Heme oxygenase-1 arrests Leydig cells functions and impairs their regulation by histamine

Abstract

Testicular Leydig cells (LC)aremodulated by several pathways, one of them being the histaminergic system. Heme oxygenase-1 (HO-1), whose upregulationcomprises the primary response to oxidative noxae, has a central homeostatic role and might dysregulate LC functions when induced.In this report, we aimed to determinehow hemin,anHO-1 inducer, affects LC proliferativecapacity and whether HO-1 effects on LC functions are reversible. It was also evaluatedifHO-1 interacts in any waywith histamine, affecting its regulatory action over LC. MA-10 and R2C cell lines and immature rat LC were used as models. Firstly, we show that after a 24-h incubation with 25 µmol/L hemin, LC proliferation is reversibly impaired by cell cycle arrest in G2/M phase, with no evidence of apoptosis induction. Even though progesterone production is abrogated after a 48-h exposure to 25 µmol/L hemin, steroidogenesis canbe restored to control levelsin a time-dependent manner if the inducer is removed from the medium.Regarding HO-1 and histamine interaction, it is shown that heminabrogateshistamine biphasic effect on steroidogenesis and proliferation.Working with histamine receptors agonists, we elucidated that HO-1 induction affects the regulation by receptor types 1, 2 and 4.In summary, HO-1 induction arrests LC functions, inhibiting steroid production and cell cycle progression. Despite their reversibility, HO-1 actions might negatively influencecritical phasesof LC development anddifferentiation affecting their function as well as other androgen-dependent organs. What?s more, we have described a hitherto unknown interaction between HO-1 induction and histamine effects.