Shaughnessy, P. J. (1996). In: The Leydig cell. Payne, A. H., Hardy, M. P., and Russell, L. D. (eds.). Cache River Press, Vienna, IL, pp. 259–285.
Stocco, D. M. (1999). Bioessays 21, 768–775.
Cherradi, N., Rossier, M. F., Vallotton, M. B., et al. (1997). J. Biol. Chem. 272, 7899–7907.
Saez, J. M. (1994). Endocrine Rev. 15, 574–626.
Behrman, H. R., Kodaman, P. H., Preston, S. L., and Gao, S. (2001). J. Soc. Gynecol. Investig. 8, S40-S42.
Behrman, H. R. and Aten, R. F. (1991). Endocrinology 128, 2958–2966.
Margolin, Y., Aten, R. F., and Behrman, H. R. (1990). Endocrinology 127, 245–250.
Stocco, D. M., Wells, J., and Clark, B. J. (1993). Endocrinology 133, 2827–2832.
Diemer, T., Allen, J. A., Hales, K. H., and Hales, D. B. (2003). Endocrinology 144, 2882–2891.
Chen, H., Cangello, D., Benson, S., et al. (2001). Exp. Gerontol. 36, 1361–1373.
Zirkin, B. R. and Chen, H. (2000). Biol. Reprod. 63, 977–981.
Zirkin, B. R., Santulli, R., Strandberg, J. D., Wright, W. W., and Ewing, L. L. (1993). J. Androl. 14, 118–123.
Hales, D. B. (1996). In: The Leydig cell. Payne, A. H., Hardy, M. P., and Russell, L. D. (eds.). Cache River Press, Vienna, IL, pp. 451–466.
Hales, D. B., Diemer, T., and Hales, K. H. (1999). Endocrine 10, 201–217.
Roos, D. (1991). Klin. Wochenschr. 69, 975–980.
Wei, R. Q., Yee, J. B., Straus, D. C., and Hutson, J. C. (1988). Biol. Reprod. 38, 830–835.
Lenaz, G. (1998). Biochim. Biophys. Acta 1366, 53–67.
Stocco, D. M. (2001). Annu. Rev. Physiol. 63, 193–213.
Christenson, L. K., Strauss, I., and Jerome F. (2001). Arch. Med. Res. 32, 576–586.
King, S. R. and Stocco, D. M. (1996). Endocrine Res. 22, 505–514.
King, S. R., Liu, Z., Soh, J., Eimerl, S., Orly, J., and Stocco, D. M. (1999). J. Steroid Biochem. Mol. Biol. 69, 143–154.
King, S. R., Walsh, L. P., and Stocco, D. M. (2000). Mol. Cell. Endocrinol. 166, 147–153.
Granot, Z., Geiss-Friedlander, R., Melamed-Book, N., et al. (2003). Mol. Endocrinol. 17, 2461–2476.
Held Hales, K., Diemer, T., Ginde, S., et al. (2000). Endocrinology 141, 4000–4012.
Victor, V. M. and De La Fuente, M. (2003). Physiol. Res. 52, 101–110.
Pfanner, N. (2000). Curr. Biol. 10, R412-R415.
Schatz, G. (1996). J. Biol. Chem. 271, 31763–31766.
Schmidt, S., Strub, A., and Voos, W. (2001). Biol. Signals Recept. 10, 14–25.
Abbaszade, I. G., Arensburg, J., Park, C. H., Kasa-Vubu, J. Z., Orly, J., and Payne, A. H. (1997). Endocrinology 138, 1392–1399.
Cerami, A. (1992). Clin. Immunol. Immunopathol. 62, S3-S10.
Xiong, Y. and Hales, D. B. (1994). Endocrine J. 2, 223–228.
Hales, D. B., Xiong, Y., and Tur-Kaspa, I. (1992). J. Steroid Biochem. Mol. Biol. 43, 907–914.
Victor, V. M. and De la Fuente, M. (2003). Physiol. Res. 52, 789–796.
Riedel, W., Lang, U., Oetjen, U., Schlapp, U., and Shibata, M. (2003). Mol. Cell. Biochem. 247, 83–94.
Bray, T. M. (2000). Nutrition 16, 578–581.
Chapple, I. L. (1997). J. Clin. Periodontol. 24, 287–296.
Jaeschke, H. (2000). J. Gastroenterol. Hepatol. 15, 718–724.
Raha, S. and Robinson, B. H. (2000). Trends Biochem. Sci. 25, 502–508.
Turner, T. T., Tung, K. S., Tomomasa, H., and Wilson, L. W. (1997). Biol. Reprod. 57, 1267–1274.
Schoneich, C. (1999). Exp. Gerontol. 34, 19–34.
Peltola, V., Huhtaniemi, I., and Ahotupa, M. (1995). Biol. Reprod. 53, 1146–1150.
Lesnefsky, E. J., Moghaddas, S., Tandler, B., Kerner, J., and Hoppel, C. L. (2001). J. Mol. Cell. Cardiol. 33, 1065–1089.
Zini, A. and Schlegel, P. N. (1997). J. Urol. 158, 659–663.
Ahotupa, M. and Huhtaniemi, I. (1992). Biol. Reprod. 46, 1114–1118.
Luo, L., Chen, H., and Zirkin, B. R. (2001). J. Androl. 22, 149–156.
Hales, D. B. (1992). Endocrinology 131, 2165–2172.
Wiebe, J. P. (1976). Endocrinology 98, 505–513.
Laemmli, U. K. (1970). Nature 227, 680–685.
Xiong, Y. and Hales, D. B. (1993). Endocrinology 132, 2438–2444.
Hales, D. B., Sha, L. L., and Payne, A. H. (1987). J. Biol. Chem. 262, 11200–11206.
Scaduto, R. C. Jr. and Grotyohann, L. W. (1999). Biophys. J. 76, 469–477.
Diemer, T., Held Hales, K., Ginde, S., et al. (2000). Biol. Reprod. 63, 343.
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Allen, J.A., Diemer, T., Janus, P. et al. Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit leydig cell steroidogenesis via perturbation of mitochondria. Endocr 25, 265–275 (2004). https://doi.org/10.1385/ENDO:25:3:265
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DOI: https://doi.org/10.1385/ENDO:25:3:265