PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.1 MALE REPRODUCTIVE TOXICOLOGY 215germ cell development. Without Sertoli cells, remaining progenitor germ cells are unable to begin thespermatogenic cycle.The solvent n-hexane is a demonstrated reproductive toxicant. Its testicular toxicity is related tointerference with microtubule formation in Sertoli cells by the metabolite 2,5-hexanedione. Thesusceptibility of Sertoli cells to a microtubule poison is understandable since Sertoli cells form ascaffolding supporting multiple layers of germ cells and this function relies on the assembly ofmicrotubules. This process involves extensive remodeling of the Sertoli cell architecture as the germcells are moved through the seminiferous tubule, and such remodeling is heavily dependent onmicrotubule formation.Some of the phthalate plasticizers also appear to affect Sertoli cells. The toxicity appears to occurin the Sertoli cells, involving a breakdown of the attachments between Sertoli cells and germ cells.Thus, all of the spermatogenic cells in the developmental sequence at the time of intoxication may becompromised.Bioactivation of tri-o-cresyl phosphate (TOCP) is required prior to its effects on Sertoli cells.Interestingly, the metabolism occurs in the Leydig cells but does not appear to interfere with theirfunction. The reactive metabolite subsequently reaches the Sertoli cells, which are damaged, andspermatogenesis is subsequently impaired.Another Sertoli cell toxicant of interest in occupational toxicology is dinitrobenzene (DNB). Thiscompound, and structurally related analogues, appears to disrupt Sertoli cell function, possibly throughinvolvement in a metabolic reaction cycle that depletes the cells of important reducing equivalents,impairing their functional support for the spermatogenic cells. Subsequently, all of the stages ofdeveloping germ cells may be compromised.The Sertoli cell tight junctions can also be affected by toxic agents, disrupting the blood/testisbarrier. Platinum-based anti-neoplastic drugs, such as cisplatin, appear to operate in this manner. Thegerm cells divide improperly subsequent to this toxicity; however, it is not clear whether this is duedirectly to exposure through the disrupted barrier or if the Sertoli cells are incapable of directing germcell development properly.Leydig Cells Leydig cells are located outside, but surrounding the seminiferous tubules. Their majorfunction is producing testosterone, a key to regulating spermatogenesis as well as male reproductivedevelopment and behavior. There are several toxicants that can be demonstrated to affect Leydig cellsexperimentally. It is not clear, however, whether any demonstrable human reproductive toxicity isprimarily due to actions on Leydig cells. In part, this is because androgen regulation is so complex thatit is difficult to determine which observations are primary toxic responses and which result secondarilyfrom hormonal dysregulation. Also, several of the toxicants with specific actions on Leydig cells canalso cause responses in other cell types, depending on the dose received.A well-described experimental Leydig cell toxicant which does not appear to directly affect othertesticular cell types is ethane-1,2-dimethanesulfonate (EDS). This compound affects androgen productionby the Leydig cells and appears to interfere with specific early steps in the synthesis of steroidhormones. While the mechanism leading to cell death is not clear, EDS does kill the Leydig cells. Theeventual result of EDS toxicity is, somewhat predictably, impaired spermatogenesis. In addition, Sertolicells, which are dependent to some degree on Leydig cell secretions, may also be damaged.Among the toxicants with significant human exposure that operate primarily on the testis, diethylhexylphthalate and its metabolites are the only example with specific Leydig cell effects. In additionto their Sertoli cell effects, the phthalates also appear capable of interfering with steroid synthesis andLeydig cell function. It is not yet clear what the relative contribution of the Leydig cell damage is tothe resulting spermatotoxicity.Hormonal Regulation and the Hypothalamic-Pituitary-Gonadal AxisDisruptions of male reproductive function can also occur secondary to toxic responses in the endocrinesystem. Androgen production in the testes is regulated primarily by luteinizing hormone (LH), a