PRINCIPLES OF TOXICOLOGY - Biology East Borneo

214 REPRODUCTIVE TOXICOLOGYspermatogenic potential after the toxicant was removed. This fits the observed effects on occupationallyexposed humans.Spermatocytes, particularly at the pachytene stages, are susceptible to damage from ethylene glycolmonoethyl ether (EGME), one of the glycol ethers with considerable potential for human exposure. Ametabolite of EGME, 2-methoxyacetic acid (MAA), may cause indirect damage to the spermatocyteby decreasing lactate production in the Sertoli cells. Lactate is a key metabolic substrate for developingspermatocytes.Spermatids may be a particular target for ethylene dibromide (EDB) toxicity. This is anothercompound, used as a fumigant, for which there is a least some information that occupational exposuresmay have adverse effects on male reproduction. Effects on the later, spermatid, stages of spermatogenesiswould be consistent with the abnormalities and deficits observed in some occupationallyexposed workers. Experimentally, however, EDB turns out to be an example where the stage specificitybreaks down as the dose increases.Spermatozoa can be affected by various toxic mechanisms. Epichlorohydrin (widely used intermediatein plastics/rubbers) is an example of a compound that appears to affect sperm motility byinterfering with metabolism. Motility is required for fertilization and the needed energy is producedthrough specialized metabolic pathways that operate within the sperm. Chlorpromazine, a drug usedto treat psychosis, appears to cause metabolic effects on sperm secondary to permeabilizing theirmembranes. Agents such as mercury and lead may have a combined effect on both sperm cellmembrane dynamics and on the epididymis. Sperm complete their maturation in the epididymis, andthe secretory and absorptive functions of the epididymal epithelium are required for the maintenanceof viable sperm.Another important mechanism of toxicity may also be pertinent to mature sperm. Many biochemicalreactions result in the formation of highly reactive radical groups. Cellular phospholipids, importantto the structure of cell membranes, are particularly sensitive targets for reactions with these radicals.The resulting damage, called lipid peroxidation, can impair the integrity of cell membranes. Freeradicals can be generated during the oxidative metabolism of many different compounds. Some ofthose that may be male reproductive toxicants are adriamycin, ethylene dibromide, and the herbicidesparaquat and diquat.Free radical-induced lipid peroxidation may be important to sperm for two reasons: 1) thedetoxification pathways that typically keep free radicals in check are modified in reproductive tissuesand appear to be especially limited in the sperm cells, and 2) sperm contain highly specializedmembranes that can be easily compromised. Investigations of lipid peroxidation in sperm have onlybegun recently, and currently, the only clear occurrence of such damage in human sperm is found infrozen semen samples. Freezing seems to destroy one of the major anti-oxidant defense enzymesmaking the sperm especially susceptible. As further investigations of chemical-induced lipid peroxidationare carried out, some of the membrane disruption associated with spermatotoxicity may bebetter explained.Sertoli Cells Sertoli cells are in direct contact with the germ cells and provide support for them, bothstructurally and functionally (Figure 11.1). By virtue of specialized junctions between Sertoli cells,which isolate the germ cells from any other somatic cells outside of the seminiferous tubule, the Sertolicells create a barrier that provides a degree of insulation and protection from chemicals distributedthrough the circulatory system. Thus, when Sertoli cells are targeted by toxicants, not only is theirsupport of germ cell production impaired, the blood/testis barrier may be disrupted, exposing the germcells to more potential damage.Due to their close relationship with the germ cells, it is not surprising that toxicants whichspecifically affect Sertoli cells have a subsequent effect on germ cell production. Some of thecharacteristics of Sertoli cell damage are that all stages of developing germ cells are impacted and thedamage is frequently irreversible. This is due to the limited replacement of Sertoli cells; they dividerelatively little in mature males. Also, part of the function of Sertoli cells is to initiate the sequence of