The Yin and Yang of Histamine in the regulation of testicular Leydig cell proliferation

MONDILLO, CAROLINA

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2019

SAIC-SAFE-SAB-SAP

The Yin and Yang of Histamine in the regulation of testicular Leydig cell proliferationCarolina Mondillo, PhDLaboratorio de Endocrinología Molecular y Transducción de SeñalesIBYME-CONICETHistamine (HA) is a biogenic amine with indisputable significance for medicine and biology. It is synthesized exclusively by histidine decarboxylase (HDC) in all mammalian tissues, albeit tissue-specific mechanisms operate to keep its concentration within strict limits: both a deficit of HA or a slight excess can lead to health loss. With regard to the male gonad, previous studies have linked increased mast cell numbers and mast-cell related HA with the pathogenesis of infertility. In contrast, HA levels are normally higher in the neonatal testis, and in a former report we described that HDC gene knockout mice show reduced testis weight already at 7 days of age, implying that important HA-dependent events may occur during testicular development. To assess this apparent conflict and considering the ubiquitous role of HA as modulator of cell proliferation, we speculated that testicular HA might contribute to the regulation of LC number. Firstly, we studied the effect of intratesticular HA treatment in adult male rats injected with the specific LC cytotoxic agent ethane dimethanesulphonate (EDS), a convenient model to study normal LC proliferation and development from LC precursors in vivo. As expected, LC re-population was faster in HA-treated rats. Thus, to better identify the stage/s of testicular development in which HA would play a role, we conducted in vitro experiments to evaluate its effect on the proliferation of progenitor and immature LC, isolated from 21- and 35-day old male rats, respectively. However, none exhibited a proliferative response upon stimulation with HA. We then studied HDC immunoexpression in testes of rats aged 7 to 240 days, and found that it was highest in 7-day old rats but then decreased abruptly, with remnants of the fetal LC population being the most intensively stained. In line with previous observations in HDC KO mice, these results suggest that local HA synthesis may be important to influence LC numbers in the early stages of normal testicular development, while it would be negatively regulated with age. Interestingly, we have recently detected HDC overexpression in 2 murine Leydig tumor cell lines, as well as in human LC hyperplasia and prepubertal LC tumors. Moreover, HA promoted the proliferation of Leydig tumor cells in vitro, while specific HDC inhibitors had the opposite effect. Importantly, these findings indicate that autocrine overproduction of HA might be related to abnormally increased proliferation in LC.