Testicular endocrine effects of alkane methanesulphonates related to the Leydig cell cytotoxic compound, EDS

Abstract

A series of compounds structurally similar to the specific Leydig-cell-cytotoxic substance ethane-1,2-dimethanesulphonate (EDS) were examined for Leydig cell toxicity in the rat. Within 48 h of a single injection of butane-2,3-dimethanesulphonate (BDS), propan-1,3-dimethanesulphonate (P-1,3-DS) or propan-1-chloro-2,3-DS (PCDS) there was a reduction in serum and testicular testosterone levels. The serum luteinizing hormone (LH) concentration was reduced following BDS or P-1,3-DS, and Leydig-cell LH receptors (measured by 125I-labelled hCG binding) were reduced by less than 15%, from which it is concluded that these compounds are not selectively toxic to Leydig cells. However, PCDS reduced human chorionic gonadotropin (hCG) binding by greater than 70% and could be considered to be a potential toxin. The effects of hydroxy-ethanemethane-sulphonate (HEMS), 1,5,2,4-dioxadithiepane-2,2,4,4-tetraoxide (cyclic SOSO), PCDS, propan-2,3-DS, alpha-chlorohydrin and cyclohexane-1,2-dimethane-sulphonate were compared with the effects of EDS 7 days after injection. Systemic toxicity, indicated by a loss of body weight, was associated with cyclic SOSO, PCDS and EDS, although only EDS and PCDS reduced both testicular hCG binding and serum and testis testosterone levels consistent with Leydig-cell toxicity. Further studies indicated that the potency of PCDS in reducing testicular hCG binding and serum and intratesticular testosterone levels was similar to that of EDS. However, unlike EDS, PCDS was systemically toxic and also reduced LH, which could at least in part account for changes in testosterone secretion. The experiments confirm the unique cytotoxicity of EDS. Loss of specific Leydig-cell cytotoxicity and an increase in systemic toxicity occurred when the EDS molecule was altered, even if the distance between the alkylating centres was maintained. The mechanism of action of EDS remains elusive.

Protective effects of vitamin E on ethane dimethane sulfonate-induced testicular toxicity in rats

“…Present results showed that vit E injection had only a partial protective effect on the testicular weight and histology of the rats after EDS treatment. Our data on body and testis weights were generally consistent with previous observations [13,14]. The bodyweight reducing effect of EDS might be to the result of its Leydig cell destroying effect leading to the generation of little or no testosterone that has anabolic effects and stimulates bodyweight gain.…”

“…EDS not only destroys the Leydig cells and seminiferous tubules [3,4] but also reduces body [13] and testis weights [14] after its administration. Present results showed that vit E injection had only a partial protective effect on the testicular weight and histology of the rats after EDS treatment.…”

Influence of fetal Leydig cells on the development of adult Leydig cell population in rats

“…Researchers have used EDS to completely eliminate the LC population in either neonatal or adult rat testes and then study the regeneration of LCs after EDS treatment [ 20 , 45 , 46 ]. Although FLCs in neonatal rats or ALCs in adult rats are dispelled in by 72 h post-EDS treatment, previous studies suggested that EDS treatment does not affect either the origin of ALCs or subsequent development of ALC populations [ 20 , 28 , 46 , 47 ]. Additionally, at approximately 14–21 days post-EDS treatment, the seminiferous epithelium was grossly abnormal, while by 48 days post-EDS treatment, spermatogenesis returned to normal [ 48 ].…”

Gene expression analysis of toxicological pathways in TM3 leydig cell lines treated with Ethane dimethanesulfonate

“…Leydig cells, specialized for the synthesis and secretion of testosterone, are responsible for the male reproductive system 1. Ethane dimethanesulfonate (EDS) is a well‐known alkylating agent that inhibits testosterone biosynthesis and destroys Leydig cells in rats 2–4. For this reason, it is a useful chemical for studying the reproductive system and testicular dysfunction in various animal species 5–7.…”