Testicular endocrine effects of alkane methanesulphonates related to the Leydig cell cytotoxic compound, EDS.
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.
Edwards
G
G
Department of Physiological Sciences, University of Manchester, UK.
Jackson
H
H
Morris
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ID
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006063:Chorionic Gonadotropin / Q000378:metabolism; D007985:Leydig Cells / Q000187:drug effects; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D008698:Mesylates / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000378:metabolism
D006063:Chorionic Gonadotropin; D008698:Mesylates; D013739:Testosterone; D007986:Luteinizing Hormone; C002994:ethylene dimethanesulfonate