Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria

John Allen, Thorsten Diemer, Paul Janus, Karen Held Hales, Dale B. Hales

Research output: Contribution to journalArticle

85 Citations (Scopus)

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-Δ 4- Δ 5 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 (ΔΨ m). 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 ΔΨ m. 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 ΔΨ m 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.

Original languageEnglish (US)
Pages (from-to)265-275
Number of pages11
JournalEndocrine
Volume25
Issue number3
DOIs
StatePublished - Dec 2004
Externally publishedYes

Fingerprint

Leydig Cells
Endotoxins
Lipopolysaccharides
Reactive Oxygen Species
Mitochondria
Hydroxysteroids
Isomerases
Testosterone
Oxidative Stress
Injections
Endotoxemia
Mitochondrial Membrane Potential
Serum
Hydrogen Peroxide
Lipid Peroxidation
Proteins
Chronic Disease
Cell Culture Techniques
Macrophages
Cell Membrane

Keywords

  • Leydig cell
  • LPS
  • Mitochondrial electrochemical membrane potential
  • Reactive oxygen
  • StAR, 3β-HSD
  • Steroidogenesis
  • Testosterone

ASJC Scopus subject areas

  • Endocrinology

Cite this

Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria. / Allen, John; Diemer, Thorsten; Janus, Paul; Hales, Karen Held; Hales, Dale B.

In: Endocrine, Vol. 25, No. 3, 12.2004, p. 265-275.

Research output: Contribution to journalArticle

Allen, John ; Diemer, Thorsten ; Janus, Paul ; Hales, Karen Held ; Hales, Dale B. / Bacterial endotoxin lipopolysaccharide and reactive oxygen species inhibit Leydig cell steroidogenesis via perturbation of mitochondria. In: Endocrine. 2004 ; Vol. 25, No. 3. pp. 265-275.
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